ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
ECTRIMS 2013
ABSTRACTS OF INTEREST ON INVESTIGATIONAL AGENTS
1
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
AGENTS HIGHLIGHTED IN ABSTRACTS
GnbAC1
Siponimod
BIB033
NT-KO-003
Ponesimod
Secukinumab
NDC-1308
ONO-4641
Pegylated Avonex
rHIgM22
RPC1063
VX15
Daclizumab
BG-12/Tecfidera
Alemtuzumab/Lemtrada
Laquinimod
Teriflunomide
2
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Neuroprotection
Thursday, October 03, 2013, 15:45 - 17:00
Safety and pharmacokinetics of GNbAC1, a humanised monoclonal antibody
against the multiple sclerosis associated retrovirus envelope protein in patients
with multiple sclerosis
T. Derfuss, F. Curtin, C. Guebelin, C. Bridel, M. Rasenack, A. Matthey, R. Du Pasquier, M. Schluep, J. Desmeules,
H. Porchet, A.B Lang, H. Perron, H.-P. Hartung, L. Kappos, P. Lalive (Basel, Geneva, Lausanne, CH; Düsseldorf,
DE)
Human endogenous retrovirus (HERV) genes represent about 8% of the human genome. A member of the HERV
family W, the Multiple Sclerosis associated Retrovirus (MSRV) DNA contains copies expressing an envelope protein
(Env), which can activate a pro-inflammatory and autoimmune cascade through the interaction with Toll-Like receptor
4 on antigen-presenting cells. In several independent studies, the MSRV-Env protein was evidenced to be expressed
in patients with multiple sclerosis (MS) and in particular in MS brain lesions. Due to its pro-inflammatory property as
well as an inhibitory effect on oligodendrocyte precursor cell differentiation, the MSRV-Env protein could play a critical
role in the pathology of MS.
GNbAC1 is a humanised monoclonal antibody of the IgG4 type, which selectively binds with high affinity to the
extracellular domain of the MSRV-Env protein. A Phase I single ascending dose trial has shown a very good safety
profile in healthy volunteers up to the intravenous dose of 6mg/kg, the maximum tested dose as per protocol.
We report here the results of Phase IIa placebo-controlled single ascending dose study of GNbAC1 followed by an
open-label 5-repeated dose extension. The study evaluated the safety and pharmacokinetics of GNbAC1 in 10 MS
patients. During the single ascending dose phase, in Cohort 1, 4 patients received a single intravenous infusion of 2
mg/kg of GNbAC1 and 1 patient received a placebo infusion; in Cohort 2, 4 patients received an intravenous infusion
of 6 mg/kg of GNbAC1 and 1 patient received a placebo infusion. Then, all patients of Cohorts 1 and 2 pursued
treatment with five GNbAC1 infusions at 2 mg/kg and 6 mg/kg dose respectively administered at 4-week intervals.
Safety parameters were monitored and regular blood samplings were performed to study the monoclonal antibody
pharmacokinetics. GNbAC1 appeared to be well tolerated after repeated dosing in all subjects and at both doses.
Only non-specific adverse events were recorded. Pharmacokinetic data confirm a dose linear pharmacokinetic profile.
The mean elimination half-life is about 20 days.
These first results of GNbAC1 administered with 6 monthly infusions confirm a favorable safety profile in MS patients
and the pharmacokinetics support a monthly infusion scheme. These results pave the way for a larger Phase II study
testing the efficacy and safety of the first anti-HERV monoclonal antibody for MS.
3
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Immunomonitoring of a phase II study testing the monoclonal antibody GNbAC1
in multiple sclerosis patients
M. Zimmermann, N. Sanderson, M. Rasenack, P. Lalive, F. Curtin, A. Lang, L. Kappos, T. Derfuss (Basel, Geneva,
Plan-les-Ouates, CH)
We report the results of immunological monitoring of patients enrolled in a randomized, placebo-controlled, singleblind, phase IIa study testing two doses of GNbAC1 in multiple sclerosis patients. GNbAC1 is a recombinant,
humanised, IgG4 monoclonal antibody directed against the envelope protein (env) of the Multiple Sclerosis
Associated Retrovirus (MSRV), a human endogenous retrovirus of the HERV-W family.
The hypothesis that binding of MSRV Env protein to Toll-like receptor 4 (TLR4) activates monocytes predicts that
blocking this binding with GNbAC1 should decrease the inflammation in MS patients.
Study design: Patients between 18 and 65 years with multiple sclerosis and an EDSS < 6.5 were randomized into two
groups (2 or 6 mg of GNbAC1 per kgbw given at 4 week intervals for 6 months). In addition to safety and clinical
monitoring , four immunological parameters were followed: (i) T cell response to myelin and viral antigens by ELIspot
using peripheral blood mononuclear cells (PBMC); (ii) Monocyte TLR4 signaling measured by flow cytometry of p38
phosphorylation; (iii) general immune status as reflected in proportions of lymphocytes with given phenotypes; and
(iv) multiplex assay for inflammatory cytokines in serum.
Ten patients enrolled in the study and yoked healthy volunteers were followed. T cell response (IFN-gamma spots
per 200,000 PBMC) to viral antigens was robust throughout the study for both healthy subjects (range 22 to 322) and
patients (range 30 to 534). Response to the myelin antigen Myelin Basic Protein (MBP) was not different from
negative control in any subject at any time point.
TLR4 signaling was followed by measuring phospho-p38 immunofluorescence in CD33-positive cells, both at
baseline and after lipopolysaccharide stimulation. Without stimulation, fewer than 10% of monocytes showed p38
phosphorylation in patients and in controls at all time points, other than one time-point for one patient, in whom
elevated C-reactive protein was also detected, suggesting an inflammatory infection. LPS stimulation (1 ng/ml in
whole blood) resulted in almost 100% monocyte p38 phosphorylation in both patients and controls.
These results suggest the following: (i) GNbAC1 administration is not associated with any deficit in T cell response to
viral antigens; (ii) GNbAC1 administration did not affect LPS induced TLR4 activation.
M. Zimmermann: nothing to disclose N. Sanderson: nothing to disclose M. Rasenack: nothing to disclose P. Lalive
received honoraria for speaking from Biogen-Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva; consulting fees
from Biogen-Idec, Geneuro, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from BiogenIdec, Merck Serono, Novartis. F. Curtin is an employee of GeNeuro SA A. Lang is an employee of GeNeuro SA L.
Kappos received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering,
Bayhill Therapeutics, Biogen Idec, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline,
Glenmark, MediciNova, Merck Serono, Novartis, Novartis Research Foundation, Roche, Roche Research
Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience,
UCB, and Wyeth. T. Derfuss serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec,
Genzyme, Mitsubishi Pharma, TEVA Pharma, and Bayer Schering Pharma; has received funding for travel and/or
speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research
support from Novartis Pharma, the European Union, and the Swiss MS Society
4
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Thursday, October 03, 2013, 15:45 - 17:00
Placebo-like occurrence of atrioventricular blocks and sinus pauses: results from
a siponimod QT/QTc study
K. Shakeri-Nejad, B. Brendani, N. Pezous, L. Mooney, A. Juan, M. Allison, R.G. Perry, E. Legangneux (Basel, CH;
Miami, Tempe, US)
Background: Siponimod is a next generation selective sphingosine 1-phosphate-1/5 receptor modulator, currently
being developed for the treatment of multiple sclerosis. Siponimod treatment is initiated with dose titration to mitigate
bradyarrhythmic effects.
Objective: To investigate chronotropic/dromotropic effects and the frequency, type and diurnal distribution pattern of
atrioventricular blocks (AVB) and sinus pauses (SP) at siponimod therapeutic (2mg) and supratherapeutic (10mg)
doses vs. placebo.
Methods: 12-lead Holter recordings on Days -1 (placebo baseline), 10 (therapeutic dose) and 18 (supratherapeutic
dose) from siponimod and placebo subjects were analysed. Siponimod chronotropic/dromotropic effects were
analysed based on time-matched changes in PR, QRS and heart rate (HR) extracted at 0.5, 1, 2, 3, 4, 6, 12 and 24h
on Days 10 and 18, supported by categorical outlier and concentration-response analyses. AVB (degree, conduction
ratio) and SP (defined as RR >2s) were summarized by dose, discontinuation period and by resting hours (11:00PM07:00AM [8h]) and non-resting hours (remaining 16h) for the entire Holter recording period.
Results: 186 patients (siponimod: 94; placebo: 92) were analysed. A similar pattern of increase in mean HR was
observed (between 0.5-4h and at 6h post dose) on Day -1 (60-68bpm) and Day 18 (67-76bpm) for both treatments. In
contrast, on Day 10 the increase in mean HR values after siponimod dosing was less pronounced vs. placebo. The
highest time-matched placebo-corrected mean effect of siponimod on HR (max mean change) was observed at 6h
post dose on Day 10 (-8.08bpm) and at 1h post dose on Day 18 (+2.55bpm). No notable changes in PR and QRS
were observed in any group. All detected AVBs and SPs were asymptomatic. Second degree AVBs were detected in
a total of 5 subjects (4 placebo, 1 siponimod 2mg) during resting hours. SPs were detected in 11 subjects (10
placebo, 1 siponimod 2mg) predominantly during nocturnal hours.
Conclusions: All detected AVBs and the majority of SPs were observed during resting hours, associated with
increased vagal tone. These results are consistent with the physiological diurnal distribution pattern and should be
taken into consideration to differentiate physiological vs. drug-induced effects. AVBs and SPs were less frequent
under siponimod than placebo conditions. The limited effect of siponimod on PR, QRS and HR, supports the benefit
of the up-titration regimen in mitigating bradyarrhythmic effects.
This study was funded by Novartis Pharma AG K. Shakeri-Nejad, B. Brendani, N. Pezous, L. Mooney and E.
Legangneux are employees of Novartis A. Juan, M. Allison, R.G. Perry, received support from Novartis as employees
of the Contract Research Organisations
5
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Thursday, October 03, 2013, 15:45 - 17:00
Effect of oral siponimod (BAF312) on the pharmacokinetics and
pharmacodynamics of a monophasic oral contraceptive in healthy female
subjects
S. Biswal, U.K. Veldandi, C. Derne, G. Golla, N. Muhsen, K. Shakeri-Nejad, E. Legangneux (Hyderabad, IN; Basel,
CH; Groningen, NL)
Background: Siponimod is a next generation selective sphingosine 1-phosphate -1 and -5 receptor modulator
currently in development for the treatment of multiple sclerosis. Data from animal models suggest of
teratogenic/embryocidal risks in women who are pregnant or may conceive while on treatment with siponimod.
Objectives: To investigate the effect of siponimod (4 mg qd) on pharmacokinetics (PK) and pharmacodynamics (PD)
of a monophasic oral contraceptive (OC) containing 30 mcg ethinylestradiol (EE) and 150 mcg levonorgestrel (LVG).
Methods: In this open-label single-centre study in healthy females, subjects were exposed sequentially to two
treatment periods (first 21 days of two consecutive menstrual cycles): Period 1–OC alone and Period 2–coadministration of siponimod 4 mg qd and OC. Siponimod was titrated up to 2 mg from Day 23 to 28 in cycle 1. PK
samples were collected over 24 hours on Day 21 of each period and PK parameters were compared. Follicle
stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone concentrations were measured at
baseline and Days 3, 6, 8, 11, 14, 16, 19, 21 and 23 of each period. Largest ovarian follicle size, sex hormone–
binding globulin (SHBG) concentration and Hoogland score were measured at baseline and Day 21 of each period.
Safety and tolerability of siponimod was also assessed.
Results: Of a total of 24 subjects randomised, 23 completed the study. Mean values for age and BMI were 22.3 years
and 22.62 kg/m^2. Co-administration of siponimod with OC resulted in increased AUCtau,ss of LVG by 28% and
Cmax,ss by 18%; there was no significant effect on the PK of EE. Co-administration of siponimod with OC showed no
clinically significant changes in PD markers (estradiol, FSH and LH) vs. OC alone, progesterone levels remained <5
nmol/L, all follicle sizes remained<10 mm at Day 21, and Hoogland scores at Day 21 demonstrated ‘no activity’ for all
the subjects. No clinically significant changes in SHBG in combination treatment vs. OC alone were observed. All
treatment related adverse events (AEs) were of mild intensity. There were no serious AEs or discontinuations due to
AEs.
Conclusions: Multiple oral doses of siponimod co-administered with a monophasic OC were found to be safe and well
tolerated in healthy women in an outpatient setting. The PK-PD parameters of EE and LVG were not altered to a
clinically significant extent and the efficacy of the OC pill was maintained.
The study was funded by Novartis Pharma AG, Basel S. Biswal, U.K. Veldandi, C. Derne, G. Golla, E. Legangneux
are employees of Novartis N. Muhsen received support from Novartis as an employee of a contract research
organization
6
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Friday, October 04, 2013, 15:30 - 17:00
Diurnal distribution and interpretation of atrioventricular blocks and sinus pauses
under placebo conditions
K. Shakeri-Nejad, A. Sagkriotis, N. Pezous, B. Brendani, A. Juan, M.J. Gutierrez, M. Allison, R.G. Perry, E.
Legangneux (Basel, CH; Miami, Miramar, Tempe, US)
Background: Heart rate and AV conduction are regulated by physiological mechanisms which are influenced by the
balance between sympathetic and parasympathetic systems. The potential bradyarrhythmic effects of S1P
modulators, in the treatment of multiple sclerosis, have highlighted the relevance of such mechanisms.
Physiologically, the frequency of bradyarrhythmias such as AV blocks (AVB) and sinus pauses (SP) is increased
during resting periods (sleep) associated with increased vagal tone. The effect of siponimod and placebo treatment
re-initiation on initial chronotropic effects and QT/QTc interval were studied in 2 randomised placebo-controlled
studies.
Objectives: Holter data from placebo-treated subjects in 2 studies were pooled to investigate the physiological diurnal
distribution pattern of AVBs and SPs.
Methods: 12-lead Holter ECG data of healthy subjects (18-55 years of age) under placebo conditions from 2 studies
were pooled and analyzed. ECGs were recorded between 1h-1.5h before and 24h after placebo administration at
baseline (Day -1), Days 10 and 18 (CBAF312A2118 study) and at treatment re-initiation with placebo
(CBAF312A2110). AVBs and SPs (defined by RR >2s) were summarized by resting hours (11:00 PM-07:00 AM [8h])
and non-resting hours (remaining 16h). Second degree AVBs were further characterized for type (Type I or II) and
conduction ratio.
Results: A total of 523 Holter recordings were pooled and analyzed (485 from CBAF312A2118 [281 subjects at
baseline and 102 subjects each at Days 10 and 18] and 38 subjects from CBAF312A2110). The majority of AVBs (in
7 subjects) were observed during resting periods: 2 of 3 episodes of first degree AVB and 4 of 5 second degree AVB
(4 Type I and 1 Type II). No third degree AVB was observed. 18 of 21 episodes of SPs (in 13 subjects) were
observed during resting periods. The longest observed RR duration of >=2.5s was observed in 3 subjects with 8 SPs,
all detected during resting periods.
Conclusion: The frequency of AVB and SP events was higher during resting hours, i.e. periods of physiologically
increased vagal tone. These results from 523 Holter recordings in healthy subjects are consistent with published data
on physiological diurnal distribution pattern of AVBs and SPs. These findings indicate that AVBs and SPs occur under
physiological conditions, particularly during resting periods, and their background incidence should be taken into
consideration for the evaluation of such events under treatment conditions.
This study was funded by Novartis Pharma AG K. Shakeri-Nejad, A. Sagkriotis, N. Pezous, B. Brendani, E.
Legangneux are employees of Novartis Pharma AG A. Juan ,M.J. Gutierrez, M. Allison, and R.G. Perry received
support from Novartis as employees of Contract Research Organizations
7
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
The use of magnetic resonance imaging to monitor the safety of anti-LINGO-1:
findings from phase 1 studies in healthy volunteers and subjects with multiple
sclerosis
D. Cadavid, I. Melamed, H. Gevorkyan, N. Richert (Cambridge, Centennial, Glendale, US)
Background: In patients with multiple sclerosis (MS), immunomodulatory therapies can reduce inflammation but do
not promote remyelination, a process suppressed by myelin-associated inhibitors, such as leucine-rich repeat and
immunoglobulin domain-containing neurite outgrowth inhibitor receptor-interacting protein-1 (LINGO-1). LINGO-1 is a
component of the Nogo receptor 1 (NgR1)/p75/LINGO-1 and NgR1/tumor necrosis factor receptor/LINGO-1 signaling
complexes. BIIB033, a human monoclonal antibody (aglycosyl immunoglobulin gamma 1) against LINGO-1,
promotes remyelination in rodent models.
Objective: To assess the safety of BIIB033 vs placebo in a single ascending-dose (SAD) study in healthy volunteers
and a multiple ascending-dose (MAD) study in stable subjects with MS using magnetic resonance imaging (MRI).
Methods: SAD subjects were randomized to 1 of 8 intravenous (IV) doses (0.1-100 mg/kg) or one 3.0 mg/kg
subcutaneous (SC) dose. MAD subjects were randomized to the same regimen except that 2 IV doses were given 14
days apart. Conventional MRI verified the absence of structural change, hemorrhage, infarction and inflammation.
Non-conventional MRI was done at Weeks 4 and 8 in SAD and at Weeks 8 and 16 in MAD. Magnetization transfer
ratio (MTR) measured myelin integrity of 6 regions in normal-appearing white matter (NAWM) in SAD. Short-term
safety and efficacy was explored using MTR and diffusion tensor imaging (DTI) of pre-existing lesions and nonlesional NAWM in MAD.
Results: There were no structural abnormalities, hemorrhage or infarction in SAD (N=72) or MAD (N=47). Incidental
findings of mucosal thickening in the maxillary sinuses (n=2) and small venous angioma (n=1) were noted in 3
BIIB033 subjects in SAD. In MAD, MRI showed no increase with drug versus placebo in new/enlarging T2 lesions or
Gadolinium-enhancing lesions. No change in NAWM MTR was observed in either study vs baseline. In MAD, an
exploratory efficacy analysis showed no difference in the net change or fold change vs baseline in MTR and DTI
measurements in pre-existing white matter lesions. No significant change in whole brain volume or ventricular volume
was observed with treatment at Weeks 8 or 16 in MAD.
Conclusions: BIIB033 was well-tolerated in both studies. MRIs showed no evidence that BIIB033 negatively affected
brain parenchyma tissue including myelin content. Continued evaluation of BIIB033 in Phase II studies is warranted.
Nancy Richert and Diego Cadavid are full-time employees of Biogen Idec. Isaac Melamed and Hakop Gevorkyan
have no conflict of interest to disclose. This study was funded by Biogen Idec. Linda Goldstein of UBC Scientific
Solutions provided medical writing and editorial support to the authors in the development of this abstract, which was
funded by Biogen Idec.
8
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Maintenance of efficacy, safety and tolerability of ponesimod in patients with
relapsing remitting multiple sclerosis: phase II extension study
C. Pozzilli, Ó. Fernández, T. Olsson, M.S. Freedman, M. Melanson, A. Boster, E.-W. Radue, B. Hennessy, A.
Rames, D. D'Ambrosio (Rome, IT; Malaga, ES; Stockholm, SE; Ottawa, CA; Cincinnati, Columbus, US; Basel,
Pratteln, Allschwil, CH)
Background: Ponesimod is an oral, selective, reversible sphingosine 1-phosphate receptor-1 modulator under
investigation in multiple sclerosis and psoriasis. In a 24-week multicentre, double-blind phase IIb (core) study, oncedaily ponesimod at 10, 20 and 40 mg significantly and dose-dependently reduced inflammatory magnetic resonance
imaging (MRI) activity compared with placebo; reduction in annualized relapse rate (ARR) was also observed. An
interim analysis was performed on an ongoing double-blind, long-term extension study.
Objective: Evaluate the efficacy, safety and tolerability of ponesimod in the extension study.
Design/Methods: All patients entering the extension study received ponesimod; former placebo patients were rerandomized at Week 24 to ponesimod 10, 20 or 40 mg in a 1:1:1 ratio. Exploratory efficacy endpoints included ARR
and MRI variables.
Results: Overall, 353 patients (90% of those completing the core study) entered the extension study. At the time of
data collection, mean combined (core plus extension) treatment duration was 115 weeks; study treatment was
prematurely discontinued in 12.5% patients. The ARR (95% CI) in patients continuously treated with ponesimod 10,
20, or 40 mg was 0.24 (0.16–0.35), 0.21 (0.14–0.30), and 0.14 (0.09–0.22); in the ex-placebo groups, ARR was 0.33
(0.19–0.58), 0.25 (0.13–0.48) and 0.33 (0.18, 0.61) in the placebo/10, placebo/20 and placebo/40 mg groups,
respectively. At Week 72, the mean (SD) number of new or enlarging non-enhancing T2 lesions was 0.8 (1.9), 0.2
(0.7) and 0.4 (1.4) in the ponesimod 10, 20, or 40 mg groups, and 0.7 (1.5), 0.2 (0.4) and 0.2 (0.4) in the placebo/10,
placebo/20 and placebo/40 mg groups, respectively. A dose-relationship was apparent in time to first confirmed
relapse in patients treated with ponesimod both continuously, and following switch from placebo. In patients
continuously treated with ponesimod, adverse events reported in >=15% of patients in any group were
nasopharyngitis, headache, dyspnea and upper respiratory tract infection; in ex-placebo patients, cough, dizziness,
fatigue, urinary tract infection and increased alanine aminotransferase were also reported.
Conclusion: Continued treatment with ponesimod maintained efficacy on clinical and MRI outcomes over two years.
Beneficial effects were also observed in ex-placebo patients following transition to ponesimod, although relapse rates
were numerically higher compared with patients continuously treated with ponesimod.
The study was sponsored by Actelion Pharmaceuticals Ltd. Ponesimod is an investigational compound. Dr C. Pozzilli
has received personal compensation as a speaker in meetings and as a member of advisory boards from Merck
Serono, Genzyme, Biogen Idec, Bayer, Novartis and Teva; he has received financial support for research from
Biogen Idec, Novartis, Merck Serono, Bayer and Sanofi. Dr. Ó. Fernández has received honoraria as a consultant in
advisory boards and as a chairman or lecturer in meetings from Bayer-Schering, Biogen Idec, Merck Serono, Teva,
Novartis and Sanofi; he has participated in clinical and other research projects sponsored by Bayer-Schering, Biogen
Idec, Merck Serono, Teva, Novartis, Sanofi, Actelion and Almirall. Dr T. Olsson has received personal compensation
from Biogen Idec, Genzyme, Sanofi, Novartis and Merck Serono; he has received financial support from Biogen Idec,
Sanofi, Novartis and Merck for unrestricted multiple sclerosis research grants. Dr M.S. Freedman has received
compensation for activities with Actelion, Bayer HealthCare, Biogen Idec, Celgene, EMD Canada, Genzyme,
Novartis, Opexa, Sanofi and Teva Canada Innovation; he has received financial support for research from Bayer
HealthCare and Genzyme. Dr M. Melanson is a member of the Multiple Sclerosis Advisory Council; she has received
compensation for speaking engagements and consultancy for Biogen Idec, and compensation for speaking
engagements from Teva, Pfizer, QuestCor, Novartis and Accorda. Dr A. Boster has received personal compensation
from Merck Serono, Biogen Idec, Teva, Medtronic, Genzyme and Novartis for consulting services; he has received
financial support for research activities from Actelion, Accorda, Merck Serono, Biogen Idec, Teva Neuroscience,
NMSS, Roche, Sunpharma and Novartis. Dr E.-W. Radue has received personal compensation from Bayer Schering,
9
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Biogen Idec, Novartis and Merck Serono for consulting and speaking services; he has received financial support for
research activities from Actelion, Basilea Pharmaceuticals Ltd, Biogen Idec, Merck Serono and Novartis. Mr B.
Hennessy is an employee of SDE Research GmBh, and a consultant to Actelion Pharmaceuticals Ltd. Dr A. Rames
is an employee of Actelion Pharmaceuticals Ltd. Dr D. D’Ambrosio is an employee of Actelion Pharmaceuticals Ltd.
10
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Sensitivity analysis of a phase IIa study of secukinumab in relapsing remitting
multiple sclerosis
E. Havrdova, A. Belova, A. Goloborodko, A. Tisserant, A. Wright, H. Garren, E. Wallstroem, A. de Vera, D.R. Johns
(Prague, CZ; Nizhniy Novgorod, RU; Odessa, UA; Basel, CH; East Hanover, US)
Background: Secukinumab is a fully human anti-interleukin (IL)-17A monoclonal antibody that neutralizes human IL17A bioactivity. As previously reported, secukinumab was well tolerated and significantly reduced brain magnetic
resonance imaging (MRI) lesion activity compared with placebo in a 6-month, phase IIa study of patients with
relapsing–remitting multiple sclerosis (RRMS). However, baseline patient characteristics and MRI activity differed
between treatment groups. In particular, there was one patient outlier in terms of number of gadolinium-enhancing
(Gd+) lesions.
Objective: To determine the impact of disease activity at screening and study outliers on the efficacy of secukinumab
in the phase IIa RRMS study.
Methods: In this 6-month, double-blind, multicentre study, patients with RRMS were randomized 1:1 to 10 mg/kg of
secukinumab or placebo given intravenously at baseline and weeks 2, 4, 8, 12, 16 and 20. Efficacy outcome was the
cumulative number of new lesions, defined as Gd+ or combined unique active lesions observed on brain MRI
performed every 4 weeks (week 4– 24). The treatment difference was estimated with a negative binomial regression
model adjusted for the number of Gd+ lesions at screening and the number of missing MRI scans. Statistical
analyses were repeated excluding the outlier.
Results: In total, 73 patients were randomized (38 to secukinumab; 35 to placebo); 61 completed the study. At
screening, the mean Gd+ lesion count was higher in the secukinumab group (4.5) than in the placebo group (2.1).
After excluding one patient outlier with 133 Gd+ lesions, mean lesion count decreased to 0.9 in the secukinumab
group. As previously reported, the observed mean cumulative number of new Gd+ lesions during weeks 4–24 was
lower in the secukinumab group (5.4) than the placebo group (11.1). Excluding the outlier lowered the lesion count to
1.8 in the secukinumab group. In the previous report, secukinumab was estimated to reduce the number of new Gd+
lesion by 67% (p = 0.003) compared with placebo after adjustment for screening values. Excluding the outlier,
resulted in little change in this reduction (69%; p = 0.005).
Conclusion: Secukinumab therapy resulted in a significant 67% reduction in the cumulative number of new Gd+
lesions over 6 months compared with placebo and removing an outlier patient had little impact on this result. A phase
IIb clinical trial to further characterize the effect of secukinumab in MS will start in 2013
This study was supported by the Novartis Institutes for BioMedical Research. Eva Havrdová has received speaker
honoraria and payments for consultant services and clinical trials from Biogen Idec, Bayer, Genzyme, GSK, Merck
Serono, Novartis, and TEVA.. Anna Belova and Alla Goloborodko have nothing to disclose. Andrew Wright, Erik
Wallstroem Anne Tisserant, , Hideki Garren and Donald Johns, are employees of Novartis.
11
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Looking into the future: experimental studies of new therapies
Friday, October 04, 2013, 14:40 - 14:52
NDC-1308 induces remyelination in experimental models of multiple sclerosis
S.H. Nye, S. Medicetty, B.D. Trapp, J.G. Yarger (Mequon, Cleveland, US)
Background: Previous reports using animal models of demyelinating diseases provided rationale for hormones as
potential therapeutics to treat patients with multiple sclerosis (MS). Yet, while estrogens (like estriol) have advanced
in clinical trials, they appear to impact only the neuroprotective aspects of MS, rather than remyelination. We
investigated whether analogs of 17beta-estradiol (E2) could be created to remyelinate damaged axons in MS
patients.
Objectives: A library of E2 analogs was assessed to: i) identify an analog of E2 with potent activity to differentiate
oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes, ii) compare the potency of E2 analogs to other
estrogens for their ability to remyelinate brain slices, and iii) determine whether a lead E2 analog can induce
remyelination in different MS models.
Methods: E2 was modified with different C-6 alkoxyalkyl moieties and/or substitution of the C-18 methyl group. E2
analogs were characterized for estrogen receptor (ER) binding using recombinant human ERs, while ER activation
was determined using luciferase reporter constructs. Differential gene expression of the E2 analogs was evaluated by
microarray, followed by analysis of OPC differentiation/myelin synthesis pathways. Based on this data, a subset of E2
analogs was screened in vitro using OPCs (differentiation assay) and lysolethicin demyelinated brain slices
(remyelination assay). A lead E2 analog (named NDC-1308) emerged and was formulated with cyclodextrin for proofof-concept efficacy studies using the EAE and cuprizone mouse models.
Results: NDC-1308 preferentially activated ER-beta and was the most potent of the E2 analogs, causing a dramatic
upregulation of genes (5 to 75-fold) in signaling pathways related to OPC differentiation and myelin production. NDC1308 was significantly more potent at differentiating OPCs than estriol or E2 (P<0.05). Studies using demyelinated
brain slices showed that NDC-1308 (3µM, 7 days), but not other estrogens, significantly enhanced remyelination.
Cuprizone demyelinated mice showed a 20% increase in remyelination of hippocampal regions (P<0.01) following a
2-week treatment with NDC-1308 (50mg/Kg, i.p., QD). Prophylactic treatment of EAE mice with NDC-1308 (10mg/Kg,
i.v., QD) delayed the onset and severity of disease for over 2 weeks. These results suggest that NDC-1308 can
induce OPC differentiation leading to remyelination of damaged axons in vivo, along with a dual anti-inflammatory
role.
Steven Nye and James Yarger are shareholders of ENDECE Neural, LLC Satish Medicetty is a full time employee of
Renovo Neural, Inc. Bruce Trapp is a consulting Chief Scientific Officer of Renovo Neural. Dr. Trapp is also a
consultant for Novartis and Biogen, and a member of the Speaker's Bureau for EMD Serono. Renovo Neural,Inc.
received compensation from ENDECE Neural,LLC to perform contracted research using the cuprizone experimental
model. All personnel affiliated with Renovo Neural,Inc. do not have a conflicting interest in ENDECE Neural,LLC.
12
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
The Anti-IL17A monoclonal antibody secukinumab (AIN457) attenuates IL17 and
TNF-induced production of IL6 in human astrocytes
K. Jeanneau, G. Elain, A.K. Mir, K.K. Dev (Basel, CH; Dublin, IE)
The family of type-I interleukin 17 receptors (IL17Rs) are composed of five subtypes IL17RA-IL17RE. These
receptors are targeted by the group of pro-inflammatory IL17 cytokines (IL17 A-F). Studies suggest that IL17
signalling plays a role in Multiple Sclerosis (MS), where the newly developed anti-IL-17A antibody secukinumab
(AIN457) has shown promise in Phase II proof of concept studies in MS. Here, to examine the role of IL17Rs in
astrocytes, the effect of IL17 and secukinumab in cytokine release from human astrocytes was demonstrated. The
data showed that human astrocytes expressed IL17RA and IL17RC receptors and in vitro treatment with IL17
increased the protein levels of IL6 in human and mouse astrocytes and significantly potentiated the effects in
combination with TNF alpha compared to TNF alpha alone. In addition, IL17 in combination with TNF alpha also
induced mRNA expression of IL6, IL8 and the Th17 attracting chemokines CXCL-1, -2 and -20, with little effect on
Th1 attracting chemokines CXCL-9, -10 and -11. Importantly, the treatment of human astrocytes with secukinumab
inhibited the increase in IL-6 induced by IL17 and by IL-17 in combination with TNF alpha.. These results suggest that
IL17 signalling plays a key role in regulating the levels of cytokines, such as IL6, in human astrocytes. The data
support the use of therapies that regulate IL17 signalling in astrocytes as a drug target for neuroinflammatory
diseases.
This work was funded by Novartis Pharma. Kumlesh K. Dev is an employee of Trinity College Dublin. Gaelle Elain,
Karine Jeanneau and Anis Mir and employees of Novartis Pharma.
13
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Friday, October 04, 2013, 15:30 - 17:00
Efficacy and safety of AIN457 (secukinumab) in patients with relapsing multiple
sclerosis: design of an adaptive dose-ranging phase 2 study
R. Rudick, H. Wiendl, L. Steinman, A. Bar-Or, R. Bhore, D. Bennett, M. Bieniek, A. de Vera, X. Montalban (Cleveland,
US; Münster, DE; Stanford, US; Montreal, CA; East Hanover, US; Warsaw, PL; Basel, CH; Barcelona, ES)
Background: Secukinumab (AIN457) is a recombinant, high-affinity fully human monoclonal anti-human interleukin17A (IL-17A) antibody that binds to and neutralizes the bioactivity of human IL-17A. Preclinical and clinical evidence
have implicated IL-17 in the pathogenesis of relapsing-remitting multiple sclerosis (MS). In a proof-of-concept study
(N=73), AIN457 10mg/kg intravenous (i.v.) significantly reduced cumulative new Gd-enhancing T1 lesions vs placebo
(67% on Week 4-24 and 70% on Week 12-24; p<0.05). Treatment benefit manifests as early as Week 12 and was
sustained up to Week 36. Incidence of adverse events (AE) was similar in AIN457 (52.6%) and placebo groups
(48.6%). Infections were more frequent in the AIN457 group (36.8% vs 22.9%). No SAEs were reported.
Objectives: To present design of an adaptive dose-ranging study intended to evaluate efficacy of AIN457 doses (3, 7,
and 15 mg/kg i.v.) compared to placebo in relapsing MS (RMS), and select the dose for further development in Phase
3 study.
Methods: This is a parallel group, randomized, double-blind, placebo-controlled, 2-stage adaptive study for 6 months.
Approximately 380 patients with RMS (2010 revised McDonald criteria), 18-55 years age, Expanded Disability Status
Scale (EDSS) score of 0-5.0, disease duration <=10 years and evidence of recent clinical disease activity will be
enrolled. Patients previously treated with >1 class of disease modifying therapies (except interferon beta/glatiramer
acetate) will be excluded. In stage 1, 260 patients will be randomized to AIN457 (3, 7, or 15mg/kg i.v.) or placebo
(1:1:1:1). AIN457 will be given on Days 1, 15, Week 4, and every 4 weeks thereafter. In stage 2, 120 patients will be
randomized to 2 AIN457 doses (either 7 and 3mg/kg or 15 and 7mg/kg) selected after an interim analysis (IA) during
stage 1, or placebo (1:1:1). The IA will be performed when at least 140 patients have completed Month 3 MRI
assessment. Primary objective is the reduction of cumulative new Gd-enhancing T1-weighted lesions, as assessed
by monthly MRI at Months 3-6. Secondary objectives include safety and tolerability, MRI and relapses. Sample size
allows estimation of the true treatment effect (relative risk) with a precision of ±0.898 (MRI) and ±0.9743 (relapses),
based on a 2-sided 95%CI.
Conclusion: This study will confirm the efficacy and safety profile of AIN457 in RMS. The adaptive dose-ranging
design allows for maximizing the selection of optimal doses for Phase 3 development.
This study was funded by Novartis Pharma AG R. Bhore, D. Bennett, M. Bieniek, and A. de Vera are employees of
Novartis. . Dr. R. Rudick has received honoraria or consulting fees from: Biogen Idec, Genzyme, Novartis, and Pfizer
and research funding from the National Institutes of Health, National Multiple Sclerosis Society, Biogen Idec,
Genzyme, and Novartis Dr. H Wiendl has received honoraria for lecturing, travel expenses for attending meetings
from Bayer Health Care, Biogen Idec/Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Sanofi Aventis, and
TEVA Neuroscience; has served/serves as a consultant for Biogen Idec, Lilly, Merck Serono, Novartis Pharma,
Sanofi Aventis; and receives research support from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Lilly,
Lundbeck, Merck Serono, Novartis, Novo Nordisk and Sanofi-Aventis Dr. L. Steinman consulting funds from Teva,
Biogen/IDEC, Novartis, MedImmune, Synthon, Tolerion, and Sanofi Dr. Amit Bar-Or has participated as a speaker at
meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Aventis, Bayhill
Therapeutics, Berlex/Bayer, Biogen Idec, BioMS, Diogenix, Eli-Lilly, Genentech, Genzyme, GlaxoSmithKline, GuthyJackson/GGF, EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi
Aventis, Teva Neuroscience, Wyeth. Dr. Xavier Montalban has received speaker honoraria and travel expenses for
scientific meetings, steering committee member and advisory board member of clinical trials for Bayer Schering
Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceutical, Almirall
14
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Experimental models
Thursday, October 03, 2013, 15:45 - 17:00
RPC1063, a potent and selective sphingosine 1-phosphate 1 receptor modulator,
has a favourable preclinical safety profile
R. Peach, J. Brooks, H. Dedman, R. Powell, F. Scott, G. Timony (San Diego, US)
Objective: Evaluate the preclinical safety profile of RPC1063, a potent and selective sphingosine 1-phosphate 1
Receptor (S1P1R) modulator
Background: RPC1063 is in clinical development to treat patients with relapsing multiple sclerosis (RMS). RPC1063,
a 260 pM S1P1R agonist, demonstrates 269-fold selectivity for S1P1R over S1P5R, and greater than 20,000-fold
selectivity over S1P2R, S1P3R and S1P4R; potential tolerability advantages conferred by selectively for S1P1R are
discussed.
Methods: RPC1063 was administered orally in rat and monkey GLP toxicology studies of up to 9-months duration.
Reduction in absolute lymphocyte count (ALC), an established biomarker for activity of S1PR modulators in RMS,
was used to set the lowest doses to a pharmacologically active dose (PAD; defined as >=50% decrease in ALC).
Results: No observed adverse effect levels (NOAEL) were established in all toxicology studies at a PAD, which was
the lowest dose level in both species (0.2 mg/kg/d in rats and 0.1 or 0.15 mg/kg/d in monkeys). Hematology findings
were limited to dose-related and rapidly reversible decreases in ALC, a change consistent with the pharmacologic
mechanism. Clinical chemistry findings were unremarkable; no changes were observed in liver parameters. NOAELs
were driven by mild and fully reversible histopathology findings in the lung (histiocytosis) and kidney (anisocytosis).
RPC1063 Cmax and AUC at the animal NOAELs substantially exceeded the clinical exposures at a dose producing
~70% reduction in ALC (based upon Phase I data) suggesting a broad safety margin. Publically available chronic
toxicology data of the non-selective S1PR modulator fingolimod (Gilenya®) demonstrate findings in multiple species
that were not observed with RPC1063 including fibrotic changes in heart and lung. The findings unique to fingolimod,
which also has S1P3R agonist activity, are consistent with fibrotic events described in the literature related to
signaling through S1P3R.
Conclusion: A favorable preclinical safety profile has been established for RPC1063. The absence of fibrotic changes
with RPC1063 is consistent with selectivity of RPC1063 towards S1P1R.
R. Peach, J. Brooks, H. Dedman, R. Powell, F. Scott and G. Timony are all employees of Receptos, Inc.
15
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Results of a thorough QT/QTc (TQT) study of orally administered RPC1063, a
novel, selective S1P1 receptor agonist, in healthy adult volunteers
J. Hartung, A. Olson, R. Peach, M. Boehm, B. Mendzelevski, D. Chanter, H. Smith, C. Pan, G. Timony, S. Gujrathi
(San Diego, US; London, GB)
Objective: Assess whether exposure to therapeutic (1 mg) or supratherapeutic (2 mg) RPC1063 in healthy subjects
increases the corrected QT (QTc) interval compared to placebo (PBO).
Background: RPC1063 is an orally available, potent, selective sphingosine-1-phosphate 1 receptor (S1P1R) agonist.
Stimulation of S1P1R results in pharmacologic activities likely to improve pathological processes in relapsing multiple
sclerosis and is associated with decrease in heart rate (HR) on initial dosing, with diminished effect on HR and
tachyphylaxis on repeat dosing. Fingolimod, a non-selective S1PR agonist, has demonstrated prolongation of QTc.
S1P3R is expressed on mouse heart conduction tissue and may be responsible for this QTc prolongation.
Methods: This was a single-centre, double-blind, randomized, placebo- and positive-controlled, parallel-group, nested
crossover for positive control, TQT study of RPC1063. 124 healthy male and female subjects, aged 18-45 years were
randomized in a 1:1 ratio to RPC1063 (0.25 to 2 mg dose titration regimen [DT]) or placebo. Moxifloxacin (MFX) 400
mg served as a positive control. QT assessments were performed at Baseline (BL), Day 10 (1 mg) and Day 14 (2
mg), and Days 2 and 17 (MFX). 24-hour continuous ECG monitoring was also performed for cardiac adverse event
(AE) monitoring and HR characterization at BL, Day 1, and at dose increases on Days 5, 8 and 11. Safety
assessments included AEs, vital signs, laboratory, electrocardiogram, telemetry, and physical exam.
Results: The upper 95% 1-sided confidence limit for QTc change from BL was always below 10 msec at both 1mg
and 2 mg doses, meeting pre-specified criteria to rule out a relevant QT effect of RPC1063. Assay sensitivity was
demonstrated with QTc change from BL >5 msec following MXF treatment. DT was well tolerated, attenuated first
dose effects, and minimized decreases in HR throughout titration period.
Generally, RPC1063 treatment was well tolerated. AEs, including cardiac AEs, were generally similar in RPC1063
and control groups, and similar to those seen previously with RPC1063. Most common AEs were administration site
reaction, headache, orthostatic hypotension, dizziness, musculoskeletal chest pain and constipation. No SAEs
occurred in the study.
Conclusions: The study confirmed the absence of a relevant effect of RPC1063 on QTc prolongation. Overall, the
emerging favourable cardiac and overall safety profile of RPC1063 support its continued development in patients with
MS.
All authors are employees of Receptos, Inc. or are vendors providing contract services to Receptos, Inc.
16
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Neuroprotection
Thursday, October 03, 2013, 15:45 - 17:00
Development of anti-SEMA4D monoclonal antibody for the treatment of multiple
sclerosis
A. Jonason, E. Klimatcheva, T. Fisher, C. Reilly, L. Winter, J. Veeraraghavan, J. Seils, H. Huang, H. Bussler, J.
Decker, S. Torno, R. Kirk, C. Cornelius, T. Richards, J. Caplan, A. Howell, P. Kenney, M. Scrivens, L. Balch, T.
Pandina, M. Doherty, G. Seigel, W. Wang, E. Evans, W. Bowers, M. Paris, J. Leonard, R. Watkins, P. Foster, M.
Zauderer, E. Smith (Rochester, US)
Semaphorin 4D (SEMA4D/CD100) is expressed on most immune cells, and its high affinity receptor, Plexin B1
(PLXNB1), is expressed on dendritic, endothelial, and neuronal cells. SEMA4D signaling through PLXNB1 induces
growth cone collapse of neurons, inhibits differentiation of oligodendrocyte precursor cells (OPCs), induces
oligodendrocyte (OD) process collapse and apoptosis, and disrupts CNS endothelial tight junctions. SEMA4D also
plays an important role in glial cell activation and may influence induction of B and T cell responses. Antibody
neutralization of SEMA4D could therefore reduce the severity of multiple sclerosis through several means. First,
blocking SEMA4D could reduce the rate of disease relapse by reducing inflammation and secondary immune
responses to CNS antigens. Second, to the extent that SEMA4D mediates apoptosis and inhibits maturation of
OPCs, blocking SEMA4D could reduce the loss of ODs and promote remyelination. Third, SEMA4D may play a role
in breakdown of the blood brain barrier (BBB), and blocking SEMA4D may reduce immune cell infiltration into the
CNS.
We have demonstrated in several preclinical models the effects of SEMA4D in the central nervous system. Inhibitory
effects on OD differentiation and myelination have been shown using recombinant SEMA4D, and anti-SEMA4D
antibody has been shown to protect the integrity of the BBB both in vitro and in vivo, and to promote neural
regeneration. Treatment with anti-SEMA4D MAbs attenuates the disease severity in several rodent EAE models,
including chronic EAE characterized by a combination of axonal and myelin loss and continuing inflammation.
Antibody neutralization of SEMA4D represents a new therapeutic strategy for multiple sclerosis. We selected a
humanized IgG4 antibody that blocks SEMA4D – PLXNB1 interactions in mouse, rat, monkey, and humans.
SEMA4D signaling through PLXNB1 has also been implicated in tumor growth and angiogenesis. Using various
tumor models we demonstrated that anti-SEMA4D antibody inhibits these processes. A Phase I clinical trial in
patients with advanced solid tumors has been completed; Infusions of VX15/2503 were well tolerated, with a
maximum dose of 20 mg/kg. A randomized, placebo-controlled, single ascending dose Phase 1 study in MS patients
began in 2012.
Alan Jonason received compensation as an employee of Vaccinex, Inc. Ekaterina Klimatcheva received
compensation as an employee of Vaccinex, Inc. Terrence Fisher received compensation as an employee of
Vaccinex, Inc. Christine Reilly received compensation as an employee of Vaccinex, Inc. Janaki Veeraraghavan
received compensation as an employee of Vaccinex, Inc. Jennifer Seils received compensation as an employee of
Vaccinex, Inc. He Huang received compensation as an employee of Vaccinex, Inc. Holm Bussler received
compensation as an employee of Vaccinex, Inc. Jessica Decker received compensation as an employee of Vaccinex,
Inc. Sebold Torno received compensation as an employee of Vaccinex, Inc. Renee Kirk received compensation as an
employee of Vaccinex, Inc. Chad Cornelius received compensation as an employee of Vaccinex, Inc. Troy Richards
received compensation as an employee of Vaccinex, Inc. Jeff Caplan received compensation as an employee of
Vaccinex, Inc. Alan Howell received compensation as an employee of Vaccinex, Inc. Patrick Kenney received
compensation as an employee of Vaccinex, Inc. Maria Scrivens received compensation as an employee of Vaccinex,
Inc. Leslie Balch received compensation as an employee of Vaccinex, Inc. Tracy Pandina received compensation as
an employee of Vaccinex, Inc. Michael Doherty received compensation as an employee of Vaccinex, Inc. Gail Seigel
received compensation as an employee of Vaccinex, Inc. Wei Wang received compensation as an employee of
Vaccinex, Inc. Elizabeth Evans received compensation as an employee of Vaccinex, Inc. William Bowers received
compensation as an employee of Vaccinex, Inc. Mark Paris received compensation as an employee of Vaccinex, Inc.
John Leonard received compensation as an employee of Vaccinex, Inc. Raymond Watkins received compensation as
an employee of Vaccinex, Inc. Paul Foster received compensation as an employee of Vaccinex, Inc. Maurice
17
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Zauderer received compensation as an employee of Vaccinex, Inc. Ernest Smith received compensation as an
employee of Vaccinex, Inc.
18
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Peginterferon beta-1a provides improvements in clinical and radiological disease
activity in relapsing-remitting multiple sclerosis: year 1 findings from the phase 3
ADVANCE study
P. Calabresi, B. Kieseier, D. Arnold, L. Balcer, A. Boyko, J. Pelletier, S. Liu, Y. Zhu, X. You, A. Seddighzadeh, B.
Sperling, S. Hung, A. Deykin (Baltimore, US; Düsseldorf, DE; Montreal, CA; New York, US; Moscow, RU; Marseille,
FR; Cambridge, US)
Background: Peginterferon beta-1a is a pharmacologically distinct molecule in which interferon (IFN) beta-1a is
pegylated to extend its half-life; thus potentially enabling less frequent dosing schedules. Pegylation of other drugs
and the use of IFN beta-1a as a disease-modifying therapy have been practiced successfully for >15 years. The
pivotal Phase 3 ADVANCE study evaluated the efficacy, safety, and tolerability of peginterferon beta-1a in patients
with relapsing-remitting multiple sclerosis (RRMS); here we present data from the first year (placebo-controlled
period) of this 2-year study.
Methods: ADVANCE is a multicentre, double-blind, parallel-group study. Patients were randomised (1:1:1) to placebo
or peginterferon beta-1a 125 µg self-administered subcutaneously every 2 (Q 2W) or 4 (Q 4W) weeks. The primary
efficacy endpoint is annualised relapse rate (ARR) at Year 1. Secondary endpoints are total number of new/newly
enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans, the proportion of patients
relapsing, and risk of 12-week confirmed disability progression at Year 1. Additional endpoints included the total
number of new T1 hypointense and gadolinium-enhancing (Gd+) lesions, along with safety and tolerability. A posthoc analysis of disease activity-free patients was also carried out.
Results: 1512 patients were randomised and received study drug (placebo n=500; peginterferon beta-1a Q 4W
n=500; peginterferon beta-1a Q 2W n=512); Year 1 completion rates were 91%, 88%, and 86%, respectively.
Compared with placebo, peginterferon beta-1a demonstrated a significant reduction in ARR (Q 2W 36% [p=0.0007];
Q 4W 27% [p=0.011]), risk of relapse (Q 2W 39% [p=0.0003]; Q 4W 26% [p=0.02]), and risk of 12-week disability
progression (38% for both Q 2W and Q 4W [p<0.04]). T2 hyperintense lesions were also reduced (Q 2W 67% and Q
4W 28%; both p<0.001), as were T1 hypointense (Q 2W 53% [p<0.0001]; Q 4W 18% [p=0.082]) and Gd+ (Q 2W 86%
[p<0.0001]; Q 4W 36% [p=0.07]) lesions. The proportion of disease activity-free patients over 1 year was significantly
higher in the Q 2W (34%; p<0.0001) and Q 4W (22%; p=0.01) groups versus placebo (15%). The safety profile of
peginterferon beta-1a was similar across both dosing regimens.
Conclusion: Peginterferon beta-1a Q 2W provides significant improvements in all clinical and radiological outcomes
versus placebo, with a safety profile reflecting that of established IFN beta-1a therapies for MS.
This study was sponsored by Biogen Idec (Cambridge, MA, USA). PC has received grants/research support from
Biogen Idec, Abbott, Vertex, Novartis and Bayer; and consulting fees from Abbott and Vertex. BK has received
grants/research support from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi
Aventis, Talecris and Teva Neurosciences; consulting fees from Bayer Schering, Biogen Idec, Genzyme, Merck
Serono, Novartis, Roche, Sanofi Aventis, Talecris and Teva Neurosciences. This study was sponsored by Biogen
Idec (Cambridge, MA, USA). DA has received grant/research support from Bayer Healthcare; and consulting fees
from Bayer Healthcare, Biogen Idec, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, NeuroRx Research,
Novartis, Roche, Merck Serono, Teva. LB has received consulting fees from Biogen Idec, Questcor and Novartis. AB
has received consulting fees from Schering, Merck Serono, Teva, Novartis, Biogen, Nycomed and Genzyme. JP has
received payment for advisory boards for Allergan, Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono,
Novartis, Sanofi, and Teva; non-profit foundation support from ARSEP, academic research support from PHRC, and
unconditional research support from Bayer Schering Pharma, Biogen Idec, BMS, GSK, Merck Serono, Novartis,
Peptimmune, Roche, Sanofi, Teva and Wyeth. SL, YZ, XY, AS, BS, SH and AD are employees of Biogen Idec.
19
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Effect of peginterferon beta-1a on disability progression in patients with relapsing
remitting multiple sclerosis: year 1 data from the pivotal phase 3 ADVANCE study
B. Kieseier, P. Calabresi, S. Liu, Y. Zhu, X. You, B. Sperling, S. Sheikh, S. Hung, A. Deykin (Düsseldorf, DE;
Baltimore, Cambridge, US)
Background: Peginterferon beta-1a is a pegylated form of interferon (IFN) beta-1a; it is being developed as an
injectable treatment option for relapsing-remitting multiple sclerosis (RRMS) with a less frequent dosing requirement
versus available non-pegylated first-line IFN therapies. Here we present the effect of peginterferon beta-1a on
disability progression in RRMS patients from the first year (placebo-controlled period) of the on-going pivotal Phase 3,
2-year, multicentre ADVANCE trial.
Methods: Patients (18–65 years, with confirmed RRMS [McDonald criteria 1–4] and baseline Expanded Disability
Status Scale [EDSS] score <=5.0) were randomised (1:1:1) to double-blind placebo or peginterferon beta-1a 125 µg
self-administered subcutaneously every 2 weeks (Q 2W) or every 4 weeks (Q 4W). The proportion of patients with
disability progression over 1 year (defined by a >=1.0- or >=1.5-point increase in EDSS score, from a baseline score
of >=1.0 or 0.0, respectively, confirmed at 12 weeks) was a secondary endpoint of the study. Disability was also
assessed by change from baseline in EDSS and Multiple Sclerosis Functional Composite (MSFC) z-scores.
Results: In the intent-to-treat population (placebo n=500; peginterferon beta-1a Q 4W n=500; peginterferon beta-1a Q
2W n=512), the estimated proportions of patients with disability progression were 0.052, 0.032, and 0.038 at Week
24, and 0.105, 0.068, and 0.068 at Week 48, respectively. Peginterferon beta-1a Q 4W and Q 2W significantly
reduced the risk of 12-week confirmed disability progression over 1 year versus placebo by 38% (hazard ratio for Q
4W and Q 2W groups: 0.62 [95% CI, 0.40, 0.97]; p=0.038 vs placebo). Mean EDSS scores were 2.43, 2.39 and 2.45
at Week 24 (mean change from baseline -0.01, -0.07 and 0.01), and 2.48, 2.41 and 2.45 at Week 48 (mean change
from baseline 0.06, -0.01 and 0.01) for placebo, peginterferon beta-1a Q 4W and Q 2W groups, respectively. Mean
change from baseline in the MSFC z-scores for peginterferon beta-1a groups at Weeks 24 or 48 were not statistically
significantly different versus placebo. Correlation between EDSS and MSFC z-score, as well as the subcomponents
of MSFC, will also be presented.
Conclusion: At Year 1 of the ADVANCE study, compared with placebo, peginterferon beta-1a Q 4W and Q 2W
significantly reduced the risk of 12-week confirmed disability progression as measured by EDSS.
This study was sponsored by Biogen Idec (Cambridge, MA, USA). BK has received grants/research support from
Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi Aventis, Talecris and Teva
Neurosciences; consulting fees from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi
Aventis, Talecris and Teva Neurosciences. PC has received grants/research support from Biogen Idec, Abbott,
Vertex, Novartis and Bayer; and consulting fees from Abbott and Vertex. SL, YZ, XY, BS, SS, SH and AD are
employees of Biogen Idec.
20
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Risk management for disease modifying treatments
Thursday, October 03, 2013, 15:45 - 17:00
Immunogenicity with peginterferon beta-1a in patients with relapsing-remitting
multiple sclerosis: data from the pivotal phase 3 ADVANCE study
J. White, P. Calabresi, Y. Zhu, T. Song, A. Seddighzadeh, S. Hung , A. Deykin, M. Subramanyam (Cambridge,
Baltimore, US)
Background: Modification by attachment of poly(ethyleneglycol) (PEG) molecules (pegylation) has been used to
increase the half-life of many drugs and may also reduce immunogenicity. Development of neutralising antibodies
against interferon (IFN) beta (NAbs) has been associated with reduced levels of efficacy on clinical and magnetic
resonance imaging variables for other IFN beta agents. Peginterferon beta-1a, a pegylated version of IFN beta-1a, is
being developed for the treatment of multiple sclerosis (MS). Here we assess the immunogenicity of peginterferon
beta-1a in patients with relapsing-remitting MS (RRMS) participating in the first year (placebo-controlled period) of the
pivotal 2-year Phase 3 ADVANCE clinical trial.
Methods: ADVANCE is a multicentre, double-blind, randomised trial evaluating the efficacy and safety of
subcutaneous peginterferon beta-1a 125 µg administered every 2 weeks (Q 2W) or every 4 weeks (Q 4W). During
Year 1 of the study, patient serum samples were collected pre-dose on Day 1 and Weeks 8, 20, 36, and 48. A tiered
testing scheme was used to measure immunogenicity. Firstly, sera samples were tested for the presence of
antibodies that bind to IFN beta-1a (BAbs) using a validated enzyme-linked immunosorbent assay (ELISA). Samples
that generated a positive response were further tested for the presence and titre of NAbs to IFN beta-1a using a
validated cell-based assay. Samples were also tested for the presence and titre of antibodies to PEG using a
validated ELISA. Data presented are from samples analysed at Year 1 of this on-going study.
Results: BAbs were evident in 2%, 4%, and 8% of patients receiving placebo, peginterferon beta-1a Q 4W and Q 2W,
respectively. The incidence and titre level of positive NAbs were also low, at <1% in the placebo and both
peginterferon beta-1a groups. The incidence of anti-PEG antibodies was low, at 9% and 7% in Q 4W and Q 2W
groups, respectively, versus 5% for placebo, with low titres for most subjects. The majority of treatment-emergent
antibodies were transient responses. Although analysis was limited by the low incidence of treatment-emergent
antibodies no discernible impact on pharmacodynamic response, clinical efficacy or safety was observed.
Conclusions: At Year 1 of the ADVANCE study, the development of BAbs and NAbs to IFN beta-1a and anti-PEG
antibodies was low and similar for peginterferon beta-1a Q 4W and Q 2W dosing groups; no discernible clinical
impact was observed in this study.
This study was sponsored by Biogen Idec (Cambridge, MA, USA). PC has received grants/research support from
Biogen Idec, Abbott, Vertex, Novartis and Bayer; and consulting fees from Abbott and Vertex. JW, YZ, TS, AS, SH,
AD and MS are employees of Biogen Idec.
21
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Risk management for disease modifying treatments
Friday, October 04, 2013, 15:30 - 17:00
Safety and tolerability of peginterferon beta-1a in patients with relapsingremitting multiple sclerosis: data from the pivotal phase 3 ADVANCE study
B. Kieseier, P. Calabresi, T. Song, Y. Zhu, S. Hung, A. Deykin, A. Seddighzadeh (Düsseldorf, DE; Baltimore,
Cambridge, US)
Background: In Phase 1 studies, peginterferon beta-1a provided a longer half-life and exposure versus non-pegylated
IFN beta-1a and was well-tolerated. Peginterferon beta-1a is being developed as an injectable treatment option for
relapsing-remitting multiple sclerosis (RRMS) with a less frequent dosing requirement versus available first-line
therapies. Here we present safety and tolerability findings from the placebo-controlled first year of the pivotal 2-year,
Phase 3, multicentre ADVANCE trial in patients with RRMS.
Methods: Patients were randomised (1:1:1) to double-blind placebo or peginterferon beta-1a 125 µg self-administered
subcutaneously every 2 weeks (Q 2W) or every 4 weeks (Q 4W). Safety and tolerability were assessed at regular
scheduled visits via clinical (including monitoring of adverse events [AEs], physical examination and vital signs), and
laboratory (haematology, blood chemistry, and urinalysis) assessments. The safety population comprised those who
received >=1 dose of study treatment.
Results: 1512 patients were randomised and received treatment (placebo n=500; peginterferon beta-1a Q 4W n=500;
peginterferon beta-1a Q 2W n=512). Peginterferon beta-1a Q 4W and Q 2W were generally well tolerated and had a
similar overall rate of AEs at Year 1 (placebo 83%; Q 4W 94%; Q 2W 94%); the majority of patients experienced AEs
that were mild or moderate in severity. The most common AEs included injection site erythema, influenza-like illness,
pyrexia, and headache. Discontinuations due to AEs were placebo 1%, Q 4W 5%, and Q 2W 5%. Overall rates of
serious AEs (SAEs) were similar across treatment groups (placebo 15%; Q 4W 14%; Q 2W 11%); MS relapse was
the most common SAE across all treatment groups. No treatment or dose-related trends were observed in the
incidence of infections or serious infections. Deaths occurring during Year 1 (placebo, n=2; Q 4W, n=1; Q 2W, n=1)
were not considered to be related to study treatment. There was a dose-dependent effect on the proportion of
patients with reductions in haematological parameters and elevated liver enzymes; the majority were not clinically
significant and did not result in treatment discontinuation. There were no clinically meaningful inter-group differences
in other clinical or laboratory assessments.
Conclusions: Data from Year 1 of ADVANCE support a favourable safety and tolerability profile for peginterferon
beta-1a Q 2W and Q 4W.
This study was sponsored by Biogen Idec (Cambridge, MA, USA). BK has received grants/research support from
Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi Aventis, Talecris and Teva
Neurosciences; consulting fees from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi
Aventis, Talecris and Teva Neurosciences. PC has received grants/research support from Biogen Idec, Abbott,
Vertex, Novartis and Bayer; and consulting fees from Abbott and Vertex. TS, YZ, SH, AD and AS are employees of
Biogen Idec.
22
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Effect of ONO-4641, a potent, oral, selective sphingosine-1-phosphate receptor-1
and -5 agonist, on MRI outcomes in patients with relapsing remitting multiple
sclerosis: subgroup analyses from the phase 2 DreaMS study
K. Selmaj, F. Zipp, T. Vollmer, A. Bar-Or, B. Due, T.Z. Fischer, K. Thangavelu on behalf of the DreaMS study
investigators
Background: ONO-4641 is an oral, non-pro-drug selective sphingosine-1-phosphate receptor-1 and -5 agonist. The
Phase II DreaMS (Drug Research and EvaluAtion in Multiple Sclerosis) study showed that ONO-4641 significantly
reduced key measures of magnetic resonance imaging (MRI) disease activity, compared with placebo (pbo), in
patients with relapsing–remitting multiple sclerosis (RRMS). A prospectively planned exploratory analysis using a
more sensitive statistical (negative binomial) method than in the original study protocol confirmed the efficacy of
ONO-4641 and better characterized the dose response.
Aim: To assess the efficacy of ONO-4641 in patient subgroups with and without T1-weighted gadolinium-enhancing
(Gd+) lesions at baseline.
Methods: Patients were randomized (1:1:1:1) to pbo or ONO-4641 (0.05, 0.10 or 0.15 mg) daily for 26 weeks. MRI
was performed at screening, baseline, and every 4 weeks thereafter from Weeks 6–26. The proportion of patients
persistently free of Gd+ lesions (Weeks 10–26) is reported for two patient subgroups: patients with and patients
without Gd+ lesions at baseline.
Results: Of 356 patients in the per-protocol set, 233 were free of Gd+ lesions at baseline (pbo, n=50 [58%]; 0.05 mg,
n=61 [69%]; 0.10 mg, n=67 [71%]; 0.15 mg, n=55 [63%]). The proportion of patients persistently free of Gd+ lesions
(Weeks 10–26) was higher in the ONO-4641 groups for both patients with and without Gd+ lesions at baseline:
proportions in pbo, 0.05, 0.10 and 0.15 mg groups were 6%, 37%, 52% and 55% for patients with Gd+ lesions at
baseline (p=0.0016 for 0.05 mg; p<0.0001 for both 0.10 and 0.15 mg doses versus pbo), and 46%, 77%, 85% and
87% for patients without Gd+ lesions (p<0.001 for all doses versus pbo), respectively. The effect of ONO-4641 was
seen from the first post-baseline scan at Week 6. The proportion of patients persistently free of Gd+ lesions over time
will be presented for the two patient subgroups.
Conclusion: ONO-4641 demonstrated dose-related benefits on MRI measures of disease activity in patients with
RRMS, both with and without Gd+ lesions at treatment initiation.
Study supported by Ono Pharmaceutical Co. Ltd, Osaka, Japan. K Selmaj: consulting services for Genzyme, Roche,
Synthon, Teva, Novartis, Ono Pharma; speaking engagements for Biogen Idec F Zipp: research grants, consultation
funds, or travel compensation from Teva, Novartis, Merck Serono, Bayer, Johnson & Johnson, Novartis, Ono
Pharma, Octapharma, Sanofi T Vollmer: consulting activities and research grants from Teva, Roche, Daiichi Sankyo,
Lilly, Sanofi-Aventis, PRIME Education, Johnson & Johnson, Projects in Knowledge, Guidepoint Global, Eisai, Biogen
Idec, Xenoport, Novartis, Schering-Plough Biopharma, Ono Pharma, Elan, Acorda, Medimmune A Bar-Or: speaking,
consulting, or grant support for/from Amplimmune, Aventis, Bayhill Therapeutics, Biogen Idec, Receptos, Berlex, Eli
Lilly, Genentech, GlaxoSmithKline, Ono Pharma, Diogenix, Roche, EMD Serono, Novartis, Teva Neuroscience B
Due: employee of ONO Pharma USA, Inc. TZ Fischer: employee of EMD Serono, Inc. K Thangavelu: employee of
EMD Serono, Inc.
23
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
ONO-4641, a potent and selective sphingosine-1-phosphate receptor-1 and -5
agonist, results in less lymphopenia than fingolimod at effective doses in a
preclinical model of multiple sclerosis
A. Savinainen, S. El Bawab, T. Crandall, R. Chang, U. Boschert, T. Dellovade (Billerica, US; Darmstadt, DE)
Background: Sphingosine-1-phosphate (S1P) receptor-1 is a clinically validated target for the treatment of relapsing
forms of multiple sclerosis (RMS). One mode of action is lymphocyte sequestration within lymph nodes, but additional
mechanisms might be involved in clinical efficacy. ONO-4641, an oral, non-pro-drug selective S1P receptor-1 and -5
agonist, is currently in clinical trials for RMS and has demonstrated efficacy in several preclinical models.
Aim: To compare the efficacy of ONO-4641 versus fingolimod, a non-selective S1P receptor-1, -3, -4, -5 agonist, and
to correlate clinical disease with lymphocyte count in a model of progressive MS.
Methods: Experimental autoimmune encephalomyelitis was induced in non-obese, diabetic mice, and daily oral
dosing with vehicle, ONO-4641 (0.001, 0.01, 0.1 mg/kg) or fingolimod (0.3 mg/kg) was started 40 days post-induction
(dpi). Disease severity was measured using a 0–5 clinical score (CS) scale denoting increasing levels of neurological
disability. To investigate the relationship between CS, lymphopenia, and plasma exposure, extensive
pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed.
Results: At dosing onset, the mean (standard error) CS of all mice was 2.8 (0.04). By 70 dpi, vehicle-treated mice had
reached a mean score of 3.5 (0.17), while mice dosed with ONO-4641 at 0.001, 0.01 and 0.1 mg/kg had an average
CS of 2.4 (0.37), 1.8 (0.45) and 1.2 (0.31), respectively (p<0.05, all doses vs vehicle). Thus, ONO-4641 not only
halted disease progression but also reversed pre-existing deficits. Peripheral lymphocyte counts revealed a dosedependent effect with ONO-4641, resulting in a 16% (0.001 mg/kg), 52% (0.01 mg/kg) and 84% (0.1 mg/kg) reduction
at 70 dpi. Therefore, the lowest dose of ONO-4641 significantly reduced CS in the absence of significant
lymphopenia. Fingolimod 0.3 mg/kg treatment resulted in a profound, 84% reduction in circulating lymphocytes and
corresponding CS decrease. PK/PD modelling confirmed the above observations and quantitatively showed that to
achieve comparable full efficacy, less lymphopenia was required for ONO-4641 (40–50%) compared with fingolimod
(70–80%).
Conclusion: These data indicate that ONO-4641 demonstrates comparable efficacy with less lymphopenia compared
with fingolimod in a preclinical model of MS. Studies are ongoing to better understand the mechanism(s) and
implications of this potentially important differentiating factor between S1P receptor-1, -n agonists.
The study was funded by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; and
EMD Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany. Anneli Savinainen:
employee of EMD Serono Research & Development Institute. Samer El Bawab: employee of Merck Serono Research
& Development, Darmstadt, Germany. Timothy Crandall: employee of EMD Serono Research & Development
Institute. Rui Chang: employee of EMD Serono Research & Development Institute. Ursula Boschert: employee of
EMD Serono Research & Development Institute. Tammy Dellovade: employee of EMD Serono Research &
Development Institute.
24
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Magnetic resonance imaging measures of efficacy in patients with multiple
sclerosis receiving ONO-4641, a sphingosine-1-phosphate receptor-1 and -5
agonist: interim results from an extension of the DreaMS study
T. Vollmer, F. Zipp, A. Bar-Or, B. Due, K. Thangavelu, T.Z. Fischer, K. Selmaj on behalf of the DreaMS study
investigators
Background: ONO-4641 is an oral, non-pro-drug selective sphingosine-1-phosphate receptor-1 and -5 agonist. The
26-week double-blind, randomized, Phase II DreaMS (Drug Research and EvaluAtion in Multiple Sclerosis) study
showed that ONO-4641 significantly reduced key measures of magnetic resonance imaging disease activity,
compared with placebo, in patients with relapsing–remitting multiple sclerosis.
Aim: To evaluate the efficacy of ONO-4641 during the first 6 months of a 225-week extension to the DreaMS study.
Methods: Patients either continued with their core study-assigned dose or were re-randomized from placebo to ONO4641 (0.05, 0.10 or 0.15 mg) in a dose-blinded fashion. An interim analysis was performed when all patients had
completed >=6 months in the extension study (Week 52 = 26 weeks of the core study and 26 weeks’ extension). The
numbers of T1-weighted gadolinium-enhancing (Gd+) lesions at Weeks 40 and 52 were compared with those at
extension study baseline, and the numbers of patients free of Gd+ lesions at both time points were recorded.
Results: Of 360 patients who had completed the core study, 343 entered the extension (placebo/0.05 mg n=29,
placebo/0.10 mg n=27, placebo/0.15 mg n=29, 0.05 mg n=89, 0.10 mg n=87, 0.15 mg n=82), 310 (90.4%) of whom
completed at least 6 months’ extension treatment. Two patients, one each in the placebo/0.15 mg and 0.15 mg
groups, did not receive study drug during this extension. At extension study baseline, the mean numbers of Gd+
lesions were 1.7 (placebo/0.05 mg), 3.6 (placebo/0.10 mg), 2.7 (placebo/0.15 mg), 0.3 (0.05 mg), 0.0 (0.10 mg) and
0.2 (0.15 mg). By Week 40 these values were 0.2, 0.3, 0.2, 0.4, 0.1 and 0.1, respectively, and by Week 52 they were
0.4, 0.1, 0.2, 0.4, 0.2 and 0.2. The proportions of patients free of Gd+ lesions at baseline were 59% (placebo/0.05
mg), 56% (placebo/0.10 mg), 21% (placebo/0.15 mg), 81% (0.05 mg), 97% (0.10 mg) and 89% (0.15 mg). By Week
40 the percentages were 83%, 91%, 79%, 79%, 93% and 94%, respectively, and by Week 52 they were 67%, 87%,
88%, 81%, 89% and 93%.
Conclusion: There were notable reductions in the numbers of Gd+ lesions in patients switching from placebo to active
treatment in the extension study, while efficacy was sustained for patients on continuous active treatment. Similarly,
the proportions of patients free of Gd+ lesions increased in groups that switched to active treatment, and were
maintained in those on continuous active treatment.
The study was funded by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; EMD
Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany; and Ono Pharmaceutical Co.
Ltd., Osaka, Japan. T Vollmer: consulting activities and research grants from Teva, Roche, Daiichi Sankyo, Lilly,
Sanofi-Aventis, PRIME Education, Johnson & Johnson, Projects in Knowledge, Guidepoint Global, Eisai, Biogen
Idec, Xenoport, Novartis, Schering-Plough Biopharma, Ono Pharma, Elan, Acorda, Medimmune F Zipp: research
grants, consultation funds, or travel compensation from Teva, Novartis, Merck Serono, Bayer, Johnson & Johnson,
Novartis, Ono Pharma, Octapharma, Sanofi A Bar-Or: speaking, consulting, or grant support for/from Amplimmune,
Aventis, Bayhill Therapeutics, Biogen Idec, Receptos, Berlex, Eli Lilly, Genentech, GlaxoSmithKline, Ono Pharma,
Diogenix, Roche, EMD Serono, Novartis, Teva Neuroscience B Due: employee of ONO Pharma USA, Inc. K
Thangavelu: employee of EMD Serono, Inc. TZ Fischer: employee of EMD Serono, Inc. K Selmaj: consulting services
for Genzyme, Roche, Synthon, Teva, Novartis, Ono Pharma; speaking engagements for Biogen Idec
25
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Safety of ONO-4641 in patients with relapsing remitting multiple sclerosis: results
from a six-month interim analysis of the DreaMS extension study
A. Bar-Or, F. Zipp, T. Vollmer, B. Due, K. Thangavelu, J. Johnson, K. Selmaj on behalf of the DreaMS study
investigators
Background: ONO-4641 is an oral, non-pro-drug selective sphingosine-1-phosphate receptor-1 and -5 agonist. The
Phase II DreaMS (Drug Research and EvaluAtion in Multiple Sclerosis) study in patients with relapsing–remitting
multiple sclerosis showed that ONO-4641 was well tolerated and incidences of adverse events (AEs) were dose
related. AEs included cardiac events at treatment initiation, gastrointestinal disorders and liver enzyme elevations.
Infection rates were similar with ONO-4641 and placebo (pbo), but non-disseminated herpes zoster was more
frequent with ONO-4641. Five patients receiving higher ONO-4641 doses had Grade 4 lymphopenia. The most
frequent serious AE (SAE) was MS relapse; 16 patients discontinued treatment due to AEs. There were no
unexpected AEs.
Aim: To evaluate the safety of ONO-4641 during the first 6 months of the extension to the core DreaMS study.
Methods: In the 225-week extension study, patients either continued with their core study-randomized dose or were
re-randomized from pbo to ONO-4641 (0.05, 0.1 or 0.15 mg). An interim analysis was performed when all patients
had completed >=6 months in the extension study.
Results: Of 360 patients who had completed the core study, 343 entered the extension (pbo/0.05 mg n=29, pbo/0.10
mg n=27, pbo/0.15 mg n=29, 0.05 mg n=89, 0.10 mg n=87, 0.15 mg n=82), 310 (90.4%) of whom completed 6
months of treatment. Overall, 64–77% patients in each group experienced at least one AE. For patients continuing
treatment with active dose, AEs that occurred in >10% of patients in any group were: headache, nasopharyngitis and
upper respiratory tract infection. For patients re-randomized from pbo to ONO-4641, AEs that occurred in >10% of
patients in any group were: increased alanine aminotransferase, arthralgia, fatigue, increased gamma-glutamyl
transpeptidase, headache, MS relapse, upper respiratory tract infection and urinary tract infection. SAEs were
reported in 25 patients (pbo/0.05 mg n=5, pbo/0.10 mg n=3, pbo/0.15 mg n=3, 0.05 mg n=7, 0.10 mg n=4, 0.15 mg
n=3); the most common SAE was MS relapse (in 17 patients). Overall, 10 patients withdrew due to AEs.
Conclusion: ONO-4641 was well tolerated during the first 6 months of the DreaMS extension study. The AE profile
was similar to that in the core trial, and no new or unexpected AEs were seen.
The study was funded by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; EMD
Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany; and Ono Pharmaceutical Co.
Ltd, Osaka, Japan. A Bar-Or: speaking, consulting, or grant support for/from Amplimmune, Aventis, Bayhill
Therapeutics, Biogen Idec, Receptos, Berlex, Eli Lilly, Genentech, GlaxoSmithKline, Ono Pharma, Diogenix, Roche,
EMD Serono, Novartis, Teva Neuroscience F Zipp: research grants, consultation funds, or travel compensation from
Teva, Novartis, Merck Serono, Bayer, Johnson & Johnson, Novartis, Ono Pharma, Octapharma, Sanofi T Vollmer:
consulting activities and research grants from Teva, Roche, Daiichi Sankyo, Lilly, Sanofi-Aventis, PRIME Education,
Johnson & Johnson, Projects in Knowledge, Guidepoint Global, Eisai, Biogen Idec, Xenoport, Novartis, ScheringPlough Biopharma, Ono Pharma, Elan, Acorda, Medimmune B Due: employee of ONO Pharma USA, Inc. K
Thangavelu: employee of EMD Serono, Inc. J Johnson: employee of EMD Serono, Inc. K Selmaj: consulting services
for Genzyme, Roche, Synthon, Teva, Novartis, Ono Pharma; speaking engagements for Biogen Idec
26
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Relapse rates in patients with multiple sclerosis receiving ONO-4641, a
sphingosine-1-phosphate receptor-1 and -5 agonist: interim results from an
extension of the DreaMS study
F. Zipp, T. Vollmer, A. Bar-Or, B. Due, K. Thangavelu, T.Z. Fischer, K. Selmaj on behalf of the DreaMS study
investigators
Background: In multiple sclerosis (MS), the entry of autoreactive lymphocytes into the central nervous system is
believed to initiate demyelination and neurodegeneration. Modulation of receptors for sphingosine-1-phosphate (S1P)
can provide therapeutic benefits in MS. ONO-4641 is an oral, non-pro-drug selective S1P receptor-1 and -5 agonist.
The efficacy and safety of ONO-4641 in patients with relapsing–remitting MS have been demonstrated in the 26week, double-blind, randomized, Phase II DreaMS (Drug Research and EvaluAtion in Multiple Sclerosis) study.
Aim: To evaluate MS relapses during the first 6 months of a 225-week extension to the DreaMS study.
Methods: Patients who completed the 26-week core study could participate in the dose-blinded extension, in which
they continued their original dose of ONO-4641 (0.05, 0.10 or 0.15mg) or were re-randomized from placebo to one of
these ONO-4641 doses in a blinded fashion. For patients in the extension, annualized relapse rates (ARRs) were
assessed using Poisson regression over the 6-month core, 6-month extension and combined 1-year periods.
Results: 343 patients entered the extension; 89, 87 and 81 patients continued to receive ONO-4641 0.05, 0.10 or
0.15mg, respectively, and 84 patients originally randomized to placebo subsequently received ONO-4641 0.05mg
(n=29), 0.10mg (n=27) or 0.15mg (n=28). During the core study, ARRs (95% confidence interval [CI]) were: 0.05mg:
0.43 (0.27, 0.66); 0.10mg: 0.16 (0.08, 0.33); 0.15mg: 0.33 (0.19, 0.55); placebo: 0.53 (0.35, 0.79); p=0.005 for
0.10mg versus placebo. ARRs (95% CI) over the 6-month extension were: 0.05mg: 0.13 (0.06, 0.29); 0.10mg: 0.19
(0.09, 0.38); 0.15mg: 0.17 (0.08, 0.35); placebo/0.05mg: 0.33 (0.13, 0.81); placebo/0.10mg: 0.27 (0.10, 0.74);
placebo/0.15mg: 0.15 (0.04, 0.61). When the core and extension periods were considered together, ARRs (95% CI)
over 1 year were: 0.05mg: 0.28 (0.19, 0.41); 0.10mg: 0.17 (0.10, 0.29); 0.15mg: 0.25 (0.16, 0.38). Over this 1-year
period, ARR (95% CI) was higher (p=0.008) in patients first randomized to placebo in the core study then rerandomized to one of the active groups in the extension (0.40 [0.28, 0.55]) versus patients receiving the 0.10mg dose
in both core and extension (0.17 [0.10, 0.29]).
Conclusion: ARRs were low and comparable between groups in patients on continuous active treatment in the
extension, while patients switching from placebo to active treatment in the extension had a dose-dependent decrease
in ARR.
The study was funded by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; EMD
Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany; and Ono Pharmaceutical Co.
Ltd., Osaka, Japan. F Zipp: research grants, consultation funds, or travel compensation from Teva, Novartis, Merck
Serono, Bayer, Johnson & Johnson, Novartis, Ono Pharma, Octapharma, Sanofi T Vollmer: consulting activities and
research grants from Teva, Roche, Daiichi Sankyo, Lilly, Sanofi-Aventis, PRIME Education, Johnson & Johnson,
Projects in Knowledge, Guidepoint Global, Eisai, Biogen Idec, Xenoport, Novartis, Schering-Plough Biopharma, Ono
Pharma, Elan, Acorda, Medimmune A Bar-Or: speaking, consulting, or grant support for/from Amplimmune, Aventis,
Bayhill Therapeutics, Biogen Idec, Receptos, Berlex, Eli Lilly, Genentech, GlaxoSmithKline, Ono Pharma, Diogenix,
Roche, EMD Serono, Novartis, Teva Neuroscience B Due: employee of ONO Pharma USA, Inc. K Thangavelu:
employee of EMD Serono, Inc. TZ Fischer: employee of EMD Serono, Inc. K Selmaj: consulting services for
Genzyme, Roche, Synthon, Teva, Novartis, Ono Pharma; speaking engagements for Biogen Idec
27
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Efficacy of ONO-4641, a potent and selective sphingosine-1-phosphate receptor-1
and -5 agonist, in a preclinical model of multiple sclerosis
F. Bernard, D. Yu, A. Gray, U. Boschert, T. Dellovade, D. Graham (Billerica, US)
Background: ONO-4641 is an oral, non-pro-drug selective sphingosine-1-phosphate receptor-1 and -5 agonist that is
in clinical trials for relapsing forms of multiple sclerosis (RMS). To better understand the therapeutic potential of the
molecule, ONO-4641 is being evaluated in an extensive set of MS animal models.
Aim: To investigate, in a dose-response experiment, the effect of ONO-4641 in a rat model of RMS and to compare
the efficacy of ONO-4641 with teriflunomide, a recently approved therapy.
Methods: Experimental autoimmune encephalomyelitis was induced in female dark agouti rats with myelin
oligodendrocyte glycoprotein (1-125). Rats received daily oral treatment with vehicle, ONO-4641 (0.1, 0.3 or 1.0
mg/kg) or teriflunomide (1.0 or 3.0 mg/kg) starting after the peak of disease. Disease severity was assessed daily
using a standardized, 0–5 clinical score (CS) scale that subjectively measures the level of locomotor deficits. A
relapse was defined as an increase in CS by 1 or more, lasting for at least 24 hours. At the end of the experiment,
brains and spinal cords were collected for histopathological analysis.
Results: In the vehicle-treated group, 100% of rats exhibited a relapse, while this proportion was significantly reduced
by ONO-4641 treatment, with relapses occurring in 11% at 0.1 mg/kg (p<0.05), 20% at 0.3 mg/kg (p<0.001) and 30%
at 1.0 mg/kg (p<0.01). In contrast, the low (1 mg/kg) dose of teriflunomide did not significantly reduce the proportion
of rats relapsing (78%), and efficacy could only be observed in the group dosed at the high (3.0 mg/kg) dose, where
relapses occurred in 22% of rats (p<0.01). Accordingly, mean duration of remission, as compared with vehicle
treatment (6.4 days), was significantly extended in all ONO-4641-treated groups (between 22.4 to 23.1 days,
p<0.001) and in the teriflunomide 3.0 mg/kg group (21.1 days, p<0.001), but not in animals dosed with 1.0 mg/kg
teriflunomide (12.1 days, p>0.05). The reduction or absence of clinical symptoms in ONO-4641-treated rats was
further confirmed by the decreased CNS pathology.
Conclusion: These data extend the preclinical efficacy profile of ONO-4641 by demonstrating efficacy in a preclinical
model of MS at doses as low as 0.1 mg/kg, and indicate that ONO-4641 might offer a new therapeutic option for
treating RMS.
The study was funded by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; and
EMD Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany. Frederic Bernard:
employee of EMD Serono Research & Development Institute. Dongzi Yu: employee of EMD Serono Research &
Development Institute. Audrey Gray: employee of EMD Serono Research & Development Institute. Ursula Boschert:
employee of EMD Serono Research & Development Institute. Tammy Dellovade: employee of EMD Serono
Research & Development Institute. Danielle Graham: employee of EMD Serono Research & Development Institute.
28
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
ONO-4641, a potent and selective sphingosine-1-phosphate receptor-1 and -5
agonist, results in less lymphopenia than fingolimod at effective doses in a
preclinical model of multiple sclerosis
A. Savinainen, S. El Bawab, T. Crandall, R. Chang, U. Boschert, T. Dellovade (Billerica, US; Darmstadt, DE)
Background: Sphingosine-1-phosphate (S1P) receptor-1 is a clinically validated target for the treatment of relapsing
forms of multiple sclerosis (RMS). One mode of action is lymphocyte sequestration within lymph nodes, but additional
mechanisms might be involved in clinical efficacy. ONO-4641, an oral, non-pro-drug selective S1P receptor-1 and -5
agonist, is currently in clinical trials for RMS and has demonstrated efficacy in several preclinical models.
Aim: To compare the efficacy of ONO-4641 versus fingolimod, a non-selective S1P receptor-1, -3, -4, -5 agonist, and
to correlate clinical disease with lymphocyte count in a model of progressive MS.
Methods: Experimental autoimmune encephalomyelitis was induced in non-obese, diabetic mice, and daily oral
dosing with vehicle, ONO-4641 (0.001, 0.01, 0.1 mg/kg) or fingolimod (0.3 mg/kg) was started 40 days post-induction
(dpi). Disease severity was measured using a 0–5 clinical score (CS) scale denoting increasing levels of neurological
disability. To investigate the relationship between CS, lymphopenia, and plasma exposure, extensive
pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed.
Results: At dosing onset, the mean (standard error) CS of all mice was 2.8 (0.04). By 70 dpi, vehicle-treated mice had
reached a mean score of 3.5 (0.17), while mice dosed with ONO-4641 at 0.001, 0.01 and 0.1 mg/kg had an average
CS of 2.4 (0.37), 1.8 (0.45) and 1.2 (0.31), respectively (p<0.05, all doses vs vehicle). Thus, ONO-4641 not only
halted disease progression but also reversed pre-existing deficits. Peripheral lymphocyte counts revealed a dosedependent effect with ONO-4641, resulting in a 16% (0.001 mg/kg), 52% (0.01 mg/kg) and 84% (0.1 mg/kg) reduction
at 70 dpi. Therefore, the lowest dose of ONO-4641 significantly reduced CS in the absence of significant
lymphopenia. Fingolimod 0.3 mg/kg treatment resulted in a profound, 84% reduction in circulating lymphocytes and
corresponding CS decrease. PK/PD modelling confirmed the above observations and quantitatively showed that to
achieve comparable full efficacy, less lymphopenia was required for ONO-4641 (40–50%) compared with fingolimod
(70–80%).
Conclusion: These data indicate that ONO-4641 demonstrates comparable efficacy with less lymphopenia compared
with fingolimod in a preclinical model of MS. Studies are ongoing to better understand the mechanism(s) and
implications of this potentially important differentiating factor between S1P receptor-1, -n agonists.
The study was funded by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; and
EMD Serono, Inc., Rockland, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany. Anneli Savinainen:
employee of EMD Serono Research & Development Institute. Samer El Bawab: employee of Merck Serono Research
& Development, Darmstadt, Germany. Timothy Crandall: employee of EMD Serono Research & Development
Institute. Rui Chang: employee of EMD Serono Research & Development Institute. Ursula Boschert: employee of
EMD Serono Research & Development Institute. Tammy Dellovade: employee of EMD Serono Research &
Development Institute.
29
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunology
Friday, October 04, 2013, 15:30 - 17:00
Evaluation of immunogenicity in multiple sclerosis patients continuously treated
with daclizumab-HYP during the SELECT and SELECTION clinical trials
G. Giovannoni, A. Mikulskis, M. McNeil, K. Riester, M. Sweetser, J. Elkins, L. Amaravadi (London, GB; Cambridge,
US; Maidenhead, GB)
Background: Daclizumab high-yield process (DAC HYP) is a humanised monoclonal antibody currently under
evaluation in a Phase 3 study for treatment of relapsing-remitting multiple sclerosis. The objective of this analysis was
to evaluate the incidence and clinical impact of immunogenicity responses in patients treated with DAC HYP for up to
2 years in the SELECT trial and its extension.
Methods: Subjects who received DAC HYP 150 mg or 300 mg for 2 years of continuous treatment in SELECT and
the extension study were evaluated for anti-drug antibodies (ADA) in serum at 14 timepoints. Binding antibodies were
measured using a validated bridging solution ELISA combined with acid pretreatment of samples. Assay sensitivity
was 40 ng/mL with a drug to antibody tolerance of 25:1. Neutralizing ADAs (NAbs) were measured using a cell-based
electrochemiluminescent assay (sensitivity <400 ng/mL) that measured interference of NAbs with the rutheniumlabeled DAC HYP binding to the IL-2 receptor on Kit225 cells. The relationship between clinical outcomes and
presence of NAbs was evaluated using descriptive statistics.
Results: During the first year of treatment, NAbs developed in 2% of subjects and were typically transient. Of the 6
subjects who developed NAbs by Week 24, only 1 remained positive at the week 52 visit. Among those subjects on
continuous DAC during Year 2, no new patients developed NAbs. ADA rates in the 150-mg and 300-mg continuous
treatment arms were 4% and 2%, respectively, in the first year of treatment and 0% and 3%, respectively, in the
second year of treatment. Although sample size was small, there was no detectable association between the
presence of ADAs or NAbs and MS activity defined by MRI or adverse events.
Conclusion: Immunogenicity to DAC HYP during the 2 year treatment period was low, occurred within the first year of
treatment, and was typically transient. The formation of ADAs (binding antibodies or NAbs) did not impact the safety
or efficacy of DAC HYP in this study.
This analysis was funded by Biogen Idec Inc. The SELECT and SELECTION studies were funded by Biogen Idec
and AbbVie Biotherapeutics Inc. Editorial assistance was provided by Maria Hovenden of UBC Scientific Solutions,
and was supported by Biogen Idec. G. Giovannoni has received research grant support from Bayer Schering
Healthcare, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and Sanofi-Aventis and personal
compensation for participating on advisory boards in relation to clinical trial design, trial steering committees, and
data and safety monitoring committees from Bayer Schering Healthcare, Biogen Idec, Canbex Therapeutics, Eisai,
Elan, Five Prime Therapeutics, Genzyme, Genentech, GSK, Ironwood Pharma, Merck Serono, Novartis, Pfizer,
Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals. A. Mikulskis, M. McNeil, K.
Riester, M. Sweetser, J. Elkins, and L. Amaravadi are full-time employees of Biogen Idec.
30
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Reduction in brain atrophy with extended daclizumab HYP treatment: results of
SELECT and the SELECT extension study
E.W. Radue, D. Stefoski, R. Gold, M. McNeill, K. Riester, J. Elkins (Basel, CH; Chicago, US; Bochum, DE;
Maidenhead, GB; Cambridge, US)
Background: Brain atrophy is accelerated in patients with multiple sclerosis (MS) compared with healthy controls, and
interventions that reduce brain atrophy may have benefits for long-term preservation of clinical function.
Methods: We evaluated the rate of brain atrophy in patients who received 2 years of daclizumab high yield process
(DAC HYP) treatment in SELECT and its extension study using the SIENA method to measure percentage brain
volume change from baseline at the 6-month, 12-month, and 24-month time points. Analyses of whole brain volume
change were adjusted for normalised brain volume at baseline.
Results: During the first 6 months of treatment, there was some evidence for pseudoatrophy in the DAC HYP-treated
patients as there was a trend for a greater increase in whole brain volume loss at 6 months in the DAC HYP 150-mg
group, which had the most active baseline MRI, compared with the placebo group (mean percentage change: DAC
HYP 150 mg [n=198]: -0.41% vs. placebo [n=194]: -0.32%; P=0.064). By month 12, consistent with the resolution of
pseudoatrophy, this trend was no longer apparent and the percentage change in whole brain volume was similar in
the DAC HYP 150-mg group and placebo group (mean percentage change: DAC HYP [n=198]: -0.79% vs. placebo
[n=194]: -0.74%; P=0.326) During the second year of DAC HYP therapy, the percentage change in whole brain
volume was reduced by 24% compared with the first year of DAC HYP treatment (combined DAC HYP groups
[n=250] Year 2: -0.53% vs. combined DAC HYP groups [n=257] Year 1: -0.70%; P=0.021) and by 27% compared
with the 1-year change in the placebo group (combined DAC HYP groups [n=250] Year 2: -0.53% vs. placebo
[n=162] Year 1: -0.73%; P=0.01).
Conclusions: These findings indicate that extended treatment with DAC HYP may result in a reduction in the rate of
brain atrophy in MS patients consistent with long-term neuroprotection.
This study was funded by Biogen Idec and AbbVie Biotherapeutics. Editorial assistance was provided by Alison
Gagnon of UBC Scientific Solutions, which was supported by Biogen Idec and AbbVie Biotherapeutics. Ernst-Wilhelm
Radue has received research support (mainly for MS projects) and lecture fees from: Actelion, Basilea, Bayer
Schering, Biogen Idec, Merck Serono, Novartis and others. Lecture fees have been mainly used for research funding
at the Medical Image Analysis Center (former MS MRI Evaluation Center), University Hospital Basel. Dusan Stefoski
has received research funding and support, and speaker bureau honoraria from: Biogen Idec, EMD Serono, Teva,
Pfizer, Elan, and Novartis. Ralf Gold has received speakers’ honoraria and research grant support from Bayer
Schering Healthcare, Biogen Idec, Merck Serono, Merz, Novartis, Teva and sanofi-aventis. Dr Gold has received
compensation for Advisory Board activities from Biogen Idec, Merck Serono, Novartis and TEVA. Manjit McNeill is a
full-time employee of Biogen Idec. Katherine Riester is a full-time employee of Biogen Idec. Jacob Elkins is a full-time
employee of Biogen Idec.
31
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Effect of BG-12 (dimethyl fumarate) on freedom from measured clinical and
neuroradiological disease activity over time in patients with relapsing remitting
multiple sclerosis: results from the phase 3 studies
E. Havrdova, R. Gold, R.J. Fox, L. Kappos, J.T. Phillips, A. Zhang, N.C. Kurukulasuriya, S.I. Sheikh, V. Viglietta, G.
Giovannoni (Prague, CZ; Bochum, DE; Cleveland, US; Basel, CH; Dallas, Weston, US; London, GB)
Background: In the Phase 3 DEFINE and CONFIRM studies, BG-12 (dimethyl fumarate) demonstrated significant
clinical and neuroradiological efficacy over 2 years vs placebo in relapsing–remitting multiple sclerosis (RRMS)
patients. Here we report a post hoc analysis of the effect of BG-12 on the proportion of patients free of measured
clinical and/or neuroradiological disease activity in the integrated DEFINE and CONFIRM data set.
Methods: Treated patients randomized to oral BG-12 240 mg twice (BID) or three times daily (TID) or placebo were
included in the integrated analysis, which was to be conducted only if baseline characteristics and treatment effects
were homogeneous across the studies. Absence of clinical disease activity (no relapses and no Expanded Disability
Status Scale [EDSS] progression over 2 years) was analysed in the intent-to-treat (ITT) population. Absence of
neuroradiological (no new/enlarging T2 and no gadolinium-enhancing lesions over 2 years) and overall disease
activity (no measured clinical or neuroradiological disease activity over 6 months, 1 year, or 2 years) were analysed in
the magnetic resonance imaging (MRI) cohort. Freedom from overall disease activity at 2 years was analysed in
patient subgroups stratified by age, gender, treatment history, prior relapses, and EDSS score at baseline.
Results: The ITT population for the integrated analysis comprised 2,301 patients, including 1,046 patients in the MRI
cohort. In the BG-12 BID and TID vs placebo groups at 2 years, the proportion of patients free of clinical disease
activity was 69% and 71% vs 53%; the proportion free of neuroradiological activity was 34% and 35% vs 20%; and
the proportion free of overall disease activity was 23% and 23% vs 11% (all p<0.0001). The proportion of patients
free of overall disease activity at 6 months was 40% in both the BG-12 BID and TID groups vs 23% with placebo
(both p<0.0001) and the proportion at 1 year was 34% and 31% in the BID and TID groups vs 18% with placebo
(p<0.0001 and p=0.0004, respectively). Benefits of BG-12 on the proportion of patients free of overall disease activity
at 2 years were generally consistent across patient subgroups with different baseline characteristics.
Conclusion: These post hoc analyses demonstrate that BG-12 significantly increased the proportions of RRMS
patients free of measured clinical, neuroradiological and overall disease activity vs placebo over time in the Phase 3
studies.
EH: honoraria from Bayer, Biogen Idec, Genzyme, Novartis, Serono, and Teva; research support from the Czech
Ministry of Education (MSM 0021620849, PRVOUK-P26/LF1/4). RG: honoraria from Bayer HealthCare, Biogen Idec,
Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck
Serono, Novartis, and Teva Neuroscience. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis,
Questcor, and Teva; grant and research support from Novartis. LK: research support from Acorda, Actelion, Allozyne,
BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim, Eisai, Elan,
European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck Serono,
Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Shire,
Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. JTP: honoraria from
Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research support from Biogen Idec and Roche. AZ, NCK, SIS,
VV: employees of Biogen Idec. GG: honoraria from Bayer HealthCare, Biogen Idec, Canbex, Genzyme,
GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, and
UCB; research support from Biogen Idec, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier
as Co-Chief Editor of MS and Related Disorders. GG: honoraria from Bayer HealthCare, Biogen Idec, Canbex,
Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva
Neuroscience, and UCB; research support from Biogen Idec, Ironwood, Merck Serono, Merz, and Novartis;
compensation from Elsevier as Co-Chief Editor of MS and Related Disorders.
32
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Treatment of specific symptoms
Thursday, October 03, 2013, 15:45 - 17:00
Effect of Aspirin pretreatment or slow dose titration on the incidence and severity
of flushing and gastrointestinal events associated with BG-12 (dimethyl fumarate)
J. O'Gorman, H. Russell, J. Li, G. Phillips, C. Hotermans, N. C. Kurukulasuriya, V. Viglietta (Weston, Cambridge, US)
Background: In Phase 3 trials, flushing and GI events were common AEs with BG-12. An 8-week, Phase 3b study in
healthy volunteers evaluated the effect of aspirin (ASA) 325 mg pretreatment or BG-12 slow dose titration (SDT) on
the incidence and severity of these events.
Methods: Subjects were randomized to 4 groups. PBO/PBO received placebo ASA 30 min prior to placebo BG-12 in
weeks 1-8. PBO/BG-12 received placebo ASA 30 min prior to BG-12 in weeks 1-4, then BG-12 alone in weeks 5-8.
ASA/BG-12 received ASA 30 min prior to BG-12 in weeks 1-4, then BG-12 alone in weeks 5-8. In both groups, BG-12
was dosed at 120 mg BID in week 1 and 240 mg BID in weeks 2-8. PBO/SDT received placebo ASA 30 min prior to
BG-12 in weeks 1-4, then BG-12 alone in weeks 5-8. BG-12 was dosed at 120 mg QD (week 1), 120 mg BID (week
2), 240 mg in the morning/120 mg at night (week 3), and 240 mg BID (weeks 4-8). Flushing (redness, warmth,
tingling, itching) and GI events (nausea, diarrhea, upper and lower abdominal pain, vomiting, indigestion,
constipation, bloating, flatulence) were rated in an eDiary using 4 tolerability scales (0-10 scale: 0=none; 1-3=mild; 46=moderate; 7-9=severe; 10=extreme) for severity in past 24 hours and daily after each dose administration.
Results: 173 subjects were randomized; 172 were dosed. Study drug compliance was high (97.8-99%). No subject
discontinued due to flushing events; 1 (PBO/PBO), 3 (PBO/BG-12), 6 (ASA/BG-12), and 2 (PBO/SDT) discontinued
due to GI events. Over the first 4 weeks, 41% (PBO/PBO), 86% (PBO/BG-12), 72% (ASA/BG-12), and 98%
(PBO/SDT) of subjects experienced flushing events, and 66% (PBO/PBO), 81% (PBO/BG-12), 79% (ASA/BG-12),
and 79% (PBO/SDT) of subjects experienced GI events. The mean worst flushing severity scores in weeks 1-4 were
1.2 (PBO/PBO), 4.4 (PBO/BG-12), 2.4 (ASA/BG-12), and 5.6 (PBO/SDT) and the mean worst severity scores across
the nine individual GI events in weeks 1-4 were 0.2-1.3 (PBO/PBO), 0.3-1.8 (PBO/BG-12), 0.3-1.7 (ASA/BG-12), and
0.2-1.6 (PBO/SDT).
Conclusion: Flushing and GI events were relatively common and reported as mild to moderate (flushing) and mild
(GI). No subject discontinued due to flushing. ASA reduced the incidence and severity of flushing events and did not
appear to worsen GI symptoms, although slightly more patients discontinued because of GI events in the ASA/BG12
group. SDT appeared to have no effect. These results suggest that flushing and GI events with BG-12 are mild or
moderate and tolerable.
Supported by: Biogen Idec Inc. JO: employee of Biogen Idec. HR: employee of PROMETRIKA LLC JL, GP, VV:
employees of Biogen Idec.
33
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Management strategies for fushing and gastrointestinal events associated with
BG-12 (dimethyl fumarate): expert panel recommendations
J. T. Phillips, M. Hutchinson, R. Fox, R. Gold, E. Havrdova (Dallas, US; Dublin, IE; Cleveland, US; Bochum, DE;
Prague, CZ)
Background: In the Phase 3 DEFINE and CONFIRM trials, common adverse events (AEs) associated with oral BG12 included flushing and gastrointestinal (GI) events. The incidence of these events was highest in the first month of
treatment and the severity was mild or moderate for most patients with events. The rate of BG-12 discontinuation due
to these AEs was relatively low, indicating that AEs were effectively managed in a clinical trial setting. The aim of this
survey was to further understand management strategies for flushing and GI events in the Phase 3 clinical trials and
identify potential strategies for use in clinical practice.
Methods: Using the Delphi process, a questionnaire was developed to characterize and identify effective approaches
for managing patients experiencing flushing or GI events in the clinical setting. Eligible investigators had at least 10
patients in DEFINE or CONFIRM.
Results: Of 84 eligible investigators, 50 agreed to participate and 30 completed the questionnaire. Participating
investigators enrolled a mean of 12.7 patients across all treatment groups. Patients of these participating
investigators represented approximately 20% of the total BG-12 study population in DEFINE and CONFIRM, and 377
patient-years of BG-12 exposure. The patient population represented by investigators who completed the survey was
similar to the patient populations of DEFINE and CONFIRM. The percentage of investigators indicating they had at
least one patient with an event was 93.3% (flushing), 70% (nausea/vomiting), 40% (abdominal pain), and 36.7%
(diarrhea). Most investigators considered it at least somewhat important to manage these events. Various flushing
and GI AE management strategies used in the studies will be reviewed. Less than half of the investigators indicated
they had used dose reduction or interruption. Recommended management strategies for clinical practice included
setting patient expectations prior to initiating treatment and taking BG-12 with food (all events); aspirin and
antihistamines (flushing); antiemetics (nausea/vomiting); proton pump inhibitors and H2 receptor antagonists
(abdominal pain); and antidiarrheals (diarrhea).
Conclusion: This survey provides experience-based guidance on the management of flushing and GI events in BG12-treated patients that may be helpful in real-world practice. Future studies prospectively evaluating the efficacy of
these management strategies are warranted.
Supported by: Biogen Idec Inc. JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research
support from Biogen Idec and Roche. MH: honoraria from Bayer Schering, Biogen Idec, and Novartis; editorial fees
from the Multiple Sclerosis Journal; research grants from the Health Research Board, Ireland and Dystonia Ireland.
RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva; grant and research support
from Novartis. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience;
research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. EH:
honoraria from Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, Merck, Novartis, Sanofi, Serono, and Teva.
34
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
4-year follow-up of oral BG-12 (dimethyl fumarate) treatment in relapsing
remitting multiple sclerosis (RRMS): integrated clinical efficacy data from the
DEFINE, CONFIRM, and ENDORSE studies
R. Gold, J. T. Phillips, A. Bar-Or, M. Hutchinson, L. Kappos, R. Zhang, M. Yang, V. Viglietta, S. I. Sheikh, R. J. Fox
(Bochum, DE; Dallas, US; Montreal, CA; Dublin, IE; Basel, CH; Weston, Cleveland, US)
Background: BG-12 (dimethyl fumarate) demonstrated efficacy and safety in RRMS in the 2-year, Phase 3 DEFINE
and CONFIRM studies. Here we report interim clinical efficacy outcomes from ENDORSE, an ongoing, 5-year, doseblind extension of DEFINE and CONFIRM.
Methods: Patients previously randomized to BG-12 240 mg twice (BID) or three times daily (TID) in
DEFINE/CONFIRM continued on the same dose in ENDORSE. Patients treated with placebo (PBO)
(DEFINE/CONFIRM) or glatiramer acetate (GA) (CONFIRM) were randomized 1:1 to BG-12 240 mg BID or TID.
Efficacy was analyzed (cutoff date 01 May 2012) according to treatment received in parent/extension study (eg,
BID/BID, TID/TID).
Results: Of 2,651 patients initially randomized and dosed, 2,079 completed DEFINE/CONFIRM and 1,736 were
dosed in ENDORSE (n=501 [BID/BID], 502 [TID/TID], 249 [PBO/BID], 248 [PBO/TID], 118 [GA/BID], and 118
[GA/TID]). Among them, 436 (BID/BID), 439 (TID/TID), 188 (PBO/BID), 192 (PBO/TID), 87 (GA/BID), and 74
(GA/TID) completed 1 year at cutoff. BID/BID and TID/TID groups showed consistent efficacy over 3 years (2 years in
DEFINE/CONFIRM; 1 year in ENDORSE): adjusted annualized relapse rate (ARR) (and 95% confidence interval [CI])
in Years 1, 2 and 3: 0.202 (0.162–0.252), 0.163 (0.128–0.208) and 0.134 (0.101–0.178) for BID/BID, and 0.239
(0.195–0.294), 0.123 (0.094–0.162) and 0.162 (0.124–0.212) for TID/TID, respectively; Kaplan–Meier estimate of
proportion relapsed at 3 years was 31.4% (27.5–35.6%) and 31.0% (27.1–35.2%), respectively. For patients
switching treatment in ENDORSE from PBO, ARR (95% CI) in Year 3 (first year of BG-12 treatment) was 0.167
(0.115–0.245) for PBO/BID, and 0.116 (0.076–0.177) for PBO/TID. Disability progression results will be presented.
Conclusion: BG-12 demonstrated consistent efficacy over 3 years of treatment. Together with an acceptable safety
profile, these results support the potential for BG-12 to be a long-term treatment option for MS.
Supported by: Biogen Idec Inc. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and
Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva
Neuroscience. JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research support from
Biogen Idec and Roche. ABO: honoraria or research support from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec,
BioMS, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Medimmune, Merck Serono, Novartis,
Ono Pharmacia, Receptos, Roche, Sanofi Aventis, Teva Neuroscience, and Wyeth. MH: honoraria from Bayer
Schering, Biogen Idec, and Novartis; editorial fees from the Multiple Sclerosis Journal; research grants from the
Health Research Board, Ireland and Dystonia Ireland. LK: research support from Acorda, Actelion, Allozyne,
BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim, Eisai, Elan,
European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck Serono,
Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Shire,
Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience, UCB, and Wyeth. RZ, MY, VV, SIS:
employees of Biogen Idec. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva;
grant and research support from Novartis.
35
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Flushing and gastrointestinal tolerability events in relapsing remitting multiple
sclerosis (RRMS) patients treated with oral BG-12 dimethyl fumarate) in the phase
3 DEFINE and CONFIRM trials
K. Selmaj, R. Gold, R. J. Fox, E. Havrdova, G. Giovannoni, A. Pace, M. Novas, L. Meltzer, C. Hotermans, V. Viglietta,
J. T. Phillips (Lodz, PL; Bochum, DE; Cleveland, US; Prague, CZ; London, GB; Weston, Dallas, US)
Background: BG-12 demonstrated an acceptable safety profile in the Phase 3 DEFINE and CONFIRM trials.
Common AEs included flushing and GI events. To further investigate these tolerability events, a post-hoc, integrated
analysis of the Phase 3 trials was conducted focusing on the initial treatment period (months 0-3) with the
recommended dosing of BG-12 (240 mg twice daily [BID]).
Methods: Incidence, nature, severity, and management of flushing and GI events were summarized for BG-12 240
mg BID versus placebo. AEs were recorded at scheduled clinic visits occurring every 4 weeks. Use of symptomatic
therapy and dose reduction were permitted to manage tolerability issues. Treatment of flushing and GI events with
symptomatic therapies was evaluated by manual review of concomitant medications temporally associated with and
indicated for each event.
Results: A total of 1,540 patients (safety population) were randomized and received treatment with placebo (n=771)
or BG-12 BID (n=769), with 65% and 70%, respectively, completing 2 years of study treatment. The incidence of
flushing and GI events was highest in the first month of treatment, declining thereafter. In months 0-3, the incidence
of GI events was 17% (placebo) and 27% (BG-12) and of flushing events was 4% (placebo) and 32% (BG-12). The
percentage of patients who experienced GI or flushing events in months 0-3 and discontinued study treatment at any
time was <1% (placebo) and 3% (BG-12) for GI events and 0% (placebo) and 2% (BG-12) for flushing events. The
percentage of patients who experienced GI or flushing events in months 0-3 and used symptomatic treatment was
4% (placebo) and 11% (BG-12) for GI events and <1% (placebo) and 2% (BG-12) for flushing events. The most
common GI events in months 0-3 in BG-12-treated patients were nausea (9%), diarrhea (9%), upper abdominal pain
(7%), abdominal pain (7%), and vomiting (5%). Most GI and flushing events were of mild or moderate severity (9196% and 97%, respectively) and resolved during the study (93-96% and 76%, respectively). The events were
temporally associated with the use of diverse symptomatic therapies (efficacy not assessed).
Conclusion: The integrated analysis indicates that, in a clinical trial setting, flushing and GI events associated with
BG-12 treatment are mild to moderate for the vast majority of events, are manageable, and rarely lead to treatment
discontinuation.
Supported by: Biogen Idec Inc. KS: compensation for consulting services from Genzyme, Novartis, Ono, Roche,
Synthon, and Teva, and compensation for speaking from Biogen Idec. RG: honoraria from Bayer HealthCare, Biogen
Idec, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck
Serono, Novartis, and Teva Neuroscience. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis,
Questcor, and Teva; grant and research support from Novartis. EH: honoraria from Bayer, Biogen Idec, Genzyme,
GlaxoSmithKline, Merck, Novartis, Sanofi, Serono, and Teva. GG: honoraria from Abbvie, Bayer HealthCare, Biogen
Idec, Canbex, Genzyme, GlaxoSmithKline, GW Pharma, FivePrime, Medimmune, Merck Serono, Novartis, Protein
Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB and Vertex; research support from Biogen Idec,
Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as Co-Chief Editor of MS and Related
Disorders. AP, MN, LM, CH: employees of Biogen Idec. JTP: honoraria from Acorda, Biogen Idec, Genzyme,
Novartis, and Teva; research support from Biogen Idec, and Roche.
36
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Clinical efficacy of BG-12 (dimethyl fumarate) for relapsing remitting multiple
sclerosis according to prior therapy: an integrated analysis of the phase 3
DEFINE and CONFIRM studies
M. Hutchinson, R. Gold, R. J. Fox, E. Havrdova, G. Giovannoni, A. Zhang, C. Hotermans, M. Stephan, A. Bar-Or
(Dublin, IE; Bochum, DE; Cleveland, US; Prague, CZ; London, GB; Weston, US; Montreal, CA)
Background: Oral BG-12 (dimethyl fumarate) demonstrated strong positive efficacy and an acceptable safety profile
in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. A posthoc, integrated analysis of DEFINE and CONFIRM, contingent upon homogeneous baseline characteristics and
treatment effects across studies, was conducted to evaluate the clinical efficacy of BG-12 according to prior treatment
with one or any number of approved interferon beta-1a/b (IFN) or glatiramer acetate (GA) treatments (ABCR).
Methods: Eligible patients were aged 18-55 years and had a diagnosis of RRMS per McDonald criteria and an
Expanded Disability Status Scale (EDSS) score of 0-5.0, inclusive. Patients were randomized to receive placebo, BG12 240 mg twice (BID) or three times daily (TID), or subcutaneous GA (a reference comparator; CONFIRM only).
Primary endpoints at 2 years were the proportion of patients relapsed (DEFINE) and annualized relapse rate
(CONFIRM).
Results: The integrated intent-to-treat (ITT) population comprised 771, 769, and 761 patients assigned to placebo,
BG-12 BID, and BG-12 TID, respectively, of whom 221, 202, and 193 had received treatment with any number of
approved ABCR therapy(s) and 164, 155, and 145 had received one prior ABCR. BG-12 BID and TID showed a
consistent positive effect on clinical outcomes over 2 years versus placebo. Rate ratios (95% confidence intervals) for
reductions in annualized relapse rate with BG-12 BID and TID, respectively, versus placebo at 2 years were as
follows: any prior ABCR, 0.60 (0.43-0.82) and 0.48 (0.34-0.68); one prior ABCR, 0.60 (0.42-0.85) and 0.41 (0.280.61).
Conclusion: The integrated analysis indicates consistent clinical efficacy of both BG-12 dosing regimens in RRMS
patients previously treated with one or any number of ABCR therapies. The findings mirror the results reported for the
overall DEFINE and CONFIRM study populations evaluated in the integrated analysis.
Supported by: Biogen Idec Inc. MH: honoraria from Bayer Schering, Biogen Idec, and Novartis; editorial fees from the
Multiple Sclerosis Journal; research grants from the Health Research Board, Ireland and Dystonia Ireland. RG:
honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience; research support
from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. RJF: consultant fees from
Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva; grant and research support from Novartis. EH:
honoraria from Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, Merck, Novartis, Sanofi, Serono, and Teva. GG:
honoraria from Abbvie, Bayer HealthCare, Biogen Idec, Canbex, Genzyme, GlaxoSmithKline, GW Pharma,
FivePrime, Medimmune, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva
Neuroscience, UCB and Vertex; research support from Biogen Idec, Ironwood, Merck Serono, Merz, and Novartis;
compensation from Elsevier as Co-Chief Editor of MS and Related Disorders. AZ, CH, MS: employees of Biogen
Idec. ABO: honoraria or research support from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix,
Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Medimmune, Merck Serono, Novartis, Ono Pharmacia,
Receptos, Roche, Sanofi Aventis, Teva Neuroscience, and Wyeth.
37
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Quality of life
Thursday, October 03, 2013, 15:45 - 17:00
Health-related quality of life in relapsing remitting multiple sclerosis (RRMS)
patients treated with placebo or BG-12 (dimethyl fumarate): comparison with
other medical conditions
S. Sarda, G. Phillips, J. A. Gaebler, N. C. Kurukulasuriya (Weston, US)
Background: BG-12 demonstrated clinical and neuroradiological efficacy in the Phase 3 DEFINE and CONFIRM
studies. MS patients often experience increasingly impaired HRQoL as the disease progresses; hence, it is useful to
assess health-related quality of life (HRQoL) when evaluating potential treatments. We examined the impact of MS
and other medical conditions on HRQoL (measured by the Short Form-36 version 1 [SF-36v1]) and the effect of BG12 on HRQoL over 2 years in a prespecified, integrated analysis of DEFINE and CONFIRM.
Methods: The SF-36 consists of 8 multi-item domains (physical functioning [PF], role-physical [RP], bodily pain [BP],
general health [GH], vitality [VT], social functioning [SF], role-emotional [RE], and mental health [MH]). PF, RP, BP,
and GH assess physical aspects of HRQoL (Physical Component Summary [PCS]) and VT, SF, RE, and MH assess
mental aspects (Mental Component Summary [MCS]). Normative mean domain scores for hypertension, congestive
heart failure, diabetes type II, recent acute myocardial infarction, and clinical depression were obtained from the SF36v1 Manual. RRMS patients (aged 18-55 years; EDSS 0-5.0) were randomized to receive placebo, BG-12 240 mg
twice (BID) or three times daily (TID), or glatiramer acetate (reference comparator; CONFIRM only) for up to 96
weeks. The SF-36v1 was administered at baseline and 6, 12, and 24 months.
Results: The US general population mean score for PCS and MCS is 50. In the RRMS patients, across the placebo,
BID, and TID groups, mean baseline score ranges were 43.0-43.4 (PCS) and 45.0-45.3 (MCS); mean baseline
domain score ranges were 67.1-68.9 (PF), 55.0-55.8 (RP), 68.5-68.6 (BP), 53.2-53.9 (GH), 49.2-49.8 (VT), 69.5-70.4
(SF), 63.3-64.4 (RE), and 65.0-65.1 (MH). Domain score ranges across the five other medical conditions were 47.573.4 (PF), 34.4-62.0 (RP), 58.8-72.8 (BP), 47.1-63.3 (GH), 40.1-58.3 (VT), 57.2-86.7 (SF), 38.9-76.7 (RE), and 46.377.9 (MH). BG-12-treated patients reported no change or improvement from baseline in all domains except RE (BID
group); placebo-treated patients reported reductions. Improvements vs placebo were significant on all domains
except BP (BID group) and VT (TID group).
Conclusion: The disease burden of MS is high compared with the US general population and other medical
conditions, which tend to affect individual HRQoL domains relatively selectively. Benefits of BG-12 on patientreported HRQoL further support the use of BG-12 in relapsing MS.
Supported by: Biogen Idec Inc. SPS, GP, JAG, NCK: employees of Biogen Idec.
38
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Others
Friday, October 04, 2013, 15:30 - 17:00
Efficacy of oral fingolimod versus dimethyl fumarate on measures of freedom
from disease activity in patients with multiple sclerosis, based on indirect
comparisons of phase 3 trials
N. Bergvall, R. Nixon, D. Tomic, N. Sfikas, G. Cutter, G. Giovannoni (Basel, CH; Alabama, US; London, GB)
Background: There is much interest in the comparative efficacy of two oral therapies, fingolimod and dimethyl
fumarate (DMF; BG-12). With no head-to-head data, simple endpoint comparisons can be confounded by differences
in patient populations and endpoint definitions between trials, as demonstrated by a recent indirect comparison of
fingolimod and natalizumab.
Aim: To compare the efficacy of fingolimod and DMF on measures of freedom from disease activity using statistical
modeling to account for differences between trials.
Methods: Freedom from disease activity was evaluated as the proportion of patients free from relapses and 3-month
confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly
enlarged T2 lesions (magnetic resonance imaging [MRI] composite), or free from all disease measures (overall
composite). Freedom from disease activity on the individual component measures was also assessed. Individual
patient data from the fingolimod phase 3 trials, FREEDOMS and FREEDOMS II (pooled by including a study level
stratifying variable) were used to build binomial regression models that represented endpoints as a function of
baseline characteristics. Analyses controlled for differences in endpoint definitions and methods of dealing with noncompleters. Models predicted the indirect relative risk (RR) of freedom from disease activity for fingolimod vs DMF in
an average patient from the DMF phase 3 trials DEFINE and CONFIRM (pooled by fixed-effect inverse varianceweighted method).
Results: In unadjusted comparisons, the RR for fingolimod vs placebo in the FREEDOMS trials was numerically
greater (i.e. fingolimod more efficacious) than those for DMF vs placebo in DEFINE and CONFIRM for all composite
measures of freedom from disease activity. In adjusted comparisons, the predicted RR of freedom from disease
activity was significantly greater for fingolimod vs DMF twice daily for all composite measures in a pooled DEFINE
and CONFIRM population (clinical: 1.21, 95% CI, 1.06–1.38; MRI: 1.52, 1.11–2.07; overall: 1.56, 1.01–2.42). The
corresponding RRs for fingolimod vs DMF three times daily were similar (clinical: 1.18, 1.03–1.34; MRI: 1.59, 1.16–
2.18; overall: 1.59, 1.02–2.47).
Conclusions: Fingolimod has greater efficacy than DMF for composite measures of freedom from disease activity in
both unadjusted and adjusted indirect comparisons. These results should ideally be confirmed in head-to-head
clinical trials.
Analyses were funded by Novartis Pharma AG, Basel, Switzerland. Niklas Bergvall is an employee of Novartis
Pharma AG, Basel, Switzerland. Richard Nixon is an employee of Novartis Pharma AG, Basel, Switzerland. Davorka
Tomic is an employee of Novartis Pharma AG, Basel, Switzerland. Nikolaos Sfikas is an employee of Novartis
Pharma AG, Basel, Switzerland. Gary Cutter has received personal compensation for participation in Data and Safety
Monitoring Committees for Sanofi-Aventis, Cleveland Clinic, Daiichi Sankyo, GlaxoSmithKline Pharmaceuticals,
Genmab, Eli Lilly, Medivation, Modigenetech, Ono Pharmaceutical, PTC Therapeutics, Teva Pharmaceuticals, Vivus,
University of Pennsylvania, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and
Stroke, and National Multiple Sclerosis Society. He has also received consulting and speaking fees, and served on
advisory boards for Alexion Pharmaceuticals, Bayhill Therapeutics, Bayer Pharmaceuticals, Celgene, Novartis,
Consortium of Multiple Sclerosis Centers (grant), Genzyme, Klein Buendel Inc., Nuron Biotech,Peptimmune, Somnus
Therapeutics, Sandoz, Teva Pharmaceuticals, University of Texas Southwestern, and Visioneering Technologies Inc.
He is President of Pythagoras Inc. and has received Consortium of Multiple Sclerosis Centers task orders that involve
research for various pharmaceutical organizations. Gavin Giovannoni has received honoraria from Bayer HealthCare,
Biogen Idec, Canbex, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Roche,
Synthon, Teva Neuroscience, and UCB; research support from Biogen Idec, Ironwood, Merck Serono, Merz, and
Novartis; and compensation from Elsevier as co-chief editor of MS and Related Disorders.
39
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Quality of life
Friday, October 04, 2013, 15:30 - 17:00
Interim analysis of quality of life in patients with relapsing remitting multiple
sclerosis treated with BG-12 (dimethyl fumarate) in the ENDORSE study
M. Kita, R.J. Fox, R. Gold, G. Giovannoni, J.T. Phillips, S.P. Sarda, J. Kong, R. Zhang, V. Viglietta, S.I. Sheikh, L.
Kappos (Seattle, Cleveland, US; Bochum, DE; London, GB; Dallas, Weston, US; Basel, CH)
Background: Efficacy and safety of oral BG-12 for the treatment of relapsing–remitting multiple sclerosis (RRMS) was
demonstrated in two Phase 3, placebo-controlled studies (DEFINE and CONFIRM). Here we present interim analysis
of health-related quality of life (HRQoL) data from ENDORSE, an ongoing, 5-year, dose-blind extension of the
DEFINE and CONFIRM studies.
Methods: Patients randomized to BG-12 240 mg twice (BID) or three times daily (TID) in DEFINE and CONFIRM
continued the same dose regimen in ENDORSE. Placebo patients (DEFINE/CONFIRM) and glatiramer acetate
patients (CONFIRM) were randomized 1:1 to blinded treatment with BG-12 BID or TID. Measures of HRQoL
included: the Short Form-36 (SF-36) Physical and Mental Component Summary (PCS/MCS) scales and the
EuroQoL-5D (EQ-5D). For all scales, higher scores indicated better HRQoL. Baseline was defined as the baseline of
the parent studies, DEFINE and CONFIRM
Results: In the integrated analyses of DEFINE and CONFIRM, which included 769, 761, and 771 patients assigned to
BG-12 BID, TID, and placebo, respectively, physical and mental health functioning were significantly improved with
BG-12 vs placebo. At 2 years, mean SF-36 PCS scores increased from baseline by 0.47 (BID) and 0.43 (TID) vs a
reduction of -1.05 (placebo) (both p<0.0001), and SF-36 MCS scores increased by 0.31 (BID) and 0.63 (TID) vs a
reduction of -0.60 (placebo) (p=0.0246 and p=0.0107, respectively). The intent-to-treat population of patients
continuing BG-12 in ENDORSE (N=1,003) included 501 (BID/BID) and 502 (TID/TID) patients who showed a
consistent improvement trend at 2 years in DEFINE and CONFIRM. At 3 years (1 year in ENDORSE), mean change
from DEFINE/CONFIRM baseline in SF-36 PCS scores for patients continuing on BG-12 was 0.96 (BID/BID) and
0.11 (TID/TID). Corresponding changes in MCS scores were 0.74 (BID/BID) and 0.33 (TID/TID). For the EQ-5D index
score, mean change from baseline was 0.01 (BID/BID) and 0.01 (TID/TID).
Conclusion: In this 3-year follow-up interim analysis, HRQoL assessed by SF-36 PCS and MCS scores showed slight
increases in patients who continued to receive BG-12 after the parent studies. Slight increases from baseline were
also seen in EQ-5D scores. These results suggest that HRQoL in patients treated with BG-12 remains relatively
stable over time. Assessments of HRQoL in patients in the ENDORSE study are ongoing.
MK: research support from Biogen Idec. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor,
and Teva; grant and research support from Novartis. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck
Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono,
Novartis, and Teva Neuroscience. GG: honoraria from Bayer HealthCare, Biogen Idec, Canbex, Genzyme,
GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, and
UCB; research support from Biogen Idec, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier
as Co-Chief Editor of MS and Related Disorders. JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and
Teva; research support from Biogen Idec, and Roche. SPS, JK, VV, SIS: employees of Biogen Idec. LK: research
support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen
Idec, Boehringer Ingelheim, Eisai, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline,
Glenmark, MediciNova, Merck Serono, Novartis, Novartis Research Foundation, Roche, Roche Research
Foundation, Sanofi-Aventis, Santhera, Shire, Swiss MS Society, Swiss National Research Foundation, Teva
Neuroscience, UCB, and Wyeth. Supported by: Biogen Idec Inc.
40
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Safety profile of BG-12 (dimethyl fumarate) in relapsing remitting multiple
sclerosis: long-term interim results from the ENDORSE extension study
J.T. Phillips, R.J. Fox, K. Selmaj, R. Zhang, M. Novas, M.T. Sweetser, V. Viglietta, R. Gold (Dallas, Cleveland, US;
Lodz, PL; Weston, US; Bochum, DE)
Background: The efficacy and safety of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple
sclerosis (MS) was demonstrated in the 2-year, Phase 3 studies, DEFINE and CONFIRM. Here we report updated
safety results from ENDORSE, an ongoing 5-year extension of DEFINE and CONFIRM.
Methods: Patients previously randomized to BG-12 240 mg twice (BID) or three times daily (TID) continued on the
same dose in ENDORSE. Those randomized to placebo (PBO; DEFINE and CONFIRM) or glatiramer acetate (GA;
CONFIRM) were re-randomized 1:1 to BG-12 240 mg BID or TID. Adverse events (AEs) were analysed according to
treatment received in the parent/extension study: BID/BID, TID/TID, PBO/BID, PBO/TID, GA/BID, and GA/TID.
Results: As of 30 March 2012 database lock, the overall incidences of AEs in each group were: 80% BID/BID
(n=501), 82% TID/TID (n=501), 85% PBO/BID (n=249), 84% PBO/TID (n=248), 75% GA/BID (n=118), and 79%
GA/TID (n=119). The incidences of serious AEs were: 10% BID/BID, 12% TID/TID, 16% PBO/BID, 9% PBO/TID, 8%
GA/BID, and 10% GA/TID. The most frequent AEs (>=10% in any group) were MS relapse and nasopharyngitis in the
BID/BID and TID/TID groups, and flushing, MS relapse, nasopharyngitis, diarrhea, and upper abdominal pain in
patients new to BG-12 treatment in ENDORSE. Discontinuations due to AEs were: 2% BID/BID, 4% TID/TID, 14%
PBO/BID, 15% PBO/TID, 10% GA/BID, and 22% GA/TID. The incidence of serious infections was <=2% in all
treatment groups and there were no confirmed opportunistic infections. Lymphocyte counts <0.5 x 10^9 cells/L were
observed in 4–7% of patients in the BID/BID and TID/TID groups, and 2–4% of patients in the groups new to BG-12
treatment in ENDORSE. Hepatic AEs were <=2% in all treatment groups and elevations from baseline in liver
transaminases were consistent with the findings from DEFINE and CONFIRM. There was no evidence of an
increased risk of renal or urinary events in patients continuing BG-12 treatment or those new to BG-12 in ENDORSE.
There were 14 malignancies of diverse types in 13 patients, 6 of whom were continuing BG-12 treatment and 7 of
whom were new to BG-12 in ENDORSE. There were three deaths, none of which were considered related to study
drug. Updated long-term safety data will be presented.
Conclusion: The long-term safety profile of BG-12 appears to be consistent with previous findings from DEFINE and
CONFIRM. No new or worsening safety signals have been observed.
JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research support from Biogen Idec and
Roche. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva; grant and research
support from Novartis. KS: honoraria from Biogen Idec, Genzyme, Novartis, Ono Pharma, Roche, Synthon, and
Teva. RZ, MN, MTS, VV: employees of Biogen Idec. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck
Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono,
Novartis, and Teva Neuroscience. Supported by: Biogen Idec Inc.
41
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
4-year follow-up of oral BG-12 (dimethyl fumarate) treatment in relapsing
remitting multiple sclerosis (RRMS): integrated magnetic resonance imaging
(MRI) outcomes from DEFINE, CONFIRM, and ENDORSE
D. H. Miller, R. J. Fox, R. Gold, E. Havrdova, L. Kappos, D. MacManus, T. Yousry, R. Zhang, M. Yang, V. Viglietta, S.
I. Sheikh, K. T. Dawson, D. L. Arnold (London, GB; Cleveland, US; Bochum, DE; Prague, CZ; Basel, CH; Weston,
Montreal, US)
Background: Oral BG-12 (dimethyl fumarate) demonstrated efficacy and safety in RRMS in the 2-year, Phase 3
DEFINE and CONFIRM studies. Here we report interim MRI outcomes from ENDORSE, an ongoing, 5-year, doseblind extension of DEFINE and CONFIRM.
Methods: Patients randomized to BG-12 240 mg twice (BID) or three times daily (TID) in DEFINE/CONFIRM
continued on the same dose in ENDORSE. Patients treated with placebo (PBO) (DEFINE/CONFIRM) or glatiramer
acetate (GA) (CONFIRM) were randomized 1:1 to BG-12 240 mg BID or TID in ENDORSE. Brain MRI scans were
obtained yearly in a subset of patients (MRI cohort). Efficacy was analyzed (cutoff 01 May 2012) by parent/extension
study treatment: BID/BID, TID/TID, PBO/BID, PBO/TID, GA/BID, and GA/TID.
Results: Of 1,221 patients in the MRI cohort of DEFINE/CONFIRM, 982 completed those parent studies, and 725
were dosed in the ENDORSE extension study (n=210 [BID/BID], 216 [TID/TID], 96 [PBO/BID], 94 [PBO/TID], 49
[GA/BID], and 60 [GA/TID]). MRI data were available for Year 1 of ENDORSE for 187 (BID/BID), 193 (TID/TID), 67
(PBO/BID), 75 (PBO/TID), 39 (GA/BID), and 41 (GA/TID) patients. Among patients continuing BG-12 treatment in
ENDORSE, 64% (BID/BID) and 60% (TID/TID) were free of new/enlarging T2 lesions during Year 3, 73% (BID/BID)
and 67% (TID/TID) were free of new T1 hypointense lesions during Year 1 of ENDORSE, and 89% (BID/BID) and
84% (TID/TID) were free of gadolinium-enhancing (Gd+) lesions at Year 1 of ENDORSE. For patients switching from
PBO to BG-12 in ENDORSE, the proportion with no new/enlarging T2 lesions was 31% (PBO/BID) and 19%
(PBO/TID) during Year 1 of DEFINE/CONFIRM and 43% (PBO/BID) and 49% (PBO/TID) during Year 1 of ENDORSE
(first year receiving BG-12).
Conclusion: Reductions in T2, T1, and Gd+ lesions were sustained over 3 years of BG-12 treatment, and similar
outcomes were attained by patients switching from PBO to BG-12 in ENDORSE. Together with clinical efficacy and
an acceptable safety profile, these results support the potential for BG-12 as a long-term treatment option for MS.
Supported by: Biogen Idec Inc. DHM: honoraria from Biogen Idec, GlaxoSmithKline, Novartis, and Bayer Schering
Pharma; research grants from Biogen Idec , Schering AG, Apitope, Richmond Pharma, GlaxoSmithKline, and
Novartis. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva; grant and research
support from Novartis. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva
Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva
Neuroscience. EH: honoraria from Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, Merck, Novartis, Sanofi, Serono,
and Teva. LK: research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering,
Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim, Eisai, Elan, European Union, Genmab, Gianni Rubatto
Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck Serono, Novartis, Novartis Research Foundation,
Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Shire, Swiss MS Society, Swiss National Research
Foundation, Teva Neuroscience, UCB, and Wyeth. DM: research grants (held by University College London) from
Biogen Idec, GlaxoSmithKline, Schering AG, Apitope, Richmond Pharma, and Novartis for analysis of MRI data in
MS trials. TY: research grants from Biogen Idec, GlaxoSmithKline, Schering AG, and Novartis for analysis of data
from MS trials and has received honoraria and travel expenses for advisory committee work from Biogen Idec, Bayer
Schering, and Novartis. RZ, MY, VV, SIS, KTD: employees of Biogen Idec. DLA: honoraria/revenue from Bayer
HealthCare, Biogen Idec, Coronado Biosciences, Eli Lilly, EMD Serono, Genentech, Genzyme, NeuroRx Research,
Novartis, Roche, and Teva; research support from Bayer HealthCare and Biogen Idec.
42
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Oral BG-12 (dimethyl fumarate) and pregnancy: preclinical studies and pregnancy
outcomes reported during the clinical development programme
R. Gold, J. T. Phillips, E. Havrdova, A. Bar-Or, L. Kappos, J. Clarke, H. Yuan, M. Novas, M. T. Sweetser, N. C.
Kurukulasuriya, V. Viglietta, R. J. Fox (Bochum, DE; Dallas, US; Prague, CZ; Montreal, CA; Basel, CH; Weston,
Cleveland, US)
Background: No formal studies of oral BG-12 were conducted in pregnant women, but pregnancies have occurred
during the BG-12 clinical development program. Here we present the outcomes of those pregnancies as well as
preclinical data from animal reproductive toxicology studies.
Methods: In the preclinical studies, reproductive and developmental toxicology was evaluated in rats and rabbits
given dimethyl fumarate during organogenesis or during pregnancy and lactation. BG-12 clinical studies included
2665 multiple sclerosis (MS) patients, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 338 healthy
volunteers. Subjects were required to use reliable contraception and immediately discontinue drug in the event of
pregnancy. Pregnancy outcomes as of January 2, 2013 (data cutoff) are reported.
Results: There was no evidence of impaired fertility in rats or teratogenicity in rats and rabbits given dimethyl
fumarate at doses that caused reductions in maternal weight gain. As of January 2, 2013 (data cutoff), 38
pregnancies in subjects exposed to BG-12 (37 MS patients, 1 healthy volunteer) and 14 pregnancies in placebo
recipients were reported in clinical studies. Outcomes are known for all pregnancies in placebo recipients. One
subject exposed to BG-12 was lost to follow-up and information is pending for three subjects exposed to BG-12;
hence, results for BG-12 are reported for the 34 pregnancies with known outcomes. In patients exposed to BG-12, 22
live births (64.7%), 3 spontaneous abortions (8.8%), and 9 elective terminations (26.5%) were reported. In placebo
recipients, 9 live births (64.3%), 3 spontaneous abortions (21.4%), and 2 elective terminations (14.3%) were reported.
No fetal abnormalities have been reported. The incidence of spontaneous abortion in both BG-12- and placebotreated subjects was consistent with the expected rate of early pregnancy loss in the general population (12-22%).
Conclusion: Based on limited data, no increased risk of fetal abnormalities or adverse pregnancy outcomes
associated with gestational exposure to BG-12 during the first trimester has been observed. Further data will be
collected through a pregnancy registry.
Supported by: Biogen Idec Inc. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and
Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva
Neuroscience. JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research support from
Biogen Idec and Roche. EH: honoraria from Bayer, Biogen Idec, Genzyme, GlaxoSmithKline, Merck, Novartis,
Sanofi, Serono, and Teva. ABO: honoraria or research support from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec,
BioMS, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Medimmune, Merck Serono, Novartis,
Ono Pharmacia, Receptos, Roche, Sanofi Aventis, Teva Neuroscience, and Wyeth. LK: research support from
Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen Idec,
Boehringer Ingelheim, Eisai, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline,
Glenmark, MediciNova, Merck Serono, Novartis, Novartis Research Foundation, Roche, Roche Research
Foundation, Sanofi-Aventis, Santhera, Shire, Swiss MS Society, Swiss National Research Foundation, Teva
Neuroscience, UCB, and Wyeth. JC, HY, MN, MTS, NCK, VV: employees of Biogen Idec. RJF: consultant fees from
Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva; grant and research support from Novartis.
43
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Effect of BG-12 (dimethyl fumarate) in newly diagnosed relapsing remitting
multiple sclerosis (RRMS) patients from the DEFINE and CONFIRM studies
R. Gold, G. Giovannoni, J. T. Phillips, R. J. Fox, A. Zhang, L. Meltzer, N. C. Kurukulasuriya (Bochum, DE; London,
GB; Dallas, Cleveland, Weston, US)
Background: BG-12 (dimethyl fumarate) demonstrated consistent clinical and radiological efficacy across a broad
range of patients with relapsing-remitting multiple sclerosis (RRMS) in clinical trials.
Objectives: To evaluate the impact of BG-12 on the clinical efficacy in the newly diagnosed RRMS patient population
from the DEFINE and CONFIRM trials.
Methods: Patients included in these post-hoc analyses were diagnosed with RRMS within one year of entry into
DEFINE or CONFIRM and were naive to treatment with a disease-modifying therapy. Treatment efficacy was
assessed by annualized relapse rate (ARR) and time to first relapse over 2 years. ARR was analyzed using a
negative binomial model. Time to relapse was analyzed using a Cox proportional hazards model adjusted for the
number of relapse(s) one year prior to study entry, baseline age (<40, >=40 years), EDSS score (<=2.0, >2.0), and
region.
Results: A total of 678 patients were assigned to placebo (N=223), BG-12 240 mg twice daily (BID) (N=221), or BG12 240 mg three times daily (TID) (N=234). Baseline demographic and clinical characteristics were similar across
treatment groups. A median (range) of 2.0 (0-31.0), 2.0 (0-42.0), and 2.0 (0-23.0) years had elapsed since first MS
symptoms, and 1.0 (0-1.0) year had elapsed since diagnosis in each of the placebo, BG-12 BID, and BG-12 TID
groups. ARR in the newly diagnosed population over 2 years was 0.38 (95% CI 0.30-0.50) in the placebo group
compared with 0.17 (0.12-0.23) in the BG-12 BID group and 0.15 (0.11-0.21) in the BG-12 TID group. At 2 years, BG12 BID and BG-12 TID reduced ARR versus placebo by 56% (rate ratio 0.44 [95% CI 0.30.-0.65]) and by 60% (0.40
[0.27-0.58]), respectively. The proportion of subjects relapsed over 2 years was 42.2% with placebo, 21.3% with BG12 BID, and 20.5% with BG-12 TID using the Kaplan-Meier method. The risk of relapse at 2 years was reduced by
54% (hazard ratio 0.46 [0.32-0.67]) and 57% (0.43 [0.30- 0.62]) in the BG-12 BID and BG-12 TID groups vs placebo,
respectively.
Conclusion: BG-12 demonstrated strong treatment effect on ARR and time to first relapse in the newly diagnosed MS
population. Together with an acceptable safety profile in the overall population, this analysis further supports the
potential for BG-12 to become a valuable oral treatment option for patients newly diagnosed with MS.
Study Supported by: Biogen Idec Inc. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis,
and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva
Neuroscience. GG: honoraria from Abbvie, Bayer HealthCare, Biogen Idec, Canbex, Genzyme, GlaxoSmithKline,
GW Pharma, FivePrime, Medimmune, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon,
Teva Neuroscience, UCB and Vertex; research support from Biogen Idec, Ironwood, Merck Serono, Merz, and
Novartis; compensation from Elsevier as Co-Chief Editor of MS and Related Disorders. JTP: honoraria from Acorda,
Biogen Idec, Genzyme, Novartis, and Teva; research support from Biogen Idec and Roche. RJF: consultant fees
from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva; grant and research support from Novartis. AZ, LM,
NCK: employees of Biogen Idec.
44
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Lymphocyte count reductions in relapsing remitting multiple sclerosis (RRMS)
patients treated with oral BG-12 (dimethyl fumarate): integrated analysis of the
placebo-controlled studies
R. J. Fox, R. Gold, J. T. Phillips, K. Selmaj, K. Raghupathi, H. Yuan, J. O'Gorman, M. Novas, V. Viglietta, N. C.
Kurukulasuriya (Cleveland, US; Bochum, DE; Dallas, US; Lodz, PL; Weston, US)
Background: BG-12 demonstrated significant efficacy and an acceptable safety profile in placebo-controlled clinical
trials, including a Phase 2b trial and the Phase 3 DEFINE and CONFIRM studies. The most common AEs with BG-12
were flushing and GI events, but BG-12 was also associated with a reduction in lymphocyte counts. An integrated
analysis of the placebo-controlled studies was conducted to examine the severity, reversibility, and implications of
lymphocyte count reductions in patients treated with BG-12 or placebo (PBO).
Methods: The population for this integrated analysis comprised 2,428 RRMS patients (aged 18-55 years; EDSS score
0-5.0) who were randomized and received treatment with placebo (n=836) or BG-12 240 mg BID (n=769) or TID
(n=823) for up to 96 weeks. CONFIRM included a GA reference comparator arm (n=351). Hematological tests were
performed at weeks 4, 8, and 12, and at 12-week intervals thereafter.
Results: Results are shown here for placebo and the recommended dosing regimen of BG-12 (240 mg BID). Mean
lymphocyte counts decreased by approximately 30% from baseline to Week 48 in BG-12 BID-treated patients, then
plateaued, but remained within normal limits (lower limit of normal [LLN]: 0.91x109/L) throughout the 2-year
observation period. The minimum post-baseline lymphocyte count was =0.8x109/L (CTC Grade 1) in 2% (PBO) and
10% (BG-12 BID) of patients; <0.8->=0.5x109/L (CTC Grade 2) in 2% (PBO) and 22% (BG-12 BID) of patients; and
<0.5x109/L (CTC Grade 3) in <1% (PBO) and 6% (BG-12 BID) of patients. No patients discontinued BG-12 BID due
to AEs associated with low lymphocyte counts. The incidence of infections (56% PBO, 60% BG-12 BID) and serious
infections (1.4% PBO, 2.2% BG-12 BID) was similar across groups. There were no opportunistic infections in BG-12
BID-treated patients. There was no increased incidence of serious infections observed in BG-12 BID-treated patients
with lymphocyte counts <0.8x109/L or <0.5x109/L. In a subgroup of subjects with data available 4 weeks after
stopping BG-12 BID, lymphocyte counts increased slightly but did not return to baseline.
Conclusion: In PBO-controlled studies, lymphocyte count reductions associated with BG-12 BID were not associated
with an increased risk of infections, serious infections, or opportunistic infections. Slight increases in lymphocytes
counts were observed within 4 weeks following the last dose of BG-12 BID.
Supported by: Biogen Idec Inc. RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and
Teva; grant and research support from Novartis. RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono,
Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis,
and Teva Neuroscience. JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research support
from Biogen Idec and Roche. KS: compensation for consulting services from Genzyme, Novartis, Ono, Roche,
Synthon, and Teva, and compensation for speaking from Biogen Idec. KR, HY, JO, VV, NCK: employees of Biogen
Idec.
45
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Treatment of specific symptoms
Thursday, October 03, 2013, 15:45 - 17:00
Alemtuzumab improves expanded disability status scale (EDSS) via effects on
functional systems: CARE-MS II
V. Brinar, D.L. Arnold, J. Cohen, A.J. Coles, E.J. Fox, H.-P. Hartung, E. Havrdova, K. Selmaj, H. Weiner, J. Palmer,
D.H. Margolin, M.A. Panzara, D.A.S. Compston (Zagreb, HR; Montreal, CA; Cleveland, US; Cambridge, GB; Round
Rock, US; Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, Cambridge, US)
Background: In CARE-MS II (NCT00548405), which enrolled patients with relapsing-remitting multiple sclerosis
(RRMS) and disease activity despite disease-modifying therapy (DMT), alemtuzumab treatment significantly
improved mean Expanded Disability Status Scale (EDSS) scores compared with subcutaneous interferon beta-1a
(SC IFNB-1a) and with patients’ own baseline. Changes in EDSS Functional System (FS) scores are important in
earlier stages of MS, when disability is evident in areas other than ambulation.
Objective: To assess effects of alemtuzumab vs. SC IFNB-1a on the EDSS FS scores in CARE-MS II.
Patients and Methods: Patients were randomized to receive alemtuzumab (12 mg/day intravenously on 5 consecutive
days at study start and on 3 consecutive days 12 months later) or IFNB-1a (44 mcg SC 3 times weekly). Entry criteria
included EDSS score 0.0–5.0 and onset of MS symptoms within 10 years of screening. Proportional odds analyses
compared the proportion of patients that improved vs. remained stable or worsened at Months 12 and 24 for each FS
score (pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, and cerebral).
Results: Alemtuzumab patients had larger mean reductions from baseline in FS scores over time than SC IFNB-1a
patients, with a significant difference between groups in cerebellar, cerebral, pyramidal, sensory, and visual scores at
Month 24. These results are supported by a greater proportion of alemtuzumab patients with improvements from
baseline compared with SC IFNB-1a patients in all 7 FS; the differences were significant for cerebellar (Month 12:
p=0.0002; Month 24: p<0.0001), cerebral (Month 12: p=0.0003; Month 24: p<0.0001), pyramidal (Month 12:
p=0.0462; Month 24: p=0.0044), sensory (Month 12, p=0.0124; Month 24, p=0.0003), and visual (Month 24,
p=0.0122) scores.
Conclusions: Reversal of disability was significantly more likely with alemtuzumab than with SC IFNB-1a in CARE-MS
II. Improvement in all 7 FS (5 of which reached statistical significance for between-treatment comparisons)
contributed to reduction in mean EDSS scores after alemtuzumab. This suggests that whatever impairment a patient
may have developed as a result of prior MS attacks, alemtuzumab treatment increases the odds that it will improve
and lead to a meaningful recovery of neurological function.
Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals. Brinar V - Dr. Vesna
Brinar reports having nothing to disclose. Arnold DL - Dr. Douglas L. Arnold reports receiving personal compensation
or research support form Bayer Healthcare, Biogen Idec, Genentech, Genzyme, Roche, and Teva Pharmaceuticals.
Cohen JA - Dr. Cohen reports personal compensation for serving as a consultant or speaker from Biogen Idec, Elan,
Novartis, Teva, and Vaccinex and research support paid to his institution from Biogen Idec, Consortium of MS
Centers, US Department of Defense, Genzyme, National Institutes of Health, National MS Society, Novartis,
Receptos, Synthon, and Teva. Coles AJ - Dr Alasdair J. Coles reports receiving consulting fees, lecture fees, and
institutional grant support from Genzyme, Merck-Serono, and UCB-Celltech. Fox EJ - Dr Edward Fox reports
receiving consultancy fees, honoraria, travel, and research support from Bayer Healthcare, Novartis, Ono, SanofiAventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics, Pfizer, Teva Pharmaceuticals, and Eli Lilly.
Hartung HP - Dr. Hans-Peter Hartung reports receiving the approval of the Rector of Heinrich-Heine-University, for
consulting, lectures and activities in Steering Committees of the following companies: Bayer Healthcare, Biogen Idec,
Genzyme, Medimmune, Merck Serono, Novartis, Roche, Teva Sanofi. Havrdova E - Dr. Eva Havrdova reports
receiving honoraria and consulting fees from Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck
Serono, Roche, Teva and Novartis for consulting services, speaking and serving on scientific advisory boards and
research support from the Czech Ministry of Education. Selmaj KW - Dr Krzysztof Selmaj reports receiving consulting
fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees from Novartis, Merck-Serono, Biogen Idec, and
46
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Bayer Healthcare; and financial compensation, including travel, from Genzyme for scientific presentations. Weiner HL
- Dr Howard Weiner reports receiving consulting/honoraria from Biogen Idec, EMD Serono, Genzyme, Teva
Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research support from EMD Serono and
GlaxoSmithKline. Palmer J – Jeffrey Palmer reports receiving personal compensation as an employee of Genzyme, a
Sanofi company. Margolin D - Dr. David H. Margolin reports receiving personal compensation as an employee of
Genzyme, a Sanofi company. Panzara M - Dr. Michael Panzara reports receiving personal compensation as an
employee of Genzyme, a Sanofi company. Compston DAS - Prof Alastair Compston reports receiving consulting
fees, lecture fees, and grant support from Genzyme and lecture fees from Bayer Schering Pharma on behalf of the
University of Cambridge.
47
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Treatment of progressive MS
Thursday, October 03, 2013, 15:45 - 17:00
Phase 1 trial monitoring response to alemtuzumab (ALE) in naive and ALEexperienced subjects with refractory multiple sclerosis (MS)
S.F. Hunter, H.M. Hunter, D. Kantor (Franklin, Golden Valley, Ponte Vedra, US)
Background: Early studies suggested less benefit of ALE in patients with progressive features. Given risks and
benefits, ALE will be used in higher disability, active disease in highly treatment-experienced patients, differing from
previous phase II/III clinical trials. Hypothesis: ALE manifests efficacy equivalent or better than prior treatment
strategies for treatment-refractory multiple sclerosis, with reasonable incidence of serious adverse events (SAEs).
Preliminary data: Retrospective analyses 12&33 months’ median follow up of a highly refractory, active, large (n=55)
clinic cohort of high disability, ALE-treated MS patients receiving 60 mg 1st cycle and subsequent 30-36 mg cycles
annually (AAN 2009 P07.147 and 2011 PD6.007); cohort median 47 years with 9 years’ MS duration, marked gait
disability (median/mean EDSS 5.5/6.0, MSSS 6.9), many progressive features, median three prior DMTs, generally
receiving corticosteroids multiple times a year. At 12 months ALE did not change relapses and marginally improved
EDSS by 0.39 (median 0, range -3.5 to +1.5; p=0.04 Student’s t); in contrast, MSSS improved a mean of 0.50 (range
-3.7 to +2.1, median 0.4, p<0.001, Student’s t). At 33 months and most receiving 3 cycles, a majority (55%) improved
by median 1.5 EDSS, with 33% stable; ARR significantly declined from 1.36 (median 1.5) in the baseline period
before alemtuzumab to 0.93 during the follow up period.
Design and Outcomes: Two arms (n=30 each) include ALE-experienced and ALE-naïve, high disability (EDSS 3-7),
treatment-refractory MS. ALE is given per standard protocols. EDSS, relapses and MS functional composite, annual
MRI imaging and ocular tomography are both prospectively and retrospectively collected. Safety outcomes will be
assessed and tabulated.
Objectives: Determine if improved EDSS and ARR are heralded by change in MSSS at 12 months. Primary outcomes
will be: change in EDSS and MSSS. Secondary outcomes will be: changes in ARR, high dose corticosteroids, MRIbased cerebral volumes and burden of disease (in selected subjects), OCT nerve fiber layer measurements.
Summary: High disability, refractory MS patients may benefit from long-term aggressive immunotherapies with
improved prognosis on MSSS and improved/stabilized EDSS. Using MSSS may permit demonstration of efficacy in
shorter and more practical studies in these complex patients with an expectation of progression, for whom a
prolonged randomized trial is not possible.
SFH receives a grant from Genzyme this investigator-initiated trial. SFH performs research for Abbott, Acorda, Avanir,
Bayer, BiogenIdec, Genzyme/Sanofi, Lilly, Novartis, Roche, Synthon, TEVA, and Xenoport, speaks for Acorda,
Avanir, Bayer, BiogenIdec, Questcor, TEVA; consults for Bayer, BiogenIdec, Roche and Osmotica. HMH speaks for
Acorda, Questcor, Novartis, and TEVA Neuroscience, and is an advisory board member for BiogenIdec and
Genzyme. DK consults for Acorda, Allergan, Avanir, Biogen Idec, Novartis, Questcor, Osmotica; speaks for Acorda,
Allergan, Avanir, Biogen Idec, Novartis, Questcor, Depomed, Teva; receives research funding from Acorda, Avanir,
Biogen Idec, Novartis, Teva
48
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Risk management for disease modifying treatments
Thursday, October 03, 2013, 15:45 - 17:00
Detection, incidence and management of glomerulonephritis in the alemtuzumab
clinical development programme
D. Wynn, D.L. Arnold, J.A. Cohen, A.J. Coles, E.J. Fox, H.-P.. Hartung, E. Havrdova, K.W. Selmaj, H.L. Weiner, J.
Palmer, D.H. Margolin, P. Oyuela, M.A. Panzara, DAS Compston (Northbrook, US; Montreal, CA; Cleveland, US;
Cambridge, GB; Round Rock, US; Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, Cambridge, US)
Background: Alemtuzumab has been evaluated in 1 phase 2 (CAMMS223) and 2 phase 3, head-to-head trials
(CARE-MS I [treatment-naïve patients] and II [patients with disease activity on prior DMT]). Rarely, alemtuzumab
treatment has been associated with glomerulonephritis of autoimmune etiology.
Objective: To summarize cases of glomerulonephritis in alemtuzumab-treated patients in clinical trials.
Patients and Methods: Patients received alemtuzumab 12 or 24 mg/day IV on 5 consecutive days at study start and
on 3 consecutive days 12 months later. After the core studies, eligible patients could enroll in an extension study for
further follow-up and re-treatment (or initial alemtuzumab treatment for those treated with SC IFNB-1a in core
studies). Patients were monitored by monthly serum creatinine and urinalysis; an educational component ensured
patient and investigator awareness of signs and symptoms of renal dysfunction. All nephritis cases reported in the
1486 patients treated with alemtuzumab to date in the core and extension trials are described here, some previously
reported.
Results: Nephritis was reported in 5 patients (all treated with alemtuzumab 12 mg); 4 were glomerular disease.
Case 1: Anti-glomerular basement membrane (anti-GBM) disease at 5 months after last dose, identified by urinalysis
(microhematuria).
Case 2: Anti-GBM disease at 39 months after last dose, identified through serum creatinine monitoring. Both events
were treated with plasmapheresis, cyclophosphamide, and oral steroids.
Case 3: Non-serious grade 3 membranous glomerulonephritis at 6 months after last dose, identified by urinalysis
(proteinuria), and treated with diuretics and ACE inhibitors.
Case 4: Membranous glomerulonephritis at 13 months after last alemtuzumab dose, presenting with peripheral
edema, and treated with diuretics and albumin.
Case 5: Grade 2 tubulointerstitial nephritis (non-glomerular) associated with antibiotic use. All cases had normal
serum creatinine at last assessment.
Conclusions: Two types of glomerulonephritis have been observed in MS patients after alemtuzumab. Anti-GBM
disease rapidly progresses to renal failure unless treated; hematuria or rising creatinine require urgent nephrology
referral. Membranous glomerulonephritis causes an indolent nephrotic syndrome. These events are rare and may
occur months or years after alemtuzumab treatment. Safety monitoring and education are essential for early
detection, effective management, and positive outcomes.
Wynn D - Dr Daniel Wynn reports receiving research support and/or consulting fees from Acorda Therapeutics,
Avanir Pharmaceuticals, EMD Serono, Genzyme, GlaxoSmithKline, Hoffman LaRoche/Genentech, Novartis, Ono
Pharmaceutical, Opexa Therapeutics, Osmotica, Pfizer, Questcor, Receptos, Sanofi-Aventis, Teva, and XenoPort.
Arnold DL - Dr Douglas L. Arnold reports receiving personal compensation or research support form Bayer
Healthcare, Biogen Idec, Genentech, Genzyme, Roche, and Teva Pharmaceuticals. Cohen JA - Dr. Cohen reports
personal compensation for serving as a consultant or speaker from Biogen Idec, Elan, Novartis, Teva, and Vaccinex
and research support paid to his institution from Biogen Idec, Consortium of MS Centers, US Department of Defense,
Genzyme, National Institutes of Health, National MS Society, Novartis, Receptos, Synthon, and Teva. Coles AJ - Dr
Alasdair J. Coles reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme, MerckSerono, and UCB-Celltech. Fox EJ - Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and
research support from Bayer Healthcare, Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa
Therapeutics, Pfizer, Teva Pharmaceuticals, and Eli Lilly. Hartung HP - Dr. Hans-Peter Hartung reports receiving the
approval of the Rector of Heinrich-Heine-University, for consulting, lectures and activities in Steering Committees of
the following companies: Bayer Healthcare, Biogen Idec, Genzyme, Medimmune, Merck Serono, Novartis, Roche,
Teva Sanofi Havrdova E - Dr. Eva Havrdova reports receiving honoraria and consulting fees from Bayer,
49
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva and Novartis for consulting
services, speaking and serving on scientific advisory boards and research support from the Czech Ministry of
Education. Selmaj KW - Dr Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec,
and Roche; lecture fees from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial
compensation, including travel, from Genzyme for scientific presentations. Weiner HL - Dr Howard Weiner reports
receiving consulting/honoraria from Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax,
and GlaxoSmithKline and research support from EMD Serono and GlaxoSmithKline. Palmer J – Jeffrey Palmer
reports receiving personal compensation as an employee of Genzyme, a Sanofi company. Margolin D - Dr. David H.
Margolin reports receiving personal compensation as an employee of Genzyme, a Sanofi company. Panzara M - Dr.
Michael A. Panzarareports receiving personal compensation as an employee of Genzyme, a Sanofi company.
Compston DAS - Prof Alastair Compston reports receiving consulting fees, lecture fees, and grant support from
Genzyme and lecture fees from Bayer Schering Pharma on behalf of the University of Cambridge.
50
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Immunogenicity of alemtuzumab does not impact safety and efficacy in relapsing
remitting multiple sclerosis patients in the CARE-MS I study
T. Ziemssen, D.L. Arnold, J.A. Cohen, A.J. Coles, E.J. Fox, H.-P. Hartung, E. Havrdova, K.W. Selmaj, H.L. Weiner, J.
Palmer, D.H. Margolin, S. Richards, C. Sung, M.A. Panzara, D.A.S. Compston (Dresden, DE; Montreal, CA;
Cleveland, US; Cambridge, GB; Round Rock, US; Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, Cambridge, US)
Background: In CARE-MS I (NCT00530348), alemtuzumab reduced the relapse rate by 55% (p<0.0001) vs.
subcutaneous interferon beta-1a (SC IFNB-1a) in treatment-naïve patients with relapsing-remitting multiple sclerosis
(RRMS); there was no significant reduction in sustained accumulation of disability (SAD; p=0.22). Anti-drug
antibodies may negatively impact efficacy and/or safety of some MS treatments. Anti-alemtuzumab antibodies
develop in response to alemtuzumab administration.
Objective: To measure anti-alemtuzumab antibodies and assess effects on efficacy and safety of alemtuzumab as
first-line treatment in patients with RRMS.
Patients and Methods: Patients randomized to alemtuzumab (n=386) received 12 mg/day intravenously on 5
consecutive days initially and 3 consecutive days 1 year later. Serum samples were collected before and 1, 3, and 12
months after each course and screened for alemtuzumab-binding antibodies using a validated assay on the MSD
technology platform. Specificity was confirmed using a competitive-binding assay. Positive samples were tested for
inhibitory (neutralizing) anti-alemtuzumab antibodies using a cell-based flow cytometric assay. The effects of antibody
status and titer on efficacy, safety, and pharmacodynamics outcomes were examined.
Results: Anti-alemtuzumab antibodies were detected in 87.0% of alemtuzumab-treated patients. Titers increased at
Months 1 and 3 of the first course, declining by Month 12, when 29.2% of patients remained antibody-positive. Among
patients with binding antibodies, 93.3% tested positive also for inhibitory anti-alemtuzumab antibodies. Development
of both binding and inhibitory antibodies was further increased after the second course, with titers peaking at Month
13 and declining thereafter. Antibody status did not affect clinical efficacy (6-month SAD or annualized relapse rate),
magnetic resonance imaging outcomes (T2-hyperintense lesion volume; T1-hypointense, T2-hyperintense, or
gadolinium-enhancing lesion counts), overall incidence of adverse events, or the incidence of infusion-associated
reactions. Through 2 courses of treatment, the presence and titer of binding or inhibitory antibodies had no
discernible effect on T- or B-lymphocyte depletion or recovery.
Conclusions: Binding and inhibitory anti-alemtuzumab antibodies were commonly detected, with no evidence of an
impact on efficacy, safety, or T- and B-cell pharmacodynamics in a 2-year study.
Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals. Ziemssen T - Dr. Tjalf
Ziemssen has received speaker honoraria from Almirall, Biogen Idec, Genzyme, GSK, Sanofi-Aventis, Merck Serono,
MSD, Novartis, Teva Pharmaceutical Industries Ltd., and Bayer Schering Pharma; serves as a consultant for Biogen
Idec, Novartis, Teva Pharmaceutical Industries Ltd., Novartis, and Bayer Schering Pharma; and receives research
support from the Hertie Foundation, Deutsche Diabetes Stiftung, Roland Ernst Foundation and the Robert Pfleger
Foundation. Arnold DL - Dr Douglas L. Arnold reports receiving personal compensation or research support form
Bayer Healthcare, Biogen Idec, Genentech, Genzyme, Roche, and Teva Pharmaceuticals. Cohen JA - Dr. Cohen
reports personal compensation for serving as a consultant or speaker from Biogen Idec, Elan, Novartis, Teva, and
Vaccinex and research support paid to his institution from Biogen Idec, Consortium of MS Centers, US Department of
Defense, Genzyme, National Institutes of Health, National MS Society, Novartis, Receptos, Synthon, and Teva. Coles
AJ - Dr Alasdair J. Coles reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme,
Merck-Serono, and UCB-Celltech. Fox EJ - Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and
research support from Bayer Healthcare, Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa
Therapeutics, Pfizer, Teva Pharmaceuticals, and Eli Lilly. Hartung HP - Dr. Hans-Peter Hartung reports receiving the
approval of the Rector of Heinrich-Heine-University, for consulting, lectures and activities in Steering Committees of
the following companies: Bayer Healthcare, Biogen Idec, Genzyme, Medimmune, Merck Serono, Novartis, Roche,
Teva Sanofi Havrdova E - Dr. Eva Havrdova reports receiving honoraria and consulting fees from Bayer,
51
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva and Novartis for consulting
services, speaking and serving on scientific advisory boards and research support from the Czech Ministry of
Education. Selmaj KW - Dr Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec,
and Roche; lecture fees from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial
compensation, including travel, from Genzyme for scientific presentations. Weiner HL - Dr Howard Weiner reports
receiving consulting/honoraria from Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax,
and GlaxoSmithKline and research support from EMD Serono and GlaxoSmithKline. Palmer J – Jeffrey Palmer
reports receiving personal compensation as an employee of Genzyme, a Sanofi company. Margolin D - Dr. David H.
Margolin reports receiving personal compensation as an employee of Genzyme, a Sanofi company. Richards S –
Susan Richards reports receiving personal compensation as an employee of Genzyme, a Sanofi company. Sung C –
Crystal Sung reports receiving personal compensation as an employee of Genzyme, a Sanofi company. Panzara M Dr. Michael A. Panzarareports receiving personal compensation as an employee of Genzyme, a Sanofi company.
Compston DAS - Prof Alastair Compston reports receiving consulting fees, lecture fees, and grant support from
Genzyme and lecture fees from Bayer Schering Pharma on behalf of the University of Cambridge.
52
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Lymphocyte counts and efficacy outcomes after alemtuzumab in relapsing
remitting multiple sclerosis patients: the CARE-MS studies
P.S. Sorensen, D.L. Arnold, J.A. Cohen, E.J. Fox, H.-P. Hartung, E. Havrdova, K. Selmaj, H. Weiner, J. Palmer, D.H.
Margolin, M.A. Panzara, D.A.S. Compston, A.J. Coles (Copenhagen, DK; Montreal, CA; Cleveland, Round Rock, US;
Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, Cambridge, US; Cambridge, GB)
Background: Alemtuzumab is a humanized monoclonal antibody that selectively targets CD52, to deplete circulating
T and B lymphocytes; lymphocyte depletion is followed by a distinctive pattern of T- and B-cell repopulation. Two 2year, phase 3, head-to-head trials comparing alemtuzumab with subcutaneous interferon beta-1a (SC IFNB-1a) in
relapsing-remitting multiple sclerosis (RRMS) patients who were treatment-naïve (CARE-MS I; NCT00530348) or who
had disease activity despite disease-modifying therapy (CARE-MS II; NCT00548405) found significant positive
treatment effects for alemtuzumab on clinical efficacy. A published report (Cossburn et al., Neurology 2013;80:55)
suggested that differential lymphocyte recovery following alemtuzumab may be a biomarker for post-treatment
relapse risk.
Objective: To determine whether lymphocyte depletion/reconstitution after alemtuzumab predicts clinical efficacy in
CARE-MS patients.
Methods: Patients randomized to alemtuzumab received 12 mg/day intravenously on 5 consecutive days at study
start and on 3 consecutive days 12 months later. Relapses were assessed by blinded raters and confirmed by a
blinded relapse adjudication committee. Six-month sustained accumulation of disability (SAD) was defined as an
increase of >=1 point on the Expanded Disability Status Scale (EDSS) sustained over 6 months or >=1.5 points if
baseline EDSS=0. Blood counts were tested monthly, and lymphocytes were phenotyped by flow cytometry quarterly
and at Months 1 and 13. The rate of lymphocyte repopulation per month was estimated from a linear mixed model
with covariate adjustment for course, visit, and pre-course lymphocyte count.
Results: 864 alemtuzumab-treated CARE-MS patients were followed longitudinally for 2 years. The mean cell counts
for total lymphocytes and for CD3+, CD4+, CD8+, and CD19+ lymphocyte subsets were similar at both time points
assessed (Months 1 and 13) in patient subgroups stratified by whether they experienced a relapse or SAD event
subsequent to the time point being assessed. The rate (slope) of lymphocyte repopulation was also similar between
subgroups.
Conclusions: Lymphocyte counts and repopulation rates after alemtuzumab did not distinguish between patients at
higher or lower risk of post-treatment relapse or disability accumulation.
Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals Sørensen P - Professor
Per Soelberg Sorensen has received honoraria or consultation fees: Biogen Idec, Merck Serono, TEVA, SanofiAventis, Novartis, Genzyme; and grants from: Biogen Idec, TEVA, Sanofi-Aventis, Novartis, Roche Arnold DL - Dr
Douglas L. Arnold reports receiving personal compensation or research support form Bayer Healthcare, Biogen Idec,
Genentech, Genzyme, Roche, and Teva Pharmaceuticals. Cohen JA - Dr. Cohen reports personal compensation for
serving as a consultant or speaker from Biogen Idec, Elan, Novartis, Teva, and Vaccinex and research support paid
to his institution from Biogen Idec, Consortium of MS Centers, US Department of Defense, Genzyme, National
Institutes of Health, National MS Society, Novartis, Receptos, Synthon, and Teva. Coles AJ - Dr Alasdair J. Coles
reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck-Serono, and
UCB-Celltech. Fox EJ - Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and research support
from Bayer Healthcare, Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics,
Pfizer, Teva Pharmaceuticals, and Eli Lilly. Hartung HP - Dr. Hans-Peter Hartung reports receiving the approval of the
Rector of Heinrich-Heine-University, for consulting, lectures and activities in Steering Committees of the following
companies: Bayer Healthcare, Biogen Idec, Genzyme, Medimmune, Merck Serono, Novartis, Roche, Teva Sanofi
Havrdova E - Dr. Eva Havrdova reports receiving honoraria and consulting fees from Bayer, GlaxoSmithKline,
Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva and Novartis for consulting services, speaking
and serving on scientific advisory boards and research support from the Czech Ministry of Education. Selmaj KW - Dr
53
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees
from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial compensation, including travel, from
Genzyme for scientific presentations. Weiner HL - Dr Howard Weiner reports receiving consulting/honoraria from
Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research
support from EMD Serono and GlaxoSmithKline. Palmer J – Jeffrey Palmer reports receiving personal compensation
as an employee of Genzyme, a Sanofi company. Margolin D - Dr. David H. Margolin reports receiving personal
compensation as an employee of Genzyme, a Sanofi company. Panzara M - Dr. Michael A. Panzarareports receiving
personal compensation as an employee of Genzyme, a Sanofi company. Compston DAS - Prof Alastair Compston
reports receiving consulting fees, lecture fees, and grant support from Genzyme and lecture fees from Bayer Schering
Pharma on behalf of the University of Cambridge.
54
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Risk management for disease modifying treatments
Thursday, October 03, 2013, 15:45 - 17:00
Infection risk with alemtuzumab in patients with relapsing remitting multiple
sclerosis: pooled results from the CARE-MS I and CARE-MS II trials
E. Havrdova, D.L. Arnold, J.A. Cohen, A.J. Coles, E.J. Fox, H.-P. Hartung, K. Selmaj, H.L. Weiner, J. Palmer, D.H.
Margolin, P. Oyuela, M.A. Panzara, D.A.S. Compston (Prague, CZ; Montreal, CA; Cleveland, US; Cambridge, GB;
Round Rock, US; Düsseldorf, DE; Lodz, PL; Boston, Cambridge, US)
Background: Alemtuzumab had superior efficacy vs. subcutaneous interferon beta-1a (SC IFNB-1a) in 2 phase 3
trials in relapsing-remitting multiple sclerosis (RRMS) patients who were treatment-naïve (CARE-MS I;
NCT00530348) or had disease activity despite disease-modifying therapy (CARE-MS II; NCT00548405). Infections
occurred in 67% and 77% of alemtuzumab patients vs. 45% and 66% of SC IFNB-1a patients in each trial,
respectively.
Objective: Evaluate infection risk with alemtuzumab vs. SC IFNB-1a in CARE-MS studies.
Methods: Patients (active RRMS) were randomized to alemtuzumab 12 mg/day intravenously on 5 consecutive days
initially and 3 consecutive days 1 year later, or SC IFNB-1a (44 mcg) 3 times per week. Patients were followed up for
2 years after first study treatment. Circulating lymphocyte counts were performed quarterly and at Months 1 and 13.
Results: 1361 patients received alemtuzumab 12 mg (n=811) or SC IFNB-1a (n=389). Infections occurred more
frequently with alemtuzumab (72.6%) vs. IFNB-1a (56.8%), were predominantly (>95%) mild to moderate in severity
across groups, and responded to standard treatment. Incidence was highest in the first month after the first
alemtuzumab treatment course, with no increase in infection rate following the second course. The most common
infections after alemtuzumab were upper respiratory and urinary tract infections, sinusitis, herpes, and localized
fungal infections. Incidence of serious infections was low for alemtuzumab (2.8%) and SC IFNB-1a (1.3%). No
patients discontinued the study due to infection; no infections were fatal. Serious infections occurring in >= 0.2% of
alemtuzumab patients included pneumonia (0.5%), appendicitis (0.5%), gastroenteritis (0.4%), herpes zoster (0.2%),
and tooth infection (0.2%); there was 1 case of active pulmonary tuberculosis from a region of known endemicity,
which resolved with antituberculous treatment. Incidence of herpes simplex infection was reduced in patients given
acyclovir prophylaxis for 1 month after alemtuzumab treatment. There was no difference in lymphocyte counts in
alemtuzumab-treated patients who did/did not develop infections.
Conclusions: Although infections were more common with alemtuzumab compared with SC IFNB-1a in the CARE-MS
studies, all infections were manageable, most were mild to moderate, and none led to study discontinuation.
Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals. Havrdova E - Dr. Eva
Havrdova reports receiving honoraria and consulting fees from Bayer, GlaxoSmithKline, Genzyme, Biogen Idec,
Sanofi-Aventis, Merck Serono, Roche, Teva and Novartis for consulting services, speaking and serving on scientific
advisory boards and research support from the Czech Ministry of Education. Arnold DL - Dr Douglas L. Arnold reports
receiving personal compensation or research support form Bayer Healthcare, Biogen Idec, Genentech, Genzyme,
Roche, and Teva Pharmaceuticals. Cohen JA - Dr. Cohen reports personal compensation for serving as a consultant
or speaker from Biogen Idec, Elan, Novartis, Teva, and Vaccinex and research support paid to his institution from
Biogen Idec, Consortium of MS Centers, US Department of Defense, Genzyme, National Institutes of Health,
National MS Society, Novartis, Receptos, Synthon, and Teva. Coles AJ - Dr Alasdair J. Coles reports receiving
consulting fees, lecture fees, and institutional grant support from Genzyme, Merck-Serono, and UCB-Celltech. Fox EJ
- Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and research support from Bayer Healthcare,
Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics, Pfizer, Teva
Pharmaceuticals, and Eli Lilly. Hartung HP - Dr. Hans-Peter Hartung reports receiving the approval of the Rector of
Heinrich-Heine-University, for consulting, lectures and activities in Steering Committees of the following companies:
Bayer Healthcare, Biogen Idec, Genzyme, Medimmune, Merck Serono, Novartis, Roche, Teva Sanofi Selmaj KW - Dr
Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees
55
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial compensation, including travel, from
Genzyme for scientific presentations. Weiner HL - Dr Howard Weiner reports receiving consulting/honoraria from
Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research
support from EMD Serono and GlaxoSmithKline. Palmer J – Jeffrey Palmer reports receiving personal compensation
as an employee of Genzyme, a Sanofi company. Margolin D - Dr. David H. Margolin reports receiving personal
compensation as an employee of Genzyme, a Sanofi company. Panzara M - Dr. Michael A. Panzara reports
receiving personal compensation as an employee of Genzyme, a Sanofi company. Compston DAS - Prof Alastair
Compston reports receiving consulting fees, lecture fees, and grant support from Genzyme and lecture fees from
Bayer Schering Pharma on behalf of the University of Cambridge.
56
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Long-term treatment monitoring
Thursday, October 03, 2013, 15:45 - 17:30
Reduction of disability with alemtuzumab in relapsing remitting multiple sclerosis
patients who participated in CARE-MS II: three year follow-up
H.-P. Hartung, D.L. Arnold, J.A. Cohen, A.J. Coles, E.J. Fox, E. Havrdova, K.W. Selmaj, H.L. Weiner, J. Palmer, D.H.
Margolin, M.A. Panzara, D.A.S. Compston (Dusseldorf, DE; Montreal, CA; Cleveland, US; Cambridge, GB; Round
Rock, US; Prague, CZ; Lodz, PL; Boston, Cambridge, US)
Background: In the 2-year, phase 3 CARE-MS II study, alemtuzumab reduced annualized relapse rate by 49%, and
6-month sustained accumulation of disability (SAD) by 42%, vs. subcutaneous interferon beta-1a (SC IFNB-1a) in
relapsing-remitting multiple sclerosis (RRMS) patients with disease activity despite disease-modifying therapy. After
study completion, eligible patients could enroll in an extension study.
Objective: Examine durability of disability reduction in patients who received alemtuzumab in the core CARE-MS II
trial (NCT00548405) and entered the extension.
Methods: In CARE-MS II, patients were randomized to alemtuzumab (12 mg intravenously [IV] on 5 consecutive days
at study start and 3 consecutive days 12 months later) or IFNB-1a (44 mcg SC 3 times weekly). In the extension,
former alemtuzumab patients were eligible to receive additional alemtuzumab (12 mg/day IV on 3 days) for disease
activity (>=1 relapse or >=2 new or enlarging brain or spinal lesions on MRI). EDSS was assessed quarterly by
blinded raters; worsening and improvement of disability were defined as >=0.5 point increase and decrease,
respectively, from core study baseline EDSS score. SAD was defined as >=1 point EDSS increase sustained for 3 or
6 months (>=1.5 points if core baseline EDSS=0). Sustained reduction in disability (SRD) was defined as >=1 point
EDSS decrease sustained for 3 or 6 months in patients with core baseline EDSS >=2.
Results: 386 of 426 CARE-MS II alemtuzumab patients enrolled in the extension; most (80%) did not receive retreatment during Year 3. Mean EDSS scores remained below pre-treatment values during the third year: Year 2 (core
study), -0.17; Year 3 (extension), -0.07. At Year 3, patients were more likely to improve from core baseline mean
EDSS score (45%) than worsen (30%) or remain stable (25%), with results similar to those seen at Year 2 (46%,
24%, 30%, respectively). At Year 2 (core) and Year 3 (extension): proportions of patients with 6-month SAD were
13% and 20%; proportions with 3-month SAD were 17% and 24%; proportions of patients attaining 6-month SRD
were 29% and 36%; and proportions attaining 3-month SRD were 35% and 43%.
Conclusions: Extension data suggest durable efficacy of alemtuzumab on disability through year 3 in patients who
relapsed on prior therapy, despite most patients receiving only 2 treatment courses (Months 0 and 12). After the first
year of extension, 80% of patients remained free from 6-month SAD.
Dr. Hans-Peter Hartung reports receiving the approval of the Rector of Heinrich-Heine-University, for consulting,
lectures and activities in Steering Committees of the following companies: Bayer Healthcare, Biogen Idec, Genzyme,
Medimmune, Merck Serono, Novartis, Roche, Teva Sanofi
57
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Long-term treatment monitoring
Friday, October 04, 2013, 15:30 - 17:00
Adverse event profile of alemtuzumab in active relapsing remitting multiple
sclerosis patients who participated in the CARE-MS studies: three-year follow-up
J. Lycke, D.L. Arnold, J.A. Cohen, A.J. Coles, E.J. Fox, H.-P. Hartung, E. Havrdova, K.W. Selmaj, H.L. Weiner, J.
Palmer, D.H. Margolin, P. Oyuela, M.A. Panzara, D.A.S. Compston (Gothenburg, SE; Montreal, CA; Cleveland, US;
Cambridge, GB; Round Rock, US; Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, Cambridge, US)
Background: Two phase 3, head-to-head trials comparing alemtuzumab with subcutaneous interferon beta-1a (SC
IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients who were treatment-naïve (CARE-MS I,
NCT00530348) or had disease activity during treatment with disease-modifying therapy (CARE-MS II, NCT00548405)
demonstrated durable improvements in relapse rate and disability for alemtuzumab through 3 years
Objective: Examine alemtuzumab’s safety in CARE-MS patients who continued in the ongoing extension
Methods: In the CARE-MS studies, patients were randomized to alemtuzumab (12 mg/day intravenously [IV] on 5
consecutive days at study start and on 3 consecutive days 12 months later) or IFNB-1a (44 mcg SC 3 times weekly).
In the extension, former alemtuzumab patients were eligible for additional alemtuzumab (12 mg/day alemtuzumab IV
for 3 days) on evidence of clinical or MRI disease activity. Safety ascertainment included clinical and laboratory
monitoring
Results: 929 patients who received alemtuzumab during the core CARE-MS studies were followed up. Most of the
former alemtuzumab 12 mg-treated patients did not receive re-treatment during Year 3 (CARE-MS I, 82%; CARE-MS
II, 80%). Nature and severity of AEs in Year 3 were similar to those in Years 1–2; most were mild to moderate and
responded to standard treatment. Of patients who received alemtuzumab re-treatment in Year 3, 66% experienced
infusion-associated reactions (IARs). 50.3% of extension patients who received alemtuzumab previously experienced
infections (vs. 67% and 77% in each core study). The most common infections were nasopharyngitis, upper
respiratory, urinary tract, and sinusitis. Most infections were mild to moderate and responded to standard treatment.
As previously reported, 1 death occurred in Year 3 (from sepsis). Autoimmune disorders with onset during Year 3
included thyroid disease (19.4%), immune thrombocytopenia (0.4%), and nephropathy (0.1%) (cumulative incidences
over 3 years: 29.9%, 1.3% and 0.3%, respectively)
Conclusions: The safety profile of alemtuzumab in the third year of follow-up was consistent with the core CARE-MS
studies (IARs being common but manageable, a low incidence of serious infections). The incidence of secondary
autoimmunity increased in comparison to Year 2, consistent with what had been observed in prior studies. Patient
education and monitoring were important for early detection and treatment of autoimmune disorders
Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals Lycke J - Dr. Jan Lycke
reports having received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen Idec, Novartis,
and Genzyme/Sanofi Aventis; has served on scientific advisory boards for Almirall, Teva, Biogen Idec, and
Genzyme/Sanofi Aventis; serves on the editorial board of the Acta Neurologica Scandinavica; has received
unconditional research grants from Biogen Idec and Novartis. Arnold DL - Dr Douglas L. Arnold reports receiving
personal compensation or research support form Bayer Healthcare, Biogen Idec, Genentech, Genzyme, Roche, and
Teva Pharmaceuticals. Cohen JA - Dr. Cohen reports personal compensation for serving as a consultant or speaker
from Biogen Idec, Elan, Novartis, Teva, and Vaccinex and research support paid to his institution from Biogen Idec,
Consortium of MS Centers, US Department of Defense, Genzyme, National Institutes of Health, National MS Society,
Novartis, Receptos, Synthon, and Teva. Coles AJ - Dr Alasdair J. Coles reports receiving consulting fees, lecture
fees, and institutional grant support from Genzyme, Merck-Serono, and UCB-Celltech. Fox EJ - Dr Edward Fox
reports receiving consultancy fees, honoraria, travel, and research support from Bayer Healthcare, Novartis, Ono,
Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics, Pfizer, Teva Pharmaceuticals, and Eli
Lilly. Hartung HP - Dr. Hans-Peter Hartung reports receiving the approval of the Rector of Heinrich-Heine-University,
for consulting, lectures and activities in Steering Committees of the following companies: Bayer Healthcare, Biogen
58
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Idec, Genzyme, Medimmune, Merck Serono, Novartis, Roche, Teva Sanofi Havrdova E - Dr. Eva Havrdova reports
receiving honoraria and consulting fees from Bayer, GlaxoSmithKline, Genzyme, Biogen Idec, Sanofi-Aventis, Merck
Serono, Roche, Teva and Novartis for consulting services, speaking and serving on scientific advisory boards and
research support from the Czech Ministry of Education. Selmaj KW - Dr Krzysztof Selmaj reports receiving consulting
fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees from Novartis, Merck-Serono, Biogen Idec, and
Bayer Healthcare; and financial compensation, including travel, from Genzyme for scientific presentations. Weiner HL
- Dr Howard Weiner reports receiving consulting/honoraria from Biogen Idec, EMD Serono, Genzyme, Teva
Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research support from EMD Serono and
GlaxoSmithKline. Palmer J – Jeffrey Palmer reports receiving personal compensation as an employee of Genzyme, a
Sanofi company. Margolin D - Dr. David H. Margolin reports receiving personal compensation as an employee of
Genzyme, a Sanofi company. Panzara M - Dr. Michael A. Panzarareports receiving personal compensation as an
employee of Genzyme, a Sanofi company. Compston DAS - Prof Alastair Compston reports receiving consulting fees,
lecture fees, and grant support from Genzyme and lecture fees from Bayer Schering Pharma on behalf of the
University of Cambridge.
59
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Lymphocyte subset dynamics following alemtuzumab treatment in the CARE-MS
II study
L.H. Kasper, D.L. Arnold, J.A. Cohen, A.J. Coles, E.J. Fox, H.-P. Hartung, E. Havrdova, K.W. Selmaj, H.L. Weiner, J.
Palmer, D.H. Margolin, M.A. Panzara, D.A.S. Compston (Lebanon, US; Montreal, CA; Cleveland, US; Cambridge,
GB; Round Rock, US; Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, Cambridge, US)
Background: Alemtuzumab – a humanized monoclonal antibody – selectively targets CD52 to deplete circulating T
and B lymphocytes; lymphocyte depletion is followed by a distinctive pattern of T- and B-cell repopulation. In the
phase 3 CARE-MS II study, alemtuzumab had significant positive treatment effects on clinical efficacy in relapsingremitting multiple sclerosis (RRMS) patients with disease activity despite prior disease-modifying therapy.
Objective: To investigate the effect of alemtuzumab on lymphocyte subsets in CARE-MS II (NCT00548405).
Methods: Patients (n=667) were randomized to alemtuzumab (12 mg/day intravenously on 5 consecutive days at
study start and on 3 consecutive days 12 months later) or IFNB-1a (44 mcg SC 3 times weekly). Blood counts were
tested monthly. Circulating lymphocytes were phenotyped by flow cytometry quarterly and at Months 1 and 13.
Results: Mean alemtuzumab serum concentrations became low or undetectable within ~1 month after each course for
the 12-mg dose. Alemtuzumab selectively depleted circulating B and T lymphocytes, with lymphocyte counts being
lowest at the earliest post-treatment time point (1 month); B cells approached baseline levels by Month 6 while T cells
repopulated more slowly. Differential depletion/repopulation of lymphocyte subsets led to shifts over time in relative
proportions. With alemtuzumab 12 mg, the percentage of CD4+ cells with a naïve phenotype decreased from
baseline to Month 1 (36.7% to 2.3%), while the percentage of CD4+ memory cells increased (62.5% to 97.4%). The
percentages of both cell types then gradually returned toward baseline levels, but did not reach baseline levels by
Month 12. The proportion of CD4+ T cells with a regulatory (Treg) phenotype increased from baseline to Month 1
(3.8% to 12.5%), and remained elevated at Month 12. A similar pattern was observed for CD8+ T-cell subsets. The
proportion of B cells with a mature naïve phenotype reduced from 56.4% to 5.4% from baseline to Month 1, whereas
the immature cell fraction increased from 4.7% to 36.8%; relative proportions then approached baseline levels by
Month 6.
Conclusions: Alemtuzumab-induced lymphocyte depletion was selective and a distinctive pattern of repopulation
begins within weeks. These effects may explain alemtuzumab's sustained benefit despite infrequent (yearly)
administration.
Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals Kasper L - Dr. Lloyd H
Kasper has received support from Genzyme for advisory board and speaker bureau activities Arnold DL - Dr Douglas
L. Arnold reports receiving personal compensation or research support form Bayer Healthcare, Biogen Idec,
Genentech, Genzyme, Roche, and Teva Pharmaceuticals. Cohen JA - Dr. Cohen reports personal compensation for
serving as a consultant or speaker from Biogen Idec, Elan, Novartis, Teva, and Vaccinex and research support paid
to his institution from Biogen Idec, Consortium of MS Centers, US Department of Defense, Genzyme, National
Institutes of Health, National MS Society, Novartis, Receptos, Synthon, and Teva. Coles AJ - Dr Alasdair J. Coles
reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck-Serono, and
UCB-Celltech. Fox EJ - Dr Edward Fox reports receiving consultancy fees, honoraria, travel, and research support
from Bayer Healthcare, Novartis, Ono, Sanofi-Aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics,
Pfizer, Teva Pharmaceuticals, and Eli Lilly. Hartung HP - Dr. Hans-Peter Hartung reports receiving the approval of the
Rector of Heinrich-Heine-University, for consulting, lectures and activities in Steering Committees of the following
companies: Bayer Healthcare, Biogen Idec, Genzyme, Medimmune, Merck Serono, Novartis, Roche, Teva Sanofi
Havrdova E - Dr. Eva Havrdova reports receiving honoraria and consulting fees from Bayer, GlaxoSmithKline,
Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva and Novartis for consulting services, speaking
and serving on scientific advisory boards and research support from the Czech Ministry of Education. Selmaj KW - Dr
Krzysztof Selmaj reports receiving consulting fees from Genzyme, Novartis, Biogen Idec, and Roche; lecture fees
from Novartis, Merck-Serono, Biogen Idec, and Bayer Healthcare; and financial compensation, including travel, from
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Genzyme for scientific presentations. Weiner HL - Dr Howard Weiner reports receiving consulting/honoraria from
Biogen Idec, EMD Serono, Genzyme, Teva Pharmaceuticals, Novartis, Nasvax, and GlaxoSmithKline and research
support from EMD Serono and GlaxoSmithKline. Palmer J – Jeffrey Palmer reports receiving personal compensation
as an employee of Genzyme, a Sanofi company. Margolin D - Dr. David H. Margolin reports receiving personal
compensation as an employee of Genzyme, a Sanofi company. Panzara M - Dr. Michael A. Panzarareports receiving
personal compensation as an employee of Genzyme, a Sanofi company. Compston DAS - Prof Alastair Compston
reports receiving consulting fees, lecture fees, and grant support from Genzyme and lecture fees from Bayer Schering
Pharma on behalf of the University of Cambridge.
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Inflammation and tissue damage
Thursday, October 03, 2013, 15:45 - 17:00
Predicting brain volume loss at two years as a function of MRI activity in the first
year with laquinimod
M. Rocca, G. Comi, D. Jeffery, L. Kappos, X. Montalban, A. Boyko, T. Gorfine, Y. Sidi, M. Filippi (Milan, IT; Advance,
US; Basel, CH; Barcelona, ES; Moscow, RU; Petach Tiqva, Netanya, IL)
Background: Focal and diffuse inflammation of the CNS result in white matter (WM) lesions and damage to normalappearing WM and grey matter (GM), all of which are thought to contribute to brain atrophy. In the ALLEGRO and
BRAVO phase 3 studies, oral once-daily laquinimod significantly reduced percentage brain volume change (PBVC)
compared with placebo treatment.
Objective: To investigate whether baseline MRI measures together with changes in MRI parameters during the first
year of the study predict brain atrophy accumulation at year 2.
Methods: In ALLEGRO, a subset of RRMS patients (laquinimod n=149, placebo n=157), had MRI scans taken at
baseline, 3, 6, 12, and 24 months to assess the number of gadolinium enhancing (GdE) lesions, number of new T2
lesions, number of new hypointense T1 lesions, T1 and T2 lesion volumes, total brain volume, and the number of
permanent black holes (PBH) resulting from active lesions. Additionally, WM, GM and thalamic volume were
assessed at baseline, month 12, and month 24. The MRI protocol included dual-echo sequences for quantification of
T2-hyperintense lesions, high-resolution pre-contrast 3D T1-weighted sequences for estimation of atrophy, and postcontrast T1-weighted images for identification of GdE lesions. For analysis of WM and GM volumes, 3D T1-weighted
images were segmented using SPM8. New lesions were defined as a GdE lesion and/or a new T2 lesion arising from
an area of previously normal-appearing WM. PBH were defined as lesions with signal intensity between that of GM
and CSF on post-contrast T1-weighted images. Backward selection method with entry rule of 5% significance level
was used to choose variables that can predict PBVC from baseline to month 24 and from month 12 to month 24.
Results: Change in GM volume between baseline and month 12 (estimate=0.00001, P=0.0084) and change in
thalamic volume between baseline and month 12 (estimate=0.00142, p<0.0001) were positively correlated with PBVC
from baseline to month 24, while T2 lesion volume at baseline (estimate=-0.03123, P=0.0009) was negatively
correlated with PBVC from baseline to month 24. Cumulative number of new T1 lesions from month 3 to month 12
was negatively correlated with PBVC from month 12 to month 24 (estimate=-0.05975, P=0.0004).
Conclusion: Changes in the GM and thalamic volume, and cumulative number of new T1 lesions during the first year
of laquinimod and placebo treatment along with baseline T2 lesion volume were found to be predictors of PBVC.
M. Rocca received speakers honoraria from Biogen Idec and Serono Symposia International Foundation and
receives research support from the Italian Ministry of Health. D. Jeffery has received honoria and consulting fees from
Berlex, Serono, Teva, Glaxo and Pfizer. Dr. Jeffery received financial support for research from Bayer, Serono, Teva,
and Pfizer. L. Kappos has received institutional research support from Acorda, Actelion, Allozyne, BaroFold, Bayer
HealthCare, Bayer Schering, Bayhill, Biogen Idec, Boehringer Ingelheim, Elan, Genmab, Glenmark, GlaxoSmithKline,
Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera, Shire, Roche, Teva, UCB, Wyeth, Swiss MS Society,
Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, the Novartis and Roche
Research Foundation. X Montalban has received honoraria fro speaking and travel expenses to scientific meetings;
steering member or participated in advisory boards in corporate-sponsored clinical trials or has had consulting
agreements with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, SanofiAdventis, and Teva A. Boyko is a member of advisory boards, speaker and investigator of clinical trials from Novartis,
Merck Serono, TEVA, Genzyme, Biogen Idec and Nicomed. Tali Gorfine is employed by Teva; owns stock in and
receives travel/meeting expenses from Teva; and is a co-holder of patents with Teva. Y Sidi is employed by Teva;
owns stock in and receives travel/meeting expenses from Teva G. Comi received consulting fees for advisory boards,
consultancy and speaker activities from Novartis, Teva Pharmaceutical Ind. Ltd., sanofi-aventis, Merck Serono, and
Bayer Schering; and lecture fees from Novartis, Teva Pharmaceutical. M. Filippi serves on scientific advisory boards
for Teva Pharmaceutical Industries Ltd. and Genmab A/S; has received funding for travel from Bayer Schering
Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as a consultant
to Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.;
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serves on speakers’ bureaus for Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, and Teva
Pharmaceutical Industries Ltd.; and receives research support from Bayer Schering Pharma, Biogen Idec, Genmab
A/S, Merck Serono, Teva Pharmaceutical Industries Ltd, Italian Ministry of Health, Fondazione Italiana Sclerosi
Multipla, Cure PSP, and the Jacques and Gloria Gossweiler Foundation (Switzerland).
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Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Laquinimod modulates inflammation in peripheral blood of relapsing remitting
multiple sclerosis patients
R. Zilkha-Falb, M. Gurevich, L. Hayardeny, A. Achiron (Ramat-Gan, Petach-Tikva, IL)
Background: Laquinimod is a new immunomodulatory drug aimed as an oral treatment for relapsing remitting multiple
sclerosis (RRMS). Laquinimod affects the immune system and has immune modulatory properties; however its
molecular mechanisms of action are partially elucidated.
Objectives: To investigate peripheral blood molecular pathways associated with Laquinimod treatment in RRMS.
Methods. Peripheral blood mononuclear cells (PBMC) samples were obtained from RRMS patients that participated
in the Allegro Laquinimod trial. There were 12 patients in the active treatment arm, age 38.1±2.2 years, female to
male ratio 7:5) and 9 in the placebo arm. Gene expression using HU-133A-2 Affymetrix arrays was performed at
baseline and after 1 and 6 months of Laquinimod treatment.
Data was analyzed by Partek Genomics Solution software (www.partek.com). Most informative genes (MIGs) were
defined as those that differentiated between groups with p<0.01. Gene functional annotation, enrichment, and
pathway analyses were performed by Ingenuity (www.ingenuity.com). For each time point genes that differed in the
placebo group were excluded from further analyses.
Results: Laquinimod induced a differential gene expression of 354 MIGs at 1 month and 1562 at 6 months of
treatment. Functional enrichment analysis at 1 month of Laquinimod treatment demonstrated over-presentation of
genes involved in suppression of inflammatory response (p value range 3.4*10^-10 to 1.1*10^-2). This included down
regulation of phagocytes adhesion (p=1.2*10^-3) and chemotaxis of neutrophils (p=6.0*10^-3) based on down
regulation of TGFB1, ITGB1, ITGB3, ITGB5, CXCL5, ITGB1, MMP1, TGFB1 genes. The down regulation of
inflammation was further strengthened after 6 months of Laquinimod treatment; there was down regulation of
adhesion, migration and leukocyte extravasation signaling (p value range 4.6*10^-7 to 5.4*10^-2) followed by down
regulation of IL-1R, IL-8R, IL-22R, IL-9, TNFRSF4, and RORC.
Conclusions: The immunomodulatory effects of Laquinimod via downregulation of pro-inflammatory constituents
associated with adhesion, migration and extravasation of PBMC were demonstrated overtime, that could contribute to
amelioration of clinical symptoms of RRMS patients.
Rina Zilkha-Falb has nothing to disclose Michael Gurevich has nothing to disclose Liat Hayardeney is a Scientific
Director at Teva Pharmaceutical Anat Achiron has nothing to disclose
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Inflammation and tissue damage
Thursday, October 03, 2013, 15:45 - 17:00
Laquinimod prevents NMOIg-induced disease exacerbation in a model of
neuromyelitis optica
A. Argaw, L. Asp, J. Zhang, P. Waters, L. Hayardeny, M. Levy, G. John (New York, US; Oxford, GB; Netanya, IL;
Baltimore, US)
Neuromyelitis optica (NMO) is an autoimmune neurologic disease characterized by a serum autoantibody, NMOIg,
which targets the astrocytic water channel aquaporin-4 (AQP4) and causes significant tissue damage upon CNS entry
through a disrupted blood-brain barrier (BBB). Current therapies target autoantibody production, but agents that
restrict BBB breakdown could provide additional, perhaps synergistic patient benefits. Recently, we showed that
inflammatory BBB disruption is driven in part by reactive astroglial responses, via mechanisms that include VEGF-A
production and consequent eNOS-dependent downregulation of endothelial BBB tight junctions. Here, we show that
inhibition of these responses using the innate immunomodulator Laquinimod successfully restricts NMOIg CNS entry
and exacerbation of neuropathology and neurologic deficit in an animal model of NMO. C57BL/6 immunized with
MOG35-55 received high-titer NMOIg or control Ig via passive transfer from 14-18dpi, and mice receiving NMOIg
were also treated with Laquinimod 25mg/kg or vehicle daily from immunization. Importantly, NMOIg severely
exacerbated paralysis in MOG35-55-immunized controls, resulting in 50% mortality. In contrast, in Laquinimodtreated immunized mice, NMOIg had no exacerbatory effects, and all mice survived. Spinal cords of controls
displayed severe subpial and perivascular pathology characterized by reactive gliosis, BBB breakdown and
autoantibody entry, severe inflammation and necrotic damage to astrocytes, oligodendrocytes and axons. In contrast,
in Laquinimod-treated mice, glial reactivity, BBB breakdown and inflammatory infiltrates were strikingly reduced, and
neuropathology rescued. These effects were associated with reduced astrocytic production of inflammatory factors
including VEGF-A in spinal cords in vivo, and correlated with Laquinimod modulation of inflammatory responses in
primary human astrocyte cultures. Collectively, these data demonstrate that Laquinimod treatment prevents disease
exacerbation in a model of NMO, suggesting its use in combination therapy to restrict neuropathology and neurologic
deficits in patients.
This work was supported by a Teva Pharmaceuticals Research Award to GRJ, and by a Unity Grant Award from the
Guthy-Jackson Charitable Foundation to GRJ and ML. LH is an employee of Teva Pharmaceuticals.
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Tools for detecting therapeutic response
Friday, October 04, 2013, 15:30 - 17:00
Evaluating the relationship between laquinimod's effects on relapse and disability
progression
M.P. Sormani, G. Cutter, G. Comi, T. Vollmer, P.S. Sorensen, D. Ladkani, N. Sasson, V. Knappertz (Genoa, IT;
Birmingham, US; Milan, IT; Aurora, US; Copenhagen, DK; Petah Tikva, Netanya, IL; Düsseldorf, DE / Frazer, US)
Background: For several MS treatments a strong relationship between their effect on reducing relapses and their
therapeutic effect on disability progression in two- to three-year trials has been noted. (Sormani et al Neurology
2010;75:302-309). This derived equation was applied to the pooled data from laquinimod’s two phase 3 trials to
evaluate the relationship of laquinimod’s effect on relapses to its effect on confirmed disability progression.
Objective: To assess whether the observed laquinimod effect on disability progression is within the range of predicted
relationship between relapse rate reduction and the risk reduction in disability progression.
Methods: We used the published regression equation which linked the effect on relapse rate (REL) with that on
disability progression (DIS) in an attempt to assess if laquinimod's observed effect on disability progression is in the
range of predicted values obtained by the equation. To achieve that we used the observed effect of relapses in a
pooled data set from the phase 3 ALLEGRO and BRAVO trials.
Sormani Equation: Log (DIS-effect) = 0.10 + 0.63* log (REL-effect)
The ratio between the relapse rate in the laquinimod (n = 984) arm and placebo arm (n =1006) was used as the
summary treatment effect on relapses (REL-effect), and the ratio between the proportion of patients with confirmed
disability progression in the laquinimod and placebo arms was used as a summary estimate of the treatment effect on
disability progression.
Results: The observed effect of laquinimod on relapse rate in the pooled material was: (RR = 0.79 [95%CI: 0.69-0.89,
p = 0.0002]. Using this observed effect on relapses in the equation yielded a predicted reduction in disability
progression with laquinimod, of only 5% (RR = 0.95 [95% CI: 0.87-1.00]), which was disproportionately lower than the
observed 29% reduction in disability progression sustained for 3 months (RR = 0.71 [95% CI: 0.55-0.91]). Importantly,
only marginal overlap between the 95% CI of the predicted and observed reduction in disability progression was
apparent, suggesting a pronounced dissociation between the effect on relapses and the effect on disability.
Conclusions: The observed effect of laquinimod on reducing the risk of disability progression is larger than predicted
by the observed effects on relapse rate reduction.
M.P. Sormani has received personal compensation for consulting services and for speaking activities from Allozyne,
Merck Serono, Teva, Synthon, Actelion and Biogen Idec G. Cutter participated in the last 12 months in Data Safety
Monitoring Committees for Apotek, Biogen-Idec, Cleveland Clinic, Glaxo Smith Klein Pharmaceuticals, Gilead
Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Neuren, PCT Bio, Revalesio, SanofiAventis, Teva, Vivus, NHLBI (Protocol Review Committee), NINDS, NMSS, NICHD (OPRU oversight committee). He
has received consulting or speaking fees in the last 12 months for Alexion, Allozyne, Bayer, Celgene, Coronado
Biosciences, Consortium of MS Centers (grant), Diogenix, Klein-Buendel Incorporated, Medimmune, Novartis, Nuron
Biotech, Receptos, Spiniflex Pharmaceuticals, Teva Pharmaceuticals G. Comi received consulting fees for advisory
boards, consultancy and speaker activities from Novartis, Teva Pharmaceutical Ind. Ltd., sanofi-aventis, Merck
Serono, and Bayer Schering; and lecture fees from Novartis, Teva Pharmaceutical. T Vollmer has received consulting
fees, and his institution has received a grant and consulting fee for his participation in the BRAVO study; is a board
member of Rocky Mountain MS Center; his institution has received consultancy fees from Biogen-Idec, Teva, Elan,
Hoffman-LaRoche, Accelerated Cure Project, Genzyme, Bristol-Myers Squibb, Acorda, Novartis, Questor, Medscape,
Xenoport, and Sanofi; his institution received fees for expert testimony from Ham VS Bennett and Wagner VS Strand;
his institution received grants/grants pending from Teva, Biogen Idec, Genzyme, Ono, Eli Lilly, Novartis, BioMS,
Orasi, Sanofi-Aventis, NIH, EMD Sorono, Acorda, Accelerated Cure Project, Hoffmann-LaRoche, Jensen Research,
Daiichi Sankyo, Elan, Janssen Pharmaceutical, Avanir Pharmaceutical, MedImmune, Delta Quest, Biosite Inc.,
University of Alabama, and Genentech. P-S Sorensen has received payment as co-principal investigator and for
travel support for the BRAVO study from Teva; he has received consultancy fees from Merck Serono, Teva, Novartis,
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Sanofi-Aventis, and Biogen-Idec; his institution has received research support grants/grants pending from BiogenIdec, Novartis, and Sanofi-Aventis; and is on the speaker’s bureau of Merck Serono, Novartis, Bayer Schering, Teva,
Sanofi-Aventis, Biogen-Idec, and Genzyme. D. Ladkani is employed by Teva; owns stock in and receives
travel/meeting expenses from Teva N. Sasson is employed by Teva; owns stock in and receives travel/meeting
expenses from Teva V. Knappertz is employed by Teva; owns stock in and receives travel/meeting expenses from
Teva
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Long-term treatment monitoring
Friday, October 04, 2013, 15:30 - 17:00
Multicentre, randomized, placebo controlled study to evaluate the efficacy, safety
and tolerability of two doses of oral laquinimod (0.6mg/day and 1.2mg/day) for the
treatment of patients with relapsing remitting multiple sclerosis
T. Vollmer, X. Montalban, G. Comi, T. Ziemssen, A. Boyko, P. Vermersch, N. Sasson, T. Gorfine, V. Knappertz, M.
Filippi (Aurora, US; Barcelona, ES; Milan, IT; Frankfurt, DE; Moscow, RU; Lille, FR; Netanya, IL; Düsseldorf, DE/
Frazer, US)
Background: Orally administered laquinimod 0.6mg was tested in two phase 3 trials (ALLEGRO and BRAVO) for the
treatment of relapsing-remitting multiple sclerosis (RRMS). The observed clinical benefits of laquinimod indicate a
distinctive efficacy profile with a robust effect on relapse rate coupled with a larger than predicted effect on disability
progression. During the laquinimod development program, a pattern of dose-effect was observed suggesting a higher
dose may be associated with greater efficacy, while preserving an adequate safety and tolerability profile.
Objective: The present phase 3 study evaluates efficacy, safety and tolerability of a daily dose of 0.6 mg or 1.2 mg of
laquinimod as compared to placebo in patients with RRMS.
Method: Approximately 1800 patients diagnosed with RRMS (McDonald 2010 revised criteria) are being randomized
into one of 3 blinded treatment arms (0.6mg laquinimod daily, 1.2mg laquinimod daily or matching placebo). Sample
size reassessment is scheduled to be performed 2 months prior to the end of recruitment in order to verify event rate
assumptions. To enrol, patients aged 18–55 years must have EDSS scores 0 to 5.5, 1 relapse in previous 12 months,
and a disease duration less than 15 years. Period 1 is a double-blind, placebo-controlled period lasting until all
patients have completed at least 15 months but no more than 2 years of treatment. Based on the different efficacy
profile of laquinimod, and contrary to other clinical trials of RRMS treatments, the primary endpoint of CONCERTO is
time to confirmed disease progression (CDP). CDP is defined as an increase of EDSS >=1 point from baseline for
patients with baseline EDSS <=5.0, or an EDSS increase >=0.5 for patients with baseline EDSS of 5.5, sustained for
at least 3 months. Progression cannot be confirmed during a relapse. Secondary endpoints include percent brain
volume change from baseline to month 15 and time to first confirmed relapse during Period 1; additional endpoints
include safety, tolerability, cognition, MRI, and quality of life.
Results: Study enrolment began in February 2013 and last patient enrolment date is Feb 2015.
Conclusion: CONCERTO trial is aimed to provide additional confirmatory data to substantiate the effect of 0.6 mg/day
dose of laquinimod for the treatment of subjects with RRMS and to explore whether the 1.2 mg/day dose is
associated with a greater efficacy, while preserving an adequate safety and tolerability profile.
T. Vollmer has received consulting fees, and his institution has received a grant and consulting fee for his
participation in the BRAVO study; is a board member of Rocky Mountain MS Center; his institution has received
consultancy fees from Biogen-Idec, Teva, Elan, Hoffman-LaRoche, Accelerated Cure Project, Genzyme, BristolMyers Squibb, Acorda, Novartis, Questor, Medscape, Xenoport, and Sanofi; his institution received fees for expert
testimony from Ham VS Bennett and Wagner VS Strand; his institution received grants/grants pending from Teva,
Biogen Idec, Genzyme, Ono, Eli Lilly, Novartis, BioMS, Orasi, Sanofi-Aventis, NIH, EMD Sorono, Acorda,
Accelerated Cure Project, Hoffmann-LaRoche, Jensen Research, Daiichi Sankyo, Elan, Janssen Pharmaceutical,
Avanir Pharmaceutical, MedImmune, Delta Quest, Biosite Inc., University of Alabama, and Genentech. X. Montalban
has received honoraria for speaking and travel expenses to scientific meetings; steering member or participated in
advisory boards in corporate-sponsored clinical trials or has had consulting agreements with Bayer Schering Pharma,
Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Adventis, and Teva G. Comi received
consulting fees for advisory boards, consultancy and speaker activities from Novartis, Teva Pharmaceutical Ind. Ltd.,
sanofi-aventis, Merck Serono, and Bayer Schering; and lecture fees from Novartis, Teva Pharmaceutical. T.
Ziemssen has received speaker honoraria from Biogen Idec, Sanofi-Aventis, Merck-Serono, Novartis, Teva, and
Bayer Healthcare. He serves as a consultant for Teva, Novartis, and Bayer HealthCare, and receives research
support from the Roland Ernst Foundation. A. Boyko is a member of advisory boards, speaker and investigator of
clinical trials from Novartis, Merck Serono, TEVA, Genzyme, Biogen Idec and Nicomed. P. Vermersch has received
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consulting fees from Teva, BiogenIdec, Novartis, Bayer, Merck-Serono, Sanofi-Aventis and Genzyme and has
received grant/grant pending from Teva, Bayer, Merck-Serono and BiogenIdec. He has received travel support from
Novartis, BiogenIdec, Bayer, Merck-Serono and Teva. N. Sasson is employed by Teva; owns stock in and receives
travel/meeting expenses from Teva T. Gorfine is employed by Teva; owns stock in and receives travel/meeting
expenses from Teva; and is a co-holder of patents with Teva. V. Knappertz is employed by Teva; owns stock in and
receives travel/meeting expenses from Teva M. Filippi serves on scientific advisory boards for Teva, Pepgen, and
Genmab A/S; travel expenses from Bayer Schering Pharma, Biogen-Dompe, Genmab A/S, Merck Serono, and Teva;
serves as a consultant to Bayer Schering Pharma, Biogen-Dompe, Genmab A/S, Merck Serono, and Teva; serves on
speaker bureaus for Bayer Schering Pharma, Biogen-Dompe, Genmab A/S, Merck Serono and Teva
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Long-term treatment monitoring
Friday, October 04, 2013, 15:30 - 17:00
The risk of disability progression is associated with multiple sclerosis functional
composite (MSFC) scores in the laquinimod phase 3 trials
P.S. Sorensen, G. Cutter, T. Vollmer, G. Comi, D. Ladkani, N. Sasson, V. Knappertz (Copenhagen, DK; Birmingham,
Aurora, US; Milan, IT; Petah Tikva, Netanya, IL; Düsseldorf, DE / Frazer, US)
Background: The Multiple Sclerosis Functional Composite (MSFC) is a three-part instrument that measures cognition,
ambulation, and arm/hand function using the PACED Auditory Serial Attention Test (PASAT), Timed 25-Foot Walk
(T25FW) and the 9-Hole Peg Test (9-HPT), respectively. Laquinimod, an oral immunomodulator under development
for treatment of relapsing forms of multiple sclerosis, consistently reduced percent brain volume loss and slowed
disability progression in its phase 3 trials, but it did not significantly improve overall MSFC z-scores compared with
placebo.
Objective: To examine the association between changes in MSFC z-scores from baseline to month 24 and confirmed
disability progression (CDP) sustained for 3 months in laquinimod and placebo patients.
Methods: The pooled data set from the phase 3 ALLEGRO and BRAVO trials were used in post-hoc analyses that
classified patients based on their changes in MSFC z-scores from baseline to month 24 into 4 quartiles (25%, 50%,
75%, 100%), with the first quartile (Q25%) comprising patients with the worst changes in MSFC, and the 4th quartile
(Q100%) comprising patients with the best changes in MSFC scores. Confirmed disability progression was defined as
an increase sustained for 3 months from a baseline EDSS score of >=1.0 points if baseline EDSS was 0–5.0, or 0.5
points if baseline EDSS >=5.5.
Results: For patients with confirmed disability progression, 43.7% were from the worsened Q25% quartile and 17.8%
were from the improved Q100% quartile. For the laquinimod group, the risk for progression was lowest in the
improved Q100% quartile (6.19%), almost half the risk for the placebo patients (12.7%). For the 3 components of the
MSFC (PASAT, 25FTW, and 9-HPT) separately, there was an increased risk for disability progression associated
with the worsened Q25% quartile, and this risk was reduced for the laquinimod group relative to placebo. There was
an inverse relationship between the overall MSFC z-score and EDSS individual scores at month 12 (r = –0.52, P <
0.0001) and at month 24 (r = –0.55, P < 0.0001).
Conclusions: The risk of disability progression is associated with the change in MSFC, with highest rate of
progression in quartile showing the most worsening on the MSFC. The result was seen both for the composite score
and for the three components. The association is more prominent for laquinimod treated than placebo treated
patients.
P-S Sorensen has received payment as co-principal investigator and for travel support for the BRAVO study from
Teva; he has received consultancy fees from Merck Serono, Teva, Novartis, Sanofi-Aventis, and Biogen-Idec; his
institution has received research support grants/grants pending from Biogen-Idec, Novartis, and Sanofi-Aventis; and
is on the speaker’s bureau of Merck Serono, Novartis, Bayer Schering, Teva, Sanofi-Aventis, Biogen-Idec, and
Genzyme. G. Cutter participated in the last 12 months in Data Safety Monitoring Committees for Apotek, Biogen-Idec,
Cleveland Clinic, Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Modigenetech/Prolor, Merck/Ono
Pharmaceuticals, Merck, Neuren, PCT Bio, Revalesio, Sanofi-Aventis, Teva, Vivus, NHLBI (Protocol Review
Committee), NINDS, NMSS, NICHD (OPRU oversight committee). He has received consulting or speaking fees in the
last 12 months for Alexion, Allozyne, Bayer, Celgene, Coronado Biosciences, Consortium of MS Centers (grant),
Diogenix, Klein-Buendel Incorporated, Medimmune, Novartis, Nuron Biotech, Receptos, Spiniflex Pharmaceuticals,
Teva Pharmaceuticals T. Vollmer has received consulting fees, and his institution has received a grant and consulting
fee for his participation in the BRAVO study; is a board member of Rocky Mountain MS Center; his institution has
received consultancy fees from Biogen-Idec, Teva, Elan, Hoffman-LaRoche, Accelerated Cure Project, Genzyme,
Bristol-Myers Squibb, Acorda, Novartis, Questor, Medscape, Xenoport, and Sanofi; his institution received fees for
expert testimony from Ham VS Bennett and Wagner VS Strand; his institution received grants/grants pending from
Teva, Biogen Idec, Genzyme, Ono, Eli Lilly, Novartis, BioMS, Orasi, Sanofi-Aventis, NIH, EMD Sorono, Acorda,
Accelerated Cure Project, Hoffmann-LaRoche, Jensen Research, Daiichi Sankyo, Elan, Janssen Pharmaceutical,
70
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Avanir Pharmaceutical, MedImmune, Delta Quest, Biosite Inc., University of Alabama, and Genentech. G. Comi
received consulting fees for advisory boards, consultancy and speaker activities from Novartis, Teva Pharmaceutical
Ind. Ltd., sanofi-aventis, Merck Serono, and Bayer Schering; and lecture fees from Novartis, Teva Pharmaceutical. D.
Ladkani is employed by Teva; owns stock in and receives travel/meeting expenses from Teva N. Sasson is employed
by Teva; owns stock in and receives travel/meeting expenses from Teva V. Knappertz is employed by Teva; owns
stock in and receives travel/meeting expenses from Teva
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Immunomodulation/Immunosuppression
Friday, October 04, 2013, 15:30 - 17:00
Dose-dependent effects of laquinimod in multiple sclerosis patients on the innate
immune system
T. Sehr, K. Thomas, M. Marggraf, O. Bar-Ilan, L. Hayardeny , T. Ziemssen (Dresden, DE; Netanya, IL)
Background: Laquinimod (LAQ) is an innovative oral drug under development for the treatment of relapsing remitting
multiple sclerosis (MS). The mechanism of action is still under investigation. LAQ was demonstrated to have
significant effects on the innate immune system. Recently antigen presenting cells (APC) populations were reported
to be altered in function and frequency by LAQ therapy in experimental autoimmune encephalomyelitis (EAE) model.
Human data are rare published yet.
Methods: Patients treated with different doses of LAQ (0.6 mg to 2.7 mg) as part of the MTD trial LAQ101. Blood
samples were analyzed by FACS before and after 4 weeks on daily LAQ treatment. Special focus was on different
innate immune cell populations. Additionally apoptotic signal of Monocytes (MO) and slanDCs were analyzed after
immunomagnetic isolation (MACS) in the presence and absence of LAQ in-vitro.
Results: We could demonstrate a significant decrease of frequencies of slanDC (0,32% to 0,12%, p<0,0001) and
other DC populations after 4 weeks of LAQ treatment, while others like MO were unaffected (6.97% to 7,57%). Cell
frequencies of placebo-treated patients kept stable. There is also tendency of a dose-dependent modulation of certain
DC populations. This dose-dependency was significant for the proinflammatory slanDCs (slope, p<0,0001). In-vitro
experiments demonstrated increased apoptosis signals in slanDCs incubated with LAQ in comparison to untreated
slanDC (PI mean 426,3 vs. 284,0).
Conclusions: We could demonstrate significant dose-dependent, in-vivo effects of LAQ with special focus on the
innate immune system: While MO were not affected, we found dose-dependent effects on DC populations. The
mechanism and functional impact of this effect need further investigations.
Study supported by: TEVA U. Hainke and M. Marggraf have nothing to disclose. T. Sehr received travel support from
Teva, Novartis and Biogen idec. K. Thomas received personal compensation for oral presentation from Novartis and
travel support from Biogen idec, Genzyme and Teva. T. Schultheiss received personal compensation for oral
presentations from Biogen idec and Sanofi. T. Ziemssen received personal compensation from Biogen Idec, Bayer,
Novartis, Sanofi, Teva, Synthon for consulting services. Additionally he received financial support for research
activities from Bayer, Biogen Idec, Novartis, Teva, Sanofi Aventis. L. Hayardeny and O. Bar-Ilan are employees of
Teva-Pharmaceutical Industries
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Window of opportunity in MS treatment
Thursday, October 03, 2013, 12:01 - 12:13
TOPIC main outcomes: efficacy and safety of once-daily oral teriflunomide in
patients with clinically isolated syndrome
A. Miller, J. Wolinsky, L. Kappos, G. Comi, M.S. Freedman, T. Olsson, A. Rugina, D. Bauer, J. Delhay, B. Wamil, P.
Truffinet, P. O’Connor (New York, Houston, US; Basel, CH; Milan, IT; Ottawa, CA; Stockholm, SE; Chilly-Mazarin,
FR; Bridgewater, US; Toronto, CA)
Introduction: Teriflunomide is a novel, once-daily, oral immunomodulator approved in the USA, Argentina and
Australia for treatment of relapsing MS (RMS). Clinical studies of teriflunomide in patients with RMS (TEMSO
NCT00134563; TOWER NCT00751881) showed consistent efficacy across key clinical measures and a wellcharacterised safety profile. TOPIC (NCT00622700) is a phase 3 clinical trial conducted to assess the efficacy and
safety of teriflunomide in patients with a first clinical episode suggestive of MS (clinically isolated syndrome, CIS).
Methods: In TOPIC, a double-blind, placebo-controlled, parallel-group study, 618 patients with CIS were enrolled
from Feb 2008 to Sep 2012 (planned end Dec 2012) and randomized to placebo, teriflunomide 7 mg or teriflunomide
14 mg. TOPIC ended early as revised diagnostic criteria enabled earlier diagnosis of MS. The primary and key
secondary endpoints were conversion to clinically definite MS (CDMS) and occurrence of a new clinical relapse or
MRI lesion. Other efficacy endpoints and safety/tolerability were also assessed.
Results: Baseline characteristics were generally well balanced among treatment groups. Of the randomized
population (n=618), 59.1% had monofocal and 40.9% had multifocal lesion presentation, and 31.4% had >=1 Gdenhancing lesion. Median time since first neurological event was 2 months. Compared with placebo, teriflunomide 14
mg reduced the risk of conversion to CDMS by 42.6% (p=0.0087), with a probability of conversion to CDMS at 108
weeks of 24.0% (probability for placebo group 35.9%). Teriflunomide 14 mg also reduced the risk of occurrence of
new relapse or new MRI lesion by 34.9% (p=0.0003). Teriflunomide 7 mg reduced the risk of conversion to CDMS by
37.2% (p=0.0271; 108-week probability 27.6%), and the risk of occurrence of new relapse or new MRI lesion by
31.4% (p=0.0020). The proportion of patients experiencing adverse events (AEs) was similar across treatment
groups. The most common AEs reported more frequently in the teriflunomide arms included alanine aminotransferase
elevation, headache, hair thinning (14 mg only), diarrhoea and paraesthesia.
Conclusions: Results from the TOPIC study demonstrate the efficacy of teriflunomide 14 mg and 7 mg in the
treatment of patients with CIS, highlighting the ability of early intervention with teriflunomide to delay onset of MS
symptoms. To date, all teriflunomide phase 3 studies have shown consistent safety and efficacy, and greater efficacy
for a 14 mg dose.
Study supported by Genzyme, a Sanofi company. Aaron E Miller has received research support from Acorda
Therapeutics, Biogen Idec, Genentech, Genzyme Corporation, sanofi-aventis, Novartis, Osmotica, Roche and Teva.
He has received consulting fees from Acorda Therapeutics, , Biogen Idec, , EMD Serono, GlaxoSmithKline, Merck
Serono, Novartis, Nuron Biotech, ONO and sanofi-aventis. Jerry S Wolinsky has received consulting/speaker fees
from Celgene, Consortium of MS Clinics, Genzyme, Janssen RND, Hoffman LaRoche, Medscape CME, Novartis,
PRIME, sanofi-aventis, Serono Symposia International Foundation, Teva, Teva Neurosciences; royalties from
Millipore (Chemicon International) Corporation; research / contractual support from: Genzyme, National MS Society,
National Institutes of Health, and sanofi Ludwig Kappos has received research support from Actelion, Advancell,
Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin,
CSL Behring, Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis,
Novonordisk, Peptimmune, sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth, and from the Swiss MS Society,
the Swiss National Research Foundation, the European Union, and the Gianni Rubatto, Novartis, and Roche
Research Foundations. Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Ind. Ltd,
sanofi-aventis, Merck Serono, Actelion and Bayer Scherin; lecture fees: Novartis, Teva Pharmaceutical Ind. Ltd,
sanofi-aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation. Mark
S Freedman has received research and educational grant support from Bayer Healthcare and Genzyme;
honoraria/consultation fees from Bayer Healthcare, Biogen Idec, EMD Canada, Novartis, sanofi-aventis, Teva
Canada Innovation and is a member of Company Advisory Board/Board of Directors/or other similar group for Bayer
73
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Celgene. Tomas P Olsson has received
consulting fees and/or research support from Biogen Idec, Merck Serono, and sanofi-aventis; participation in scientific
advisory boards and/or speaking activities: Merck Serono, Biogen Idec and sanofi-aventis. Anca Rugina, Deborah
Bauer, Jean-Luc Delhay, Barbara D. Wamil, and Philippe Truffinet are employees of Sanofi Paul O’Connor has
received consulting fees and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi
Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, and Teva.
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Long-term safety and efficacy of teriflunomide in patients with relapsing forms of
multiple sclerosis in the TEMSO extension trial
M. Freedman, J. Wolinsky, G. Comi, L. Kappos, T. Olsson, A. Miller, M. Benamor, D. Dukovic, J. Liang, P. Truffinet,
P. O'Connor (Ottawa, CA; Houston, US; Milan, IT; Basel, CH; Stockholm, SE; New York, US; Chilly-Mazarin, FR;
Bridgewater, US; Toronto, CA)
Introduction: Teriflunomide is an oral immunomodulator approved in the USA, Argentina and Australia for use in
patients with relapsing multiple sclerosis (RMS). TEMSO (NCT00134563) was a randomised controlled 2-year trial of
teriflunomide (14 or 7 mg) or placebo (pbo) in 1088 patients with RMS. Here we report long-term safety and efficacy
of teriflunomide in TEMSO and its extension (NCT00803049).
Methods: Patients completing TEMSO could enrol in a double-blind extension trial starting in October 2006. Patients
previously receiving teriflunomide remained on their original dose; those previously receiving pbo were randomised
1:1 to teriflunomide 14 or 7 mg. Data presented here include patients treated for up to 8 years (cut-off June 2012); an
updated analysis will be presented, including patients receiving teriflunomide for up to 9 years (cut-off June 2013).
Results: As of June 2012, cumulative duration of exposure to teriflunomide was 1106 and 1138 patient-years for 14
and 7 mg doses, respectively; 505 patients of the 1088 originally randomised remained on study. Relapse rates
remained low from the core study throughout the extension study. Adjusted annualised relapse rates (ARR) at the
cut-off date were 0.19 and 0.22 for patients who had continuously received teriflunomide 14 or 7 mg, and 0.21 and
0.24 for patients who had switched from pbo to teriflunomide 14 or 7 mg. In comparison, the ARR at 2 years in the
core study was 0.54 in the pbo group, and 0.37 in both teriflunomide groups.
As observed in the core study, the most common (>15% in a group) adverse events (AEs) were nasopharyngitis,
diarrhoea, hair thinning, increased alanine aminotransferase (ALT), influenza, pain in extremity and headache. The
incidence of AEs did not vary between groups and did not increase with treatment duration. About 20% of patients
experienced serious AEs, the most common being increased ALT (n=14), intervertebral disc protrusion (n=7), venous
stenosis (n=4), urinary tract infection (n=4) and pneumonia (n=3). All other serious AEs occurred in 2 or fewer
patients. There were 3 deaths, none of which were considered related to study treatment.
Conclusions: Relapse rates remained low in this long-term follow up in patients receiving teriflunomide for up to 8
years in TEMSO and its extension through June 2012. Safety observations in the extension study were also
consistent with the 2-year core trial, with no new unexpected AEs with long-term exposure.
Study supported by Genzyme, a Sanofi company. Giancarlo Comi has received consulting fees from Novartis, Teva
Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Actelion and Bayer Scherin; lecture fees: Novartis, Teva
Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia
International Foundation. Ludwig Kappos has received research support from Actelion, Advancell, Allozyne,
BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CSL Behring,
Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk,
Peptimmune, sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth, and from the Swiss MS Society, the Swiss
National Research Foundation, the European Union, and the Gianni Rubatto, Novartis, and Roche Research
Foundations. Tomas P Olsson has received consulting fees and/or research support from Biogen Idec, Merck
Serono, and sanofi-aventis; participation in scientific advisory boards and/or speaking activities: Merck Serono,
Biogen Idec and sanofi-aventis. Aaron E Miller has received research support from Acorda Therapeutics, Biogen
Idec, Genentech, Genzyme Corporation, sanofi-aventis, Novartis, Osmotica, Roche and Teva. He has received
consulting fees from Acorda Therapeutics, , Biogen Idec, , EMD Serono, GlaxoSmithKline, Merck Serono, Novartis,
Nuron Biotech, ONO and sanofi-aventis. Jerry S Wolinsky has received consulting/speaker fees from Celgene,
Consortium of MS Clinics, Genzyme, Janssen RND, Hoffman LaRoche, Medscape CME, Novartis, PRIME, sanofiaventis, Serono Symposia International Foundation, Teva, Teva Neurosciences; royalties from Millipore (Chemicon
International) Corporation; research / contractual support from: Genzyme, National MS Society, National Institutes of
Health, and sanofi. Mark S Freedman has received research and educational grant support from Bayer Healthcare
75
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
and Genzyme; honoraria/consultation fees from Bayer Healthcare, Biogen Idec, EMD Canada, Novartis, sanofiaventis, Teva Canada Innovation and is a member of Company Advisory Board/Board of Directors/or other similar
group for Bayer Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Celgene. Paul O’Connor has
received consulting fees and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi
Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, and Teva.
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Others
Thursday, October 03, 2013, 15:45 - 17:00
Pooled safety data from three placebo-controlled teriflunomide studies
T. Leist, M. Freedman, L. Kappos, T. Olsson, A. Miller, J. Wolinsky, P. O'Connor, M. Benamor, J. Delhay, P. Truffinet,
D. Dukovic, J. Li, G. Comi (Philadelphia, US; Ottawa, CA; Basel, CH; Stockholm, SE; New York, Houston, US;
Toronto, CA; Chilly Mazarin, FR; Bridgewater, King of Prussia, US; Milan, IT)
Introduction: Teriflunomide is a novel, once-daily, oral immunomodulator approved in the USA, Australia and
Argentina for treatment of relapsing MS (RMS). In phase 2 and 3 studies, teriflunomide was superior to placebo on
relapse rate and disability progression, and had consistent safety findings across studies.
Methods: Data were pooled from three double-blind studies. Patients with RMS were randomised 1:1:1 to placebo,
teriflunomide 7mg or 14mg, and treated for 36 weeks (phase 2: NCT01487096), 108 weeks (TEMSO: NCT00134563)
or 48–152 weeks (TOWER: NCT00751881). Safety assessments included treatment-emergent adverse events
(TEAEs), laboratory parameters and physical examinations. Patients with confirmed alanine aminotransferase (ALT)
>3x upper limit of normal (ULN) or neutrophil counts <1000 cells/µL were required to discontinue study treatment.
Results: The analysis included 2430 patients with cumulative treatment exposure >1225 patient-years per group.
Common TEAEs reported more frequently in teriflunomide patients were hair thinning, diarrhoea, ALT elevation,
nausea and headache. Most events did not require corrective treatment and many resolved on-therapy, although
TEAEs leading to permanent discontinuation were more frequent with teriflunomide (placebo, 6.9%; 7mg, 11.0%,
14mg, 13.6%), mostly due to the protocol requirements in case of ALT elevations. While asymptomatic, transient, ALT
elevations were more frequent in teriflunomide patients, the incidence of ALT>3xULN and serious hepatic disorders
was similar across groups. Serious infections were rare (<=2.5%) in all groups. Maximum mean decreases in
neutrophil and lymphocyte counts were ~15%; mean absolute counts remained within normal range, and they were
not associated with increased infections. Neoplasms (benign or malignant) occurred in <0.5% of patients (placebo,
n=4; 7mg, n=1; 14mg, n=3); no haematological or lymphoproliferative malignancies were reported. Mean changes in
supine systolic blood pressure (BP, mm Hg) at Week 108 were -0.7 (placebo), 3.0 (7mg), 2.7 (14mg); and in diastolic
BP were -0.7 (placebo), 1.4 (7mg), 1.6 (14mg). There were 4 deaths (placebo: respiratory infection; teriflunomide:
motor vehicle accident, suicide, sepsis).
Conclusions: This pooled analysis of >2500 patient-years of teriflunomide exposure did not identify any previously
unrecognised safety signals beyond those detected in individual trials. Overall, both doses of teriflunomide had similar
and manageable safety profiles.
Study supported by Genzyme, a Sanofi company. Thomas P Leist has received honoraria as a consultant from
Biogen-Idec, Bayer, EMD Serono, Novartis, Genzyme, Teva Neuroscience and as a speaker from Teva
Neuroscience and Novartis and has participated as site investigator in clinical trials sponsored by Novartis, BiogenIdec, Sun Pharma, Genzyme, Roche, Bayer, Glaxo. Mark S Freedman has received research and educational grant
support from Bayer Healthcare and Genzyme; honoraria/consultation fees from Bayer Healthcare, Biogen Idec, EMD
Canada, Novartis, sanofi-aventis, Teva Canada Innovation and is a member of Company Advisory Board/Board of
Directors/or other similar group for Bayer Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and
Celgene. Ludwig Kappos has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health
Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CSL Behring, Elan, Genmab,
Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune,
sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth, and from the Swiss MS Society, the Swiss National
Research Foundation, the European Union, and the Gianni Rubatto, Novartis, and Roche Research Foundations.
Tomas P Olsson has received consulting fees and/or research support from Biogen Idec, Merck Serono, and sanofiaventis; participation in scientific advisory boards and/or speaking activities: Merck Serono, Biogen Idec and sanofiaventis. Aaron E Miller has received research support from Acorda Therapeutics, Biogen Idec, Genentech, Genzyme
Corporation, sanofi-aventis, Novartis, Osmotica, Roche and Teva. He has received consulting fees from Acorda
Therapeutics, , Biogen Idec, , EMD Serono, GlaxoSmithKline, Merck Serono, Novartis, Nuron Biotech, ONO and
sanofi-aventis. Jerry S Wolinsky has received consulting/speaker fees from Celgene, Consortium of MS Clinics,
Genzyme, Janssen RND, Hoffman LaRoche, Medscape CME, Novartis, PRIME, sanofi-aventis, Serono Symposia
77
ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
International Foundation, Teva, Teva Neurosciences; royalties from Millipore (Chemicon International) Corporation;
research / contractual support from: Genzyme, National MS Society, National Institutes of Health, and sanofi. Paul
O’Connor has received consulting fees and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci,
Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, and Teva. Myriam Benamor,
Jean-Luc Delhay, Philippe Truffinet, Jing Li and Debbie Dukovic are employees of sanofi. Giancarlo Comi has
received consulting fees from Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Actelion and
Bayer Scherin; lecture fees: Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Biogen Dompè,
Bayer Schering, and Serono Symposia International Foundation.
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Others
Thursday, October 03, 2013, 15:45 - 17:00
Pooled efficacy data from two phase 3 placebo-controlled trials of oral, once-daily
teriflunomide
L. Kappos, G. Comi, M.S. Freedman, A.E. Miller, T.P. Olsson, J.S. Wolinsky, P. Truffinet, S. Cavalier, J.-L. Delhay, D.
Dukovic, P. O’Connor (Basel, CH; Milan, IT; Ottawa, CA; New York, US; Stockholm, SE; Houston, US; ChillyMazarin, FR; Cambridge, US; Bridgewater, US; Toronto, CA)
Introduction: Teriflunomide is a novel, once-daily, oral, disease-modifying therapy (DMT) approved in the USA,
Australia and Argentina for relapsing MS (RMS). Here we present key efficacy outcomes from analyses of pooled
data from two pivotal clinical studies of teriflunomide in patients with RMS: TEMSO (NCT00134563) and TOWER
(NCT00751881).
Methods: TEMSO and TOWER were phase 3, double-blind, placebo-controlled, parallel-group studies. A total of 2251
patients >=18 years with RMS were randomised and treated (modified intent-to-treat population) with once-daily
placebo (pbo), teriflunomide 14 mg or 7 mg for 108 weeks (TEMSO) or 48 weeks after the last patient randomised
(TOWER). The primary and key secondary endpoints were annualised relapse rate (ARR) and 12-week confirmed
disability progression. Subgroups of patients with high disease activity were also analysed: Subgroup A: >=2 relapses
in the past year (n=710); Subgroup B: [(>=1 relapse or 1 gadolinium-enhancing [Gd+] lesion) and prior DMT] or [(>=2
relapses [or 1 relapse and 1 Gd+]) and no prior DMT, and Expanded Disability Status Scale score >=1.5].
Results: Across treatment groups (pbo n=751; 14 mg n=728; 7 mg n=772), patient demographics and baseline
disease characteristics were well balanced. Teriflunomide 14 mg reduced ARR by 33.7% and confirmed disability
progression by 30.5% (p<0.0001 and p=0.0029 vs pbo). Teriflunomide 7 mg reduced ARR by 27% (p<0.0001 vs
pbo), but did not show a significant effect on disability progression. In Subgroup A, similar effects of teriflunomide 14
mg on ARR and disability were also observed in patients with high disease activity. In Subgroup B, teriflunomide 14
mg also significantly reduced time to disability progression confirmed for 24 weeks in patients with high disease
activity (hazard ratio 0.598). Evaluations of the pooled data set revealed no new safety concerns with teriflunomide.
Conclusions: This pooled analysis supports the robust effect of teriflunomide 14 mg on ARR and confirmed disability
progression consistent with the individual studies, which was further confirmed in a group of patients with high
disease activity. The 7 mg dose demonstrated a similar effect on ARR, but no significant impact was observed on
disability progression. Together with a well-characterised and manageable safety profile, these observations indicate
that teriflunomide is a valuable new option for the treatment of RMS.
Ludwig Kappos received research support from Acorda, Actelion, Allozyne, Bayer HealthCare, Bayer Schering,
Bayhill Therapeutics, Biogen Idec, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline,
Glenmark, MediciNova, Merck Serono, Novartis, Novartis Research Foundation, Roche, Roche Research
Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience,
UCB, and Wyeth. Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Ind. Ltd, sanofiaventis, Merck Serono, Actelion and Bayer Scherin; lecture fees: Novartis, Teva Pharmaceutical Ind. Ltd, sanofiaventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation. Mark S
Freedman has received research and educational grant support from Bayer Healthcare and Genzyme;
honoraria/consultation fees from Bayer Healthcare, Biogen Idec, EMD Canada, Novartis, sanofi-aventis, Teva
Canada Innovation and is a member of Company Advisory Board/Board of Directors/or other similar group for Bayer
Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Celgene. Aaron E Miller has received research
support from Acorda Therapeutics, Biogen Idec, Genentech, Genzyme Corporation, sanofi-aventis, Novartis,
Osmotica, Roche and Teva. He has received consulting fees from Acorda Therapeutics, Biogen Idec, EMD Serono,
GlaxoSmithKline, Merck Serono, Novartis, Nuron Biotech, ONO and sanofi-aventis. Tomas P Olsson has received
consulting fees and/or research support from Biogen Idec, Merck Serono, and sanofi-aventis; participation in scientific
advisory boards and/or speaking activities: Merck Serono, Biogen Idec and sanofi-aventis. Jerry S Wolinsky has
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ECTRIMS 2013 ABSTRACTS OF INTEREST
STEPh, Inc., Dr. Jay H. Bauman, ©2013
received consulting/speaker fees from Celgene, Consortium of MS Clinics, Genzyme, Janssen RND, Hoffman
LaRoche, Medscape CME, Novartis, PRIME, sanofi-aventis, Serono Symposia International Foundation, Teva, Teva
Neurosciences; royalties from Millipore (Chemicon International) Corporation; research / contractual support from:
Genzyme, National MS Society, National Institutes of Health, and sanofi. Philippe Truffinet, Jean-Luc Delhay, and
Deborah Dukovic are employees of Sanofi. Steven Cavalier is an employee of Genzyme, a Sanofi Company. Paul
O’Connor has received consulting fees and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci,
Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, and Teva. Study supported by
Genzyme, a Sanofi company.
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Immunomodulation/Immunosuppression
Thursday, October 03, 2013, 15:45 - 17:00
Updated pregnancy outcomes from the teriflunomide clinical development
programme: retrospective analysis of the teriflunomide clinical trial database
B. Kieseier, O. Stüve, M. Benamor, J. Delhay, P. Truffinet (Düsseldorf, DE; Dallas, US; Chilly-Mazarin, FR)
Introduction: Teriflunomide is an oral, once-daily, disease-modifying therapy approved in the USA, Australia and
Argentina for use in patients with relapsing forms of multiple sclerosis (MS). Evidence from animal models suggests a
potential foetal risk from teriflunomide. Although reliable contraception was required during teriflunomide clinical trials,
a number of pregnancies have been reported across the programme.
Methods: Patients were instructed to discontinue study drug upon learning of the pregnancy and undergo accelerated
elimination with cholestyramine or activated charcoal. Pregnancies were reported in the teriflunomide clinical trial
database (data cut-off: 9 April 2013); pregnancy outcome information was collected using a Drug Exposure Via
Parent form.
Results: A total of 81 pregnancies were reported in female patients and 20 in partners of male patients; 1 study
remains blinded with 8 pregnancies (7 in female patients). In the unblinded data, 63 pregnancies were reported in
women exposed to teriflunomide and 16 in partners of men exposed to teriflunomide; the remaining pregnancies
occurred in patients or partners of patients treated with placebo, interferon beta or blinded therapy.
Pregnancy outcomes in teriflunomide-treated women were as follows: 20 healthy newborns, 26 induced abortions, 12
spontaneous abortions and 5 ongoing pregnancies. No structural defects or functional deficits have been reported to
date in the newborns. Available birth weights ranged from 2780 to 4150 g; mothers received study drug for up to 11
weeks during pregnancy. All but 2 patients giving birth underwent an accelerated elimination procedure.
Pregnancy outcomes among partners of teriflunomide-treated males included 12 healthy newborns, 1 induced
abortion, 1 spontaneous abortion and 2 ongoing pregnancies. No structural defects or functional deficits have been
reported to date in the newborns. The spontaneous abortion rate among female patients was 19%, not different from
known rates in a similar population of patients with MS [Weber-Schoendorfer, Mult Scler 2009;15:1037].
Conclusions: No structural defects or functional deficits were reported in newborns with potential prenatal
teriflunomide exposure; nearly all mothers underwent accelerated elimination. Patients should use reliable
contraception while receiving teriflunomide, discontinue treatment and undergo accelerated elimination prior to
conceiving. A new teriflunomide pregnancy registry will collect prospective data.
Study supported by Genzyme, a Sanofi company. Olaf Stuve: Research support (Teva Pharmaceuticals); consulting
and other activities (Biogen Idec, Genzyme, Novartis, Roche, Sanofi, and Teva Neuroscience) Bernd Kieseier:
Research support (Bayer Schering, Biogen Idec, Merck Serono, and Teva Neuroscience); consulting and other
activities (Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, and Teva Neuroscience) Myriam Benamor is
an employee of Sanofi. Jean-Luc Delhay is an employee of Sanofi. Philippe Truffinet is an employee of Sanofi.
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Others
Friday, October 04, 2013, 15:30 - 17:00
Teriflunomide reduces relapse-related sequelae, severe relapses, hospitalisations
and corticosteroid use: pooled data from the phase 3 TEMSO and TOWER studies
R. Macdonell, F. Lublin, G. Comi, M.S. Freedman, L. Kappos, M. Mäurer, A. Miller, T.P. Olsson, J.S. Wolinsky, S.
Bozzi, C. Dive-Pouletty, P. O'Connor (Heidelberg, AU; New York, US; Milan, IT; Ottawa, CA; Basel, CH;
Mergentheim, DE; Stockholm, SE; Houston, US; Chilly-Mazarin, FR; Toronto, CA)
Introduction: Teriflunomide is a once-daily, oral immunomodulator approved in the USA, Australia and Argentina for
relapsing multiple sclerosis (RMS). In the phase 3 TEMSO (NCT00134563) and TOWER (NCT00751881) studies,
teriflunomide 14 mg significantly reduced annualised relapse rates (ARR) and disability progression in patients with
RMS; teriflunomide 7 mg also significantly reduced ARR. Post-hoc analyses of TEMSO showed that both doses of
teriflunomide reduced annualised rates of relapses with neurological sequelae and relapses requiring healthcare
resources; these results were replicated for teriflunomide 14 mg in TOWER. Pooled data from TEMSO and TOWER
are presented.
Methods: TEMSO and TOWER were phase 3, randomised, double-blind, placebo-controlled, parallel-group studies
conducted in patients with RMS. Five relapse outcomes were analysed in the pooled modified intent-to-treat
populations (N=2251): relapses with sequelae defined by increase in Expanded Disability Status Scale (EDSS)
score/Functional Score (FS) 30 days post-relapse; relapses with sequelae defined by investigator; relapses leading to
hospitalisation, relapses treated with iv corticosteroids; and severe relapses as defined by Panitch (EVIDENCE
study). Adjusted annualised rates for each relapse outcome were derived using a Poisson model with robust error
variance, with treatment, study, baseline EDSS strata and region as covariates.
Results: Compared with placebo, teriflunomide significantly reduced annualised rates of: relapses with sequelae
defined by EDSS/FS by 36.4% (14 mg; p<0.001) and 31.4% (7 mg; p<0.001); relapses with sequelae defined by the
investigator by 53.1% (14 mg; p<0.001) and 20.4% (7 mg; p=0.046); and relapses leading to hospitalisation by 45.5%
(14 mg; p<0.001) and 25.5% (7 mg; p=0.02). Teriflunomide 14 mg and 7 mg had a significant beneficial effect on
relapses requiring iv corticosteroids with a decrease of 34.5% (14 mg) and 25.4% (7 mg); p<0.001, both doses.
Teriflunomide 14 mg significantly reduced severe relapses (defined by Panitch) by 45% (p<0.001; 7 mg NS).
Conclusions: Teriflunomide significantly reduced occurrence of severe relapses, including relapses with sequelae and
relapses requiring healthcare resources in this pooled data set. This post-hoc analysis replicates the results from the
individual TEMSO and TOWER studies, and indicates that teriflunomide may reduce relapse-related healthcare costs.
Study supported by Genzyme, a Sanofi company. Richard Macdonell has served on scientific advisory boards for
Biogen Idec, Merck Serono, Novartis and Sanofi Genzyme. He has received speaker honoraria from Biogen Idec,
Merck Serono, Bayer Schering and Sanofi Genzyme. Fred Lublin has received research support from Acorda
Therapeutics, Inc.; Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi;
Celgene; NIH; NMSS; and consultation fees and for membership of Company Advisory Boards from Bayer
HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc.; Novartis; Pfizer; Teva Neuroscience; Actelion; SanofiAventis; Acorda; Questcor; Roche, Genentech; Celgene; Johnson & Johnson; Revalesio; Coronado Bioscience,
Genzyme, MedImmune; Bristol-Myers Squibb, Xenoport, Receptos. Giancarlo Comi has received consulting fees
from Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Actelion and Bayer Scherin; lecture fees:
Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono
Symposia International Foundation. Mark S. Freedman has received research and educational grant support from
Bayer Healthcare and Genzyme; honoraria/consultation fees from Bayer Healthcare, Biogen Idec, EMD Canada,
Novartis, sanofi-aventis, Teva Canada Innovation and is a member of Company Advisory Board/Board of Directors/or
other similar group for Bayer Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Celgene. Ludwig
Kappos has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care
Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CSL Behring, Elan, Genmab, Genmark,
GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune, sanofi-aventis,
Santhera, Roche, Teva, UCB, and Wyeth, and from the Swiss MS Society, the Swiss National Research Foundation,
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the European Union, and the Gianni Rubatto, Novartis, and Roche Research Foundations. Mathias Mäurer received
honoraria for lectures from Biogen Idec, Böhringer Ingelheim, Bayer Healthcare, MerckSerono, Novartis, TEVA,
SanofiAventis, Genzyme, Talecris. Aaron E Miller has received research support from Acorda Therapeutics, Biogen
Idec, Genentech, Genzyme Corporation, sanofi-aventis, Novartis, Osmotica, Roche and Teva. He has received
consulting fees from Acorda Therapeutics, , Biogen Idec, , EMD Serono, GlaxoSmithKline, Merck Serono, Novartis,
Nuron Biotech, ONO and sanofi-aventis. Tomas P. Olsson has received consulting fees and/or research support from
Biogen Idec, Merck Serono, and sanofi-aventis; participation in scientific advisory boards and/or speaking activities:
Merck Serono, Biogen Idec and sanofi-aventis. Jerry S. Wolinsky has received consulting/speaker fees from Celgene,
Consortium of MS Clinics, Genzyme, Janssen RND, Hoffman LaRoche, Medscape CME, Novartis, PRIME, sanofiaventis, Serono Symposia International Foundation, Teva, Teva Neurosciences; royalties from Millipore (Chemicon
International) Corporation; research / contractual support from: Genzyme, National MS Society, National Institutes of
Health, and sanofi. Sylvie Bozzi is an employee of Genzyme, a Sanofi company. Catherine Dive-Pouletty is an
employee of Genzyme, a Sanofi company. Paul O’Connor has received consulting fees and/or research support from
Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche,
sanofi-aventis, and Teva.
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Others
Friday, October 04, 2013, 15:30 - 17:00
Impact of severe relapses on disability, fatigue and health-related quality of life
outcomes: a pooled dataset of the phase 3 TEMSO and TOWER studies
M. Mäurer, F. Lublin, G. Comi, M. Freedman, L. Kappos, A. Miller, T. Olsson, J. Wolinsky, C. Dive-Pouletty, S. Bozzi,
P. O'Connor (Bad Mergentheim, DE; New York, US; Milan, IT; Ottawa, CA; Basel, CH; Stockholm, SE; Houston, US;
Chilly-Mazarin, FR; Toronto, CA)
Introduction: Teriflunomide is a once-daily, oral, disease-modifying therapy approved in the USA, Australia and
Argentina for relapsing MS (RMS). In the phase 3 TEMSO and TOWER studies, teriflunomide 14mg significantly
reduced annualised relapse rate (ARR), severe relapses (with sequelae or leading to hospitalisation) and disability
progression in patients with RMS; teriflunomide 7mg also significantly reduced ARR. The objective of this TEMSO
and TOWER cohort analysis was to assess, in an RMS population, impact of severe relapses (using multiple
definitions) on disability, fatigue and health-related quality of life (HRQoL) outcomes regardless of study treatment
received.
Methods: The following (non-randomised) groups, derived from the pool of TEMSO (n=1086) and TOWER (n=1165),
were defined: patients with no relapse (Group 1); patients with non-severe relapse(s) (Group 2); patients with >=1
severe relapse (Group 3). Four definitions of severe relapse were applied: (1) relapse leading to hospitalisation; (2)
presence of post-relapse sequelae defined by Expanded Disability Status Scale (EDSS)/Functional System score; (3)
presence of post-relapse sequelae defined by investigator; (4) Panitch-defined severe relapse. EDSS score, Fatigue
Impact Scale (FIS) total score, and physical [PCS] and mental health [MCS] component summary scores and utility
index from the Short Form-36 (SF-36) were assessed. Changes from baseline (CfB) to Week 108 (completers) were
evaluated with ANCOVA (covariates: study, treatment, region, patient status relative to relapse severity, EDSS strata
at baseline and baseline value of parameter of interest).
Results: Using the relapses leading to hospitalisation definition, baseline characteristics were similar across the 3
groups. At Week 108, significant increases in disability and fatigue, and decreases in HRQoL were observed in Group
3 (>=1 severe relapse), with the following mean CfBs: EDSS 0.59, FIS total 16.6, utility index -0.047, SF-36 PCS -4.3
and SF-36 MCS -3.7 (p<0.0001 for all vs Group 1 [no relapse]). Although the effects were not as large, similar
significant effects were observed for patients in Group 2 (non-severe relapse[s]) compared to Group 1. Consistent
effects were observed when the other 3 severity definitions were applied.
Conclusions: Compared with those with no relapse, patients with severe relapse (regardless of applied definition)
consistently reported statistically significant greater disability and fatigue, and worse HRQoL.
Mathias Mäurer: : received honoraria for lectures from Biogen Idec, Böhringer Ingelheim, Bayer Healthcare,
MerckSerono, Novartis, TEVA, SanofiAventis, Genzyme, Talecris. Fred D. Lublin: Sources of Funding for Research:
Acorda Therapeutics, Inc.; Biogen Idec; Novartis Pharmaceuticals Corp; Teva Neuroscience, Inc.; Genzyme; Sanofi;
Celgene; NIH; NMSS; Consulting Agreements/Advisory Boards/DSMB: Bayer HealthCare Pharmaceuticals; Biogen
Idec; EMD Serono, Inc.; Novartis; Pfizer; Teva Neuroscience; Actelion; Sanofi-Aventis; Acorda; Questcor; Roche,
Genentech; Celgene; Johnson & Johnson; Revalesio; Coronado Bioscience, Genzyme, MedImmune; Bristol-Myers
Squibb, Xenoport, Receptos; Co-Chief Editor: Multiple Sclerosis and Related Diseases Giancarlo Comi has received
consulting fees from Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Actelion and Bayer
Scherin; lecture fees: Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Biogen Dompè, Bayer
Schering, and Serono Symposia International Foundation. Mark S Freedman has received research and educational
grant support from Bayer Healthcare and Genzyme; honoraria/consultation fees from Bayer Healthcare, Biogen Idec,
EMD Canada, Novartis, sanofi-aventis, Teva Canada Innovation and is a member of Company Advisory Board/Board
of Directors/or other similar group for Bayer Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and
Celgene. Ludwig Kappos has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health
Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CSL Behring, Elan, Genmab,
Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune,
sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth, and from the Swiss MS Society, the Swiss National
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STEPh, Inc., Dr. Jay H. Bauman, ©2013
Research Foundation, the European Union, and the Gianni Rubatto, Novartis, and Roche Research Foundations.
Aaron E Miller has received research support from Acorda Therapeutics, Biogen Idec, Genentech, Genzyme
Corporation, sanofi-aventis, Novartis, Osmotica, Roche and Teva. He has received consulting fees from Acorda
Therapeutics, Biogen Idec, EMD Serono, GlaxoSmithKline, Merck Serono, Novartis, Nuron Biotech, ONO and sanofiaventis. Tomas P Olsson has received consulting fees and/or research support from Biogen Idec, Merck Serono, and
sanofi-aventis; participation in scientific advisory boards and/or speaking activities: Merck Serono, Biogen Idec and
sanofi-aventis. Jerry S Wolinsky has received consulting/speaker fees from Celgene, Consortium of MS Clinics,
Genzyme, Janssen RND, Hoffman LaRoche, Medscape CME, Novartis, PRIME, sanofi-aventis, Serono Symposia
International Foundation, Teva, Teva Neurosciences; royalties from Millipore (Chemicon International) Corporation;
research / contractual support from: Genzyme, National MS Society, National Institutes of Health, and sanofi.
Catherine Dive-Pouletty and Sylvie Bozzi are employees of Sanofi. Paul O’Connor has received consulting fees
and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono,
Genentech, Genmab, Novartis, Roche, sanofi-aventis, and Teva. Study supported by Genzyme, a Sanofi company.
85