Overview of Current and Emerging
Small Molecules and Monoclonal
Antibodies in MS
Clyde E. Markowitz, MD
Director, Multiple Sclerosis Center
University of Pennsylvania
Philadelphia, Pennsylvania
Introduction
• Traditional 1st-line MS therapies reduce relapse rates
and slow progression
– But are only partially effective
– Require self-injection
– Some have bothersome side effects
• The 1st oral small-molecule therapy (fingolimod) and
the 1st monoclonal antibody (natalizumab) have now
been integrated into MS treatment
– Greater potency? More concerning side effects?
– Many new small molecules and monoclonal
antibodies are in development
Case Study
• 30-year-old woman has occasional numbness and tingling in
left hand for past 6 months. Now presents with optic neuritis
• MRI shows multiple T2 hyperintensities in corona radiata and
cervical spinal cord
• Results of other evaluations consistent with clinically isolated
syndrome
• After resolution of optic neuritis on corticosteroids, started on
glatiramer acetate 20 mg/day
• 7 months later, she experiences an episode of imbalance and
difficulty walking
– Treated with corticosteroids
– She has residual symptoms but she is still able to ambulate
Case Study
• She is switched to IFN β-1b 250 µg SC every
other day
• 10 months later, she presents with decreased
sensation in her right foot, worsening and
extending up her leg over the course of
3 days
• She complains about injection-site reactions and
flu-like symptoms
• She is reluctant to continue on injectable
medication
Case Study
MRI
She is a possible candidate for small molecule or monoclonal antibody therapy
Slide courtesy of Clyde E. Markowitz, MD.
Oral Small-Molecule Therapies
Oral Agents
• Currently approved
– Fingolimod
• Investigational
– Laquinimod
– Teriflunomide
– Dimethyl fumarate (BG-12)
– Cladribine
Fingolimod
The 1st Oral MS Therapy
• Sphingosine-1-phosphate (S1P) receptor modulator1
– Binds to S1P receptors on lymphocytes
– Receptors are internalized and degraded
– Lymphocytes are sequestered in secondary lymphoid
organs
 Affects naive T-cells, central memory T-cells but not
effector T-cells
• Possible CNS effect2
– Neurons, astrocytes, oligodendrocytes, and microglia
express S1P receptors
• Approved dose: 0.5 mg orally once daily3
• Terminal half-life: 6–9 days3
1. Mehling M, et al. Neurology. 2011;76(suppl 3):S20-S27. 2. Osinde M, et al. 22nd ECTRIMS;
September 27-30, 2006; Madrid, Spain. Abstract P792. 3. Gilenya [PI]. East Hanover, NJ:
Novartis Pharmaceuticals; 2010.
Fingolimod
Phase III TRANSFORMS Trial
N = 1292 RRMS + ≥1 recent relapse
12-month data
Fingolimod
0.5 mg/d
n = 429
Fingolimod
1.25 mg/d
n = 420
IFNβ-1a IM
30 μg QW
n = 431
P value
Annualized
relapse rate
0.16
(-52%)
0.20
(-38%)
0.33
<.001
Relapse-free
83%
80%
69%
<.001
Disability
progression-free
94%
93%
92%
NS
% change in
brain volume
-0.31
-0.30
-0.45
<.001
vs IFN
Decreased number of T2 and Gd-enhanced lesions on MRI
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
Fingolimod
Phase III FREEDOMS I Trial
N = 1272 RRMS + ≥1 relapse in past year or ≥2 in past 2 years; EDSS ≤5.5
24-month data
Fingolimod
0.5 mg/d
n = 425
Fingolimod
1.25 mg/d
n = 429
Annualized
relapse rate
0.18
(-54%)
Relapse-free
70%
Placebo
n = 418
P value vs
0.16
(-60%)
0.40
<.001
75%
46%
<.001
Placebo
Disability
progression-free
82%
83%
76%
.03 for 0.5 mg
.01 for 1.25
mg
% change in
brain volume
-0.84
-0.89
-1.31
<.001
Decreased number of T2 and Gd-enhanced lesions on MRI
Kappos L, et al. N Engl J Med. 2010;362:387-401.
Fingolimod Ongoing Trials
• FREEDOMS II (phase III)1
– Relapsing-remitting MS
– 2 years
– Fingolimod 0.5 mg/d vs placebo (1.25 mg/d dropped)
• INFORMS (phase III)2
– Primary-progressive MS
– ≥3 years
– Fingolimod 0.5 or 1.25 mg/d vs placebo
• FREEDOMS Extension study3
1. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://www.clinicaltrials.gov/ct2/show/NCT00355134?term=fingolimod+AND+FREEDOMS&rank=2. 2.
ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://www.clinicaltrials.gov/ct2/show/NCT00731692?term=fingolimod&cond=primaryprogressive+MS&phase=2&rank=1. 3.ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://www.clinicaltrials.gov/ct2/show/NCT00662649?term=fingolimod&cond=MS&phase=2&rank=4.
Fingolimod Safety Profile
• Bradycardia (1–6 hours after 1st dose), atrioventricular block
• Blood pressure increases
• Infections
• Macular edema
• Malignancies (mostly skin cancer)
• Peripheral-blood lymphocyte count reductions (MOA)
• ALT increases (≥3 x ULN in 7%–8.5%)
• Mild forced expiratory volume (FEV1) reductions
• Drug interactions (ketoconazole, antineoplastic/immunosuppressive drugs, vaccines, drugs affecting heart rate)
Kappos L, et al. N Engl J Med. 2010;362:387-401. Cohen JA, et al. N Engl J Med. 2010;362:402415. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals; 2010.
Fingolimod Monitoring
• Laboratory
– CBC + differential
– Liver enzymes/bilirubin (baseline and if symptomatic)
– Baseline anti-varicella-zoster virus IgG/IgM (if negative,
vaccinate and delay fingolimod 1 month)
• Ophthalmologic exam
– Baseline and at 3–4 months
– Repeat if patient reports visual disturbance
• Cardiac
– EKG if cardiac risk factors, slow/irregular heartbeat, or taking
beta-blockers, calcium channel blockers, or antiarrhythmics
– 6-hour observation after 1st dosing
– Blood pressure
• Spirometry/diffusing capacity of the lung for carbon monoxide
– If clinically indicated
Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals; 2010.
Laquinimod
• Novel oral immunomodulatory agent
(quinoline-3-carboxamide)
• High oral bioavailability1
– 0.6 mg orally once daily2
• Structurally related to roquinimex1
– Unlike roquinimex, does not increase
risk of myocardial infarction, serositis
• FDA fast-track review status
1. Polman C, et al. Neurology. 2005;64:987-991. 2. Comi G, et al. 63rd AAN; April 9-16, 2011;
Honolulu, Hawaii.
Laquinimod Mechanism of Action
• Induces Th1 to Th2 shift; inhibits proinflammatory
cytokine production1,2
• Inhibits leukocyte migration into CNS1
• Deactivates microglia and macrophages3
• Suppresses NFκB pathway in B-cells and NK cells2
• Increases brain-derived neurotrophic factor 11-fold
(possible neuroprotection)4
• Not immunosuppressive: cellular/humoral immune
responses remain intact1
1. Brück W, et al. J Neurol Sci. 2011;306:173-179. 2. Gurevich M, et al. 62nd AAN; April 1017, 2011; Toronto, Ontario, Canada. Abstract P04.208. 3. Wang J, et al. 62nd AAN; April 1017, 2011; Toronto, Ontario, Canada. Abstract P04.222. 4. Thöne J, et al. 62nd AAN; April 1017, 2010; Toronto, Ontario, Canada. Abstract PD5.004.
Laquinimod
Phase III ALLEGRO Trial
N = 1106 RRMS; 24-month data
Laquinimod 0.6 mg/d vs Placebo
Annualized relapse rate
Disability progression (EDSS)
0.304 vs 0.395—23% reduction
RR = 0.770; 95% CI 0.650–0.911; P = .0024
36% reduction
HR = 0.641; 95% CI 0.452–0.908; P = .0122)
Brain atrophy
33% reduction (P <.0001)
Mean cumulative
Gd-enhancing lesions
37% reduction (P = .0003)
Mean cumulative T2 lesions
30% reduction (P = .0002)
Abbreviations: EDSS, Expanded Disability Status Scale; RRMS, relapsing-remitting MS.
Comi G, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Gever J. MedPage Today. April 14,
2011. Accessed July 21, 2011 at:
http://www.medpagetoday.com/MeetingCoverage/AAN/25935?pfc.
Laquinimod Ongoing Trials
• BRAVO (phase III)1
– Relapsing-remitting MS (N = 1200)
– Laquinimod 0.6 mg/day vs oral placebo vs IFNβ-1a 30 µg
IM once weekly
 Double-blind for laquinimod vs placebo; rater-blind for
IFN reference arm
 Primary outcome: relapse rate
– Results expected Q3 2011
• 3 open-label extension studies2
1. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00605215?term=BRAVO+Study%3A+Laquinimod+Double+Blind+Place
bo+Controlled&rank=1. 2. ClinicalTrials.gov. 2011. Accessed July 21, 2011 at:
http://www.clinicaltrials.gov/ct2/show/NCT01047319?term=laquinimod&cond=multiple+sclerosis&rank=1,
http://www.clinicaltrials.gov/ct2/show/NCT00745615?term=laquinimod&cond=multiple+sclerosis&rank=5,
and
http://www.clinicaltrials.gov/ct2/show/NCT00988052?term=laquinimod&cond=multiple+sclerosis&rank=4.
Laquinimod Safety Profile
Adverse events in phase II and III studies
• Transient dose-related ALT increases1,2
• Budd-Chiari syndrome (single case in patient with
underlying hypercoagulability)1
• Abdominal/back pain,2 chest pain, arthralgias1
• Herpes infections1
• No cardiac events1,2
1. Comi G, et al. Lancet. 2008;371:2085-2092. 2. Gever J. MedPage Today. April 14, 2011.
Accessed July 21, 2011 at: http://www.medpagetoday.com/MeetingCoverage/AAN/25935?pfc.
Laquinimod Metabolism/Drug
Interactions
• Metabolized by CYP3A4 (low affinity)
• Strong CYP3A4 inhibitors (eg, ketoconazole) may
slow laquinimod metabolism
• Unlikely to cause competitive inhibition with other
CYP3A4 substrates
Preiningerova J. Expert Opin Investig Drugs. 2009;18:985-989.
Teriflunomide
• Active metabolite of leflunomide (approved for
rheumatoid arthritis since 1998)
• Noncompetitive reversible inhibition of mitochondrial
enzyme dihydro-orotate dehydrogenase (de novo
pyrimidine synthesis pathway)
• Cytostatic for proliferating T- and B-cells; noncytotoxic
• Inhibits protein kinase activity
– Decreased T-cell proliferation, activation, cytokine
production
• Half-life: 2 weeks
– Rapid clearance requires cholestyramine
Warneke C, et al. Neuropsychiatr Dis Treat. 2009;5:333-340.
Teriflunomide
Phase III TEMSO Trial
N = 1088 relapsing MS (RRMS or SPMS with relapses)
2-year study
Placebo
Teriflunomide
(7 mg/d)
Teriflunomide
(14 mg/d)
Annualized relapse
rate
0.539
0.370
31.2% reduction
P = .0002
0.369
31.5% reduction
P = .0005
12-week sustained
disability
27.3%
21.7%
23.7% reduction
P = NS
20.2%
29.8% reduction
P = .0279
Change in volume of
white matter
-3.741
-0.635
P = .0609
2.406
P = .0002
39% reduction
P = .032
67% reduction
P = .0003
Brain MRI total lesion
volume
Miller A, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.002. Wolinsky JS, et al. 63rd AAN; April 9-16, 2011;
Honolulu, Hawaii. Abstract S41.003. Gever J. MedPage Today. April 16, 2011. Accessed July 21, 2011 at:
http://www.medpagetoday. O'Connor P, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden.
Abstract 79.
Teriflunomide Ongoing Trials
• TOWER (phase III)
– Relapsing MS (N = 1110)
– 2 years
– Primary outcome: annualized relapse rate
– Teriflunomide 7 or 14 mg vs placebo
• TENERE (phase III)
– Relapsing MS (N = 300)
– 48 weeks
– Primary outcome: time to treatment failure (relapse or
dropout)
– Teriflunomide 7 or 14 mg vs IFN β-1a 44 μg SC 3x weekly
ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00751881?term=tower+%2B+teriflunomide&rank=1
and http://clinicaltrials.gov/ct2/show/NCT00883337?term=tenere++.
Teriflunomide Ongoing Trials
• TOPIC (phase III)
– Clinically isolated syndrome (N = 780)
– 2 years
– Primary outcome: conversion to clinically definite MS
(2nd attack)
– Teriflunomide 7 or 14 mg vs placebo
• Long-term extensions
• Phase II combination therapy trials ongoing
ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00622700?term=topic+%2B+teriflunomide&rank=1,
http://clinicaltrials.gov/ct2/show/NCT00228163?term=extension+%2B+teriflunomide&rank=2 and
http://clinicaltrials.gov/ct2/show/NCT00803049?term=teriflunomide&rank=9.
Teriflunomide Safety Profile
• Adverse effects in phase II study1
– ALT elevations
– Nasopharyngitis
– Alopecia
– Nausea, diarrhea
– Paresthesias
– Back pain, limb pain, arthralgias
• Hepatic metabolism2
• Inhibits CYP2C9, enhancing warfarin’s anticoagulative
effects2
• Teratogenic in animal studies, so washout with
cholestyramine/activated charcoal and confirmation of plasma
level <0.02 mg/L recommended before conception1
1. O’Connor PW, et al. Neurology. 2006;66:894-900. 2. Warneke C, et al. Neuropsychiatr Dis
Treat. 2009;5:333-340.
Dimethyl Fumarate (BG-12)
• Exact mechanism of action is unclear
– Inhibits expression of proinflammatory adhesion
molecules and chemokines1
– Suppresses macrophage function2
– Increases Nrf2 DNA binding (possible
neuroprotection)3
– Suppresses inflammatory activation of astrocytes
and C6 glioma cells3
• FDA fast-track review status
1. Moharregh-Khiabani D, et al. Curr Neuropharmacol. 2009;7:60-64. 2. Bista P, et al. 61st AAN; April 25May 2, 2009; Seattle, Wash. Abstract P09.114. 3. Lin SX, et al. ASN Neuro. 2011; Epub ahead of print.
Dimethyl Fumarate
Phase III DEFINE Trial
• Relapsing-remitting MS (N >1200)
• Dimethyl fumarate 240 mg 2 or 3 times daily vs placebo
for 2 years
• Preliminary data reported only via press release to date
– Significant reduction in proportion relapsing at 2 years
for both treatment arms
– Both treatment arms showed positive results on all
secondary outcomes
 Relapse rate
 MRI outcomes
 Expanded Disability Status Scale progression
ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00420212?term=multiple+sclerosis+%2B+define&rank=1. NMSS.
April 14, 2011. Accessed July 21, 2011 at: http://www.nationalmssociety.org/news/newsdetail/index.aspx?nid=4903.
Dimethyl Fumarate Ongoing Trials
• CONFIRM (phase III)1
– Relapsing-remitting (N = 1232)
– Dimethyl fumarate 240 mg 2 or 3 times
per day vs placebo vs glatiramer acetate
for 2 years
– Primary outcome: relapse rate
– Results in 2nd half of 2011
• 2-year extension study2
1. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00451451?term=fumarate+%2B+confirm&rank=1. 2.
ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00835770?term=fumarate+%2B+extension+study+%2B+multiple+scl
erosis&rank=1.
Dimethyl Fumarate Safety Profile
• Nausea, diarrhea, abdominal pain
• Flushing
• Headache
• Fatigue
• Adverse events are dose-related
Kappos L, et al. Lancet. 2008;372:1463-1472.
Cladribine Approval Status
• Approved in Australia and Russia; rejected in EU
• FDA rejected approval
– Single phase III CLARITY trial1
 Significant reductions in relapse rate, brain lesion
counts, and 3-month sustained disability
 Lymphocytopenia, infections/infestations
(especially herpes zoster)
– FDA requested additional data to clarify safety and
risk-benefit profile
– Manufacturer has chosen to no longer pursue
development of oral cladribine for MS
1. Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
Monoclonal Antibodies
Monoclonal Antibodies
• Currently approved
– Natalizumab
• Investigational
– Alemtuzumab
– Rituximab and ocrelizumab
– Daclizumab
Natalizumab
• Humanized monoclonal antibody targeting α4 subunit of α4β1
and α4β7 integrins on leukocytes, preventing them from
binding their receptors on vascular endothelial cells1
– May prevent migration of leukocytes across endothelial
cells of blood-brain barrier1
• Phase III trial (AFFIRM)2
– 68% reduction in relapse rate
– 83% reduction in new/enlarging hyperintense T2 lesions
– 92% reduction in Gd-enhancing lesions
– 42% reduction in risk of sustained progression of disability
• 300 mg IV infusion given over 1 hour every 4 weeks1
1. Tysabri [PI]. Cambridge, Mass: Biogen Idec; 2011. 2. Polman CH, et al. N Engl J Med.
2006;354:899-910.
Natalizumab
Progressive Multifocal Leukoencephalopathy
• Viral brain infection (JC virus)1
• Overall incidence is 1.23 cases per 1000 patients treated2
– Incidence varies with presence of risk factors
• Progresses to severe disability or death1
• Plasma exchange helps clear natalizumab1
- Is followed by immune reconstitution inflammatory
syndrome in almost all cases1
• TOUCH prescribing program1
• Natalizumab used only after failure of other options1
1. Tysabri [PI]. Cambridge, Mass: Biogen Idec; 2011. 2. Sandrock A, et al. 63rd
AAN; April 9-16, 2011; Honolulu, Hawaii. Poster P03.248.
Natalizumab
PML Risk Factors
•
Duration of use/number of infusions
– 1.53 cases per 1000 patients treated with ≥12 infusions
– 2.41 cases per 1000 patients treated with ≥24 infusions
•
JC virus antibodies
– About 55% of MS patients are Ab positive
– 2.24 cases per 1000 patients if Ab positive
– ≤0.11 cases per 1000 patients if Ab negative (theoretic; all cases Ab+)
•
Prior immunosuppressive (IS) therapy
– Increases risk 4-fold
•
Risk is further increased if ≥1 risk factors
– 4.5 cases per 1000 patients if history of IS therapy + natalizumab use
≥2 years
– 8.1 cases per 1000 patients if history of IS therapy + Ab positive +
natalizumab use ≥2 years
Abbreviation: PML, progressive multifocal leukoencephalopathy.
Sandrock A, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Poster P03.248.
Alemtuzumab
• Humanized monoclonal antibody directed against
CD52 antigen
– CD52 is a cell-surface glycoprotein of unknown
function, present on most T-cells, B-cells, NK
cells, dendritic cells, eosinophils, monocytes,
macrophages
• Depletes CD52-expressing cells
• Stabilizes blood-brain barrier
• Annual infusion (3 or 5 days) given with
corticosteroids
• Fast-track FDA status
Bielekova B, et al. Neurology. 2010;74:S31-S40.
Alemtuzumab’s
Effects on the Immune System
• Within 1 hour after single 5- to 10-mg dose, lymphocytes
and monocytes are no longer detectable in circulation1
Median Time to Recovery After
Discontinuation of Alemtuzumab
CD4+ T-cells1
61 months
CD8+ T-cells1
30 months
Monocytes1
3 months
B-cells1,2
3 months
• B-cells rise to 165% of pretreatment levels after
12 months posttreatment2
1. Coles A, et al. J Neurol. 2006;253:98-108. 2. Thompson SA, et al. J Clin Immunol. 2010;30:99105.
Alemtuzumab
5-Year Follow-Up of Phase II CAMMS223
Untreated RRMS (N = 334)
Alemtuzumab
(Combined
Data*)
IFN β-1a
44 µg SC TIW
Annualized relapse rate
Years 0–5
Years 3–5
0.11
0.14
0.35
0.28
Relapse-free
72%
41%
Change from baseline in EDSS
-0.30
+0.46
Patients free of sustained accumulation of
disability
87%†
62%†
Free of clinical disease activity
65%
27%
*Alemtuzumab 12 or 24 mg/day for 5 days in month 1 and 3 days in month 12; 3 additional days in month 24 at
physician’s discretion. †P <.0001; P values were not reported for the other comparisons.
Coles A, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Poster 410.
Twyman C, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.003.
Alemtuzumab
Phase III CARE-MS I Trial
Recently completed but reported only in press release form1,2
• Treatment-naive relapsing-remitting MS (N = 581)
• Alemtuzumab 12 mg/day x 5 days + 3 days at month 12 vs IFN β-1a
SC 44 μg for 2 years (rater blinded)
• 55% reduction in relapse rate (P <.0001)
• Time to 6-month sustained accumulation of disability not significantly
different
• Proportion of patients with sustained increase in disability not
significantly different (8% vs 11%; HR = 0.70; P = .22)
– Few patients accumulated disability at the rate expected based on
earlier trials, which may have reduced ability to detect significant
treatment effect on this endpoint
1. Gandey A. Medscape Today July 12, 2011. Accessed July 22, 2011 at:
http://www.medscape.com/viewarticle/746184. 2. ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://www.clinicaltrials.gov/ct2/show/NCT00530348?term=alemtuzumab+AND+multiple+sclerosis&ran
k=4.
Alemtuzumab
Ongoing Phase III Trials
• CARE-MS II
– MS with relapse during IFN or glatiramer acetate and ≥2 attacks
in past 24 months or ≥1 attack in past 12 months (N 840)
– Alemtuzumab 12-mg dose (24-mg dose dropped) vs IFN β-1a
SC 44 μg for 2 years (rater-blinded)
• CARE-MS extension
– N 1500
– 5 years
– Can receive additional cycles if resumed disease activity
ClinicalTrials.gov. 2011. Accessed July 20, 2011 at:
http://clinicaltrials.gov/ct2/show/NCT00548405?term=alemtuzumab+%2B+multiple+sclerosis+%2B+car
e&rank=1 and
http://clinicaltrials.gov/ct2/show/NCT00930553?term=alemtuzumab+%2B+multiple+sclerosis+%2B+car
e&rank=4.
Alemtuzumab Safety Profile
• Cytokine release syndrome: fever, rash, headache,
nausea/vomiting, rigor1,2
• Autoimmune disease (primarily thyroid
dysfunction): 30%1,2
• Immune thrombocytopenic purpura: ~3%1,2
• Goodpasture’s syndrome: at least 2 cases3
• Infections (~66%): upper and lower respiratory
tract, urinary tract, herpes, influenza2
• Cancers: Burkitt’s lymphoma, breast cancer,
cervical cancer2
• Serious infusion reactions: 1.4%2
1. Minager A, et al. Expert Opin Biol Ther. 2010;10:421-429. 2. CAMMS223 Investigators. N Engl J Med.
2008;359:1786-1801. 3. Buttmann M. Expert Rev Neurother. 2010;10:791-809.
Alemtuzumab Monitoring
• Complete blood count monthly1
• Thyroid-stimulating hormone every 3−4 months1
• Pretreatment: hydroxyzine or diphenhydramine, meperidine,
acetaminophen1
• Posttreatment: prophylactic acyclovir,
trimethoprim/sulfamethoxazole x 6 months1
• Creatinine and urinalysis screening2
• Autoimmunity screen?
– Increased IL-21, autoantibodies, genetic2
1. Hunter SF, et al. 61st AAN; April 25-May 2, 2009; Seattle, Washington. Poster P07.147.
2. Clyde Markowitz, MD, personal communication, July 2011.
B-Cells and CD20 in MS
• B-cell role: antigen presentation, cytokine
production, antibody secretion (plasma cells)1,2
• CD20: transmembrane protein
– Functions as Ca+2-permeable cation channel
and has role in B-cell proliferation3
– Present on premature, immature, mature,
activated, and memory B-cells and small subset
of normal/neoplastic T-cells (low density)2
 Not on plasma cells2
– Not shed after antibody binding2
• CD19 also present on pre−B-cells2
1. McFarland HF. N Engl J Med. 2008;358:664-665. 2. Dalakas MC. Neurology. 2008;70: 22522260. 3. Uchida J, et al. Int Immunol. 2004;16:119-129.
Rituximab
• IgG1 chimeric anti-CD20 monoclonal antibody1
• Approved for non-Hodgkin’s lymphoma, chronic
lymphocytic leukemia, refractory rheumatoid
arthritis (with methotrexate)1
– Indication for MS not being pursued
• Rapid depletion of B-cells2
– B-cells remain depleted for about 6 months2
– Naive B-cells return more quickly than memory
B-cells3
1. Rituxan [PI]. South San Francisco, Calif: Genentech; 2011. 2. Hauser SL, et al. N Engl J Med.
2008;358:676. 3. Roll P, et al. Arthritis Rheum. 2006;54:2377-2386.
Rituximab in RRMS
48-Week Phase II Study
N = 104
Rituximab dose: 1000 mg IV days 1 and 15
Placebo
(n = 35)
Rituximab
(n = 69)
P value
Mean number of Gd-enhancing
lesions
5.5
0.5
<.001
Mean Δ in volume of T2 lesions
from baseline to week 36 (mm3)
417.8
-175.4
.004
Patients with relapses
40%
20.3%
.04
Adjusted annualized relapse rate
0.7
0.4
.08
• 95% reduction from baseline in CD19+ B-cells at weeks 2–24; 30.7% of
baseline at 48 weeks
• 24.1% had human antichimeric antibodies at week 48
Hauser SL, et al. N Engl J Med. 2008;358:676-688.
Rituximab in PPMS
96-Week Phase II/III Study
N = 439 PPMS with abnormal cerebrospinal fluid,
EDSS 2.0–6.5
Rituximab 1000 mg IV days 1 and 15 every 24 weeks (n = 292) vs
placebo (n = 147)
Disease progression at 96 weeks
Placebo
Rituximab
P Value
38.5%
30.2%
NS
In age <51 years
HR = 0.52
.010
In patients with Gd+ lesions
HR = 0.41
.007
In age <51 + Gd+ lesions
HR = 0.33
.009
Median Δ T2 lesion volume (mm3)
809.5
302.0
.001
Median Δ brain volume
-14.0
-13.1
NS
Longer time to progression if shorter (≤3 years) disease duration; no gender
effect
Hawker K, et al. Ann Neurol. 2009;66:460-471.
Rituximab Safety Profile
• Infusion reactions: fever, chills, rigors, flu-like
symptoms, hypotension, nausea, pruritus,
asthenia1
• Infections (respiratory tract, urinary tract)1
• Progressive multifocal leukoencephalopathy
– Majority in patients using rituximab in combination with
chemotherapy for hematologic malignancies or in
patients with prior or concurrent immunosuppressive
therapy
1. Hauser SL, et al. N Engl J Med. 2008;358:676-688.
Humanized Anti-CD20 Monoclonal
Antibodies
• Ocrelizumab
– Enhanced antibody-dependent cell-mediated
cytotoxicity; reduced complement-dependent
cytotoxicity
– Binds to different overlapping epitope
• Ofatumumab
– Binds to more proximal CD20 portions
– Increased complement-dependent cytotoxicity
Buttmann M. Expert Rev Neurother. 2010;10:791-809.
Ocrelizumab
48-Week Phase II Trial
Relapsing-Remitting MS (N = 220)
Study Protocol
Cycle 1
(Weeks 0–24)
Cycle 2 (Weeks 25–48)
Group A
Double-blind
Placebo on days 1 and 15
Ocrelizumab 300 mg IV on days
1 and 15 (600 mg total)
Group B
Double-blind
Ocrelizumab 300 mg IV on
days 1 and 15 (600 mg total)
Ocrelizumab 300 mg IV on days
1 and 15 (600 mg total)
Group C
Double-blind
Ocrelizumab 1000 mg IV on
days 1 and 15 (2000 mg total)
Ocrelizumab 500 mg IV on days
1 and 15 (1000 mg total)
Group D
Open-label
IFN β-1a 30 µg IM once weekly
Ocrelizumab 300 mg IV on days
1 and 15 (600 mg total)
Kappos L, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.001.
Ocrelizumab
Phase II Trial
Cycle 1 (Weeks 0–24)1
Group A
Placebo
Relative reduction in
Gd+ lesions vs
placebo*
Annualized relapse rate
(ARR)
Δ T2 lesion volume
0.637
Group B
OCR 600 mg
Group C
OCR 2000 mg
89%
P <.0001
96%
P <.0001
0.125
80% reduction
P = .0005
0.169
73% reduction
P = .0014
NS
NS
*Both ocrelizumab arms were also significantly superior to IFN.
Cycle 2 (Weeks 0–24)—all groups taking ocrelizumab2
• ARR = 0.112 in Group B, 0.256 in Group C
• 80% and 73% relapse-free, respectively
1. Kappos L, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Poster
P114. 2. Kappos L, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.001.
Ocrelizumab
Ongoing Phase III Trials
• OPERA I and II1
– Relapsing-remitting MS (N = 800 each)
– Ocrelizumab 2 x 300 mg IV followed by 600 mg IV every
24 weeks vs IFNβ-1a 44 μg SC 3 times weekly
– Primary outcome: annualized relapse rate at 96 weeks;
time to sustained disability progression
• ORATORIO2
– Primary-progressive MS (N = 630)
– Ocrelizumab 600 mg IV every 24 weeks vs placebo
– Age 18–50 years, EDSS 3.0–6.5, abnormal CSF
 If EDSS ≤5, disease duration <10 years
 If EDSS >5, disease duration <15 years
– Primary outcome: time to sustained progression
1. Clyde Markowitz, MD, personal communication, July 2011. 2. Montalban X, et al. 63rd AAN;
April 9-16, 2011; Honolulu, Hawaii. Abstract P04.186.
Ocrelizumab Safety Profile
• Infusion reactions occurred in 34% and 46% of the 2
ocrelizumab arms in the phase II trial vs 9.3% of placebo
arm at 1st infusion
– Rates comparable to placebo at 2nd infusion
• 1 death from brain edema after systemic inflammatory
response syndrome with multiorgan failure 12 weeks
after starting ocrelizumab
• Rates of infection similar to placebo
Kappos L, et al. 26th ECTRIMS and 15th RIMS; October 13-16, 2010. Goteborg, Sweden. Poster
P114. 2. Kappos L, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract S41.001.
Ofatumumab
Phase I/II Dose-Finding Study
• Relapsing-remitting MS and 1 of the following (N = 38)
– ≥2 relapses in past 2 years
– ≥1 relapse in past 1 year
– 1 relapse in year 2 plus 1 Gd+ brain lesion in past year
• Ofatumumab 100, 300, or 700 mg IV at weeks 0 and 2 vs
placebo
• New Gd+ lesions from weeks 8–24: 0.04 for ofatumumab
(combined) vs 9.69 for placebo
– Relative risk reduction 99.8% (95% CI 94.7%–100%;
P <.001)
• No safety signals
Sorensen P, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P01.265.
Daclizumab
• Humanized IgG1 monoclonal antibody against IL2R chain (CD25)1,2
– CD25 is expressed on activated T-cells and
B-cells, but these cell counts only modestly
affected1,2
– Increases CD56bright NK cell function and
number1,2
• Approved for renal transplant rejection but marketing
discontinued
1. Schippling S, et al. Intl MS J. 2008;15:94-98. 2. Stüve O, et al. Lancet Neurol. 2010;9:337-338.
Daclizumab
24-Week Phase II CHOICE Trial
Relapsing-remitting MS with ≥1 relapse or Gd+ lesions on IFN (N = 230)1
IFN +
Placebo
(n = 77)
IFN +
Daclizumab
1 mg/kg SC
q4wk (n = 78)
IFN +
Daclizumab
2 mg/kg SC
q2wk (n = 75)
Mean number
new/enlarged Gd+
lesions
4.75
3.58
25% reduction
P = NS
1.32
72% reduction
P = .004
Mean number
new/enlarged T2 lesions
3.4
2.2
P = NS
1.1
P = .007
Unadjusted annualized
relapse rate
0.86
0.58
32% reduction
P = NS
0.49
43% reduction
P = NS
• Other small phase II trials document clinical and MRI benefits2,3
– 1–2 mg/kg every 2–4 weeks (IV or SC)
1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. Bielekova B, et al. Arch Neurol.
2009;66:483-489. 3. Rose JW, et al. Neurology. 2007;69:785-789.
Daclizumab Safety Profile
•
•
•
•
•
•
•
Rash
Lymphadenopathy
Infections
Fever
Headache
Mouth ulcers
Elevations of bilirubin, hepatic enzymes, autoantibodies
– Monitoring: routine blood tests
Wynn D, et al. Lancet Neurol. 2010;9:381-390. Bielekova B, et al. Arch Neurol. 2009;66:483-489.
Rose JW, et al. Neurology. 2007;69:785-789. Schippling S, et al. Intl MS J. 2008;15:94-98.
Conclusions
Conclusions
• New MS therapies are on the horizon
– Will expand choices for treatment, and options for
routes of administration and dosing schedules
– Will add to treatment complexity
– Personalized medicine
• Novel mechanisms of action will raise concern about
unknown, rare, or long-term safety issues
– Risk:benefit ratio analysis
• Future focus
– Optimal drug selection, induction/combination
strategies, when/how to switch, CNS repair strategies
 To be discussed in the next webcast in this series
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