Investigations • Innovation • Clinical Application
New Frontiers in Neurotherapy
for Multiple Sclerosis
Focus on the Foundation Role of Immunomodulation for
Long-Term Efficacy, Safety, Neuronal Preservation,
and Disability Mitigation
Program Chairman
Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
Program Faculty
BRUCE A. CREE, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
MARK J. TULLMAN, MD
Assistant Professor of Neurology
Director, Multiple Sclerosis Clinical Care
Center
The Neurological Institute of New York
Columbia University Medical Center
New York, New York
ROHIT BAKSHI, MD, FAAN
Associate Professor of Neurology &
Radiology
Director, Laboratory for Neuroimaging
Research
MS Center, Brigham & Women’s Hospital
Harvard Medical School
Boston, MA
GUY J. BUCKLE, MD, MPH
Director of MS Clinical Care Partners
Multiple Sclerosis Center
Brigham and Women’s Hospital
Assistant Professor of Neurology
Harvard Medical School
Boston, Massachusetts
Investigations • Innovation • Clinical Application
The Evidence for First Line Therapy
with Immune-Modulating Agents
From Mechanisms to Therapy—Landmark
Trials, Long-Term Safety Data and Clinical
Experience
Program Chairman
Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Department of Neurology
University of California
San Francisco Multiple Sclerosis Center
San Francisco, California
Overview
►
Mechanisms of action of first line therapies
►
Outcome measures in clinical trials
►
Comparison of landmark trials
►
Longitudinal studies: what do they tell us?
Goals of Treatment
►
Reduce frequency of relapse
►
Slow progression of disability
►
Reduce MRI activity
►
Prevent morbidity from symptoms and provide
palliative care
►
Maintain adherence
►
Provide long-term efficacy and safety
Immunopathogenesis of the MS Lesion
gdT
Histamine
Proteases
TNFa
NAA, ATP
NO
O2
5-HT
CD8
Oligo
MO
Virus
B7 CD28
Th1
Th17
Microglia
Mast Cell
B
IFNg
TNF
Th17
Glutamate
Ab+C9neo
Pl
NO
Oi
TNFa
MMP
IL-10
TGFb
MCP-1
MIP-1a
IP-10
RANTES
Astrocyte
BBB
ICAM-1
MMP- VCAM-1
2/9
LFA-1
VLA-4
Th1
VCAM-1
Complement
gdT
Monocyte
Granutocyte
CD8
IFNg
TNF
IL-17
Th17
IL-4
IL-5
IL-6
IL-13
TGFb
B
IL-23
TCR
Thp
Treg
Th2/
Th3
IL-4 & IL-10
IL-12
CD4
Figure courtesy of Dhib-Jalbut S, 2008
Treg
CD4+CD25+
CD40 CD40L
Mast Cell
Th2/
Th3
B7 CD28
HLA
APC
CD4
Myelin Ag
Microbial Ag
Thp
APC
CD40 CD40L
IFN-b: Activity
Blood
BBB
CNS
MMP
IFN-β
TH1+
Myelin
protein
Antigen
TH1+
APC
Resting
T cell
Activated (+)
T cells
TH1+
TH1
APC
MMP
IL-2
TNF-α
TH1+
IFN-γ
IFN-β
Adapted from Yong VW. Neurology. 2002;59:802-808.
Glatiramer Acetate: Activity
BBB
Periphery
CNS
APC
TCR
GA therapy
Macrophage
MHC
GA
TCR
Microglia
Bystander
suppression
effect
MHC
CNS Ag
TCR
IL-4
IL-10
+
+
Anti-inflammatory
cytokines
BDNF
Neurotrophins
GAspecific
T cell
TH1
TH2
Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.
TH2
Neuroregeneration
Long-Term Disability
Effect of Early Relapses
Percent Pts DSS < 6
100
Low (0-1 attacks in 2 years)
Intermediate (2-4 attacks in 2 years)
High (> 5 in 2 years)
80
60
40
p < 0.0001
20
0
0
10
20
30
40
Time from onset of MS (years)
Weinhenker B et al. Brain. 1989;112:1422
50
Development of Disability
Effect of Early Clinical Course
Clinical Characteristic
Significance*
Number of Attacks, 1st 2 years
p <0.001
Interval Between 1st 2 Attacks
p <0.001
DSS at 2 years
p < 0.001
DSS at 5 years
p < 0.001
* Controlled for age at onset, remitting at onset, cerebellar, cerebral
Weinshenker B et al. Brain. 1991;114 ( Pt 2):1045-56.
Relapses in MS
►
Relapses are the most obvious evidence of
inflammatory disease activity in RRMS
►
Relapse frequency in typical untreated RRMS
populations enables treatment effect to be rapidly
assessable in a 12-month clinical study
Total number of relapses during the study period
Total in-study person-years
% Reduction in relapse rates
Effect on Annualized Relapse Rates: Summary of
Phase III Trials – 2 years in-study
35
31%
29%
32%
29%
P=0.0001
P<0.001
P<0.0001
P=0.055
30
25
20
18%
15
P=0.04
10
5
0
8 MIU qod
IFN beta-1b
6 MIU qw
IFN beta-1a
4.4 MIU tiw
IFN beta-1a
8.8 MIU tiw
20 mg qd
IFN beta-1a glatiramer acetate
N.B.: Results are from separate clinical trials
Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655;
IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277;
Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701;
PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert.
Is MS All About Relapses?
►
Hypothesis: if relapses cause long-term
disability then patients with frequent relapses
should be at higher risk for disability
►
From the London Ontario natural history
studies patients with frequent attacks are at
highest risk for future ambulatory disability
►
Assumption: modifying the relapse rate will
influence long-term disability
Weinshenker et al. 1989 Brain 112:1419
Proportion of Placebo Groups
with Clinical Activity
Relapses
EDSS
Progress
IFNβ-1b (3 year)
86%
39%
IFNβ-1a (QW) (2 year)
77%
35%
IFNβ-1a (TIW) (2 year)
84%
38%
Glatiramer acetate (2 year)
73%
25%
Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655;
IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277;
Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701;
PRISMS Study Group. Lancet. 1998;352:1498.
How is Sustained Progression
Measured?
►
Most clinical trials define progression by
comparing the change in EDSS from baseline
to study conclusion, and then confirm the
change in EDSS at 3 or 6 months
►
Does this measure of confirmed progression
reflect permanent disability?
►
If so, then confirmed changes in EDSS during
the course of the trial should be sustained by
the end of the study
Does Sustained Disability Measure
Permanent Disability?
►
50% of patients with a 1 point change, confirmed at 3
months will improve to a lower EDSS
►
33% of patients with a 1 point change, confirmed at 6
months, will improve to a lower EDSS
►
More stringent measures of change are harder to
demonstrate in 2-year trials because relatively few MS
patients will progress
►
Conclusions: 6 months sustained EDSS change is
more rigorous than a 3-month sustained change, but
neither is a good predictor of long term disability
Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7.
Reduction in
sustained disability
progression (%)
Effect on Sustained Disability*:
Summary of Phase III Trials
40
29%
30
20
NS
37%
30%
p=0.02
22%
p<0.05
p=NS
p<0.05
12%
10
p=NS
0
8 MIU qod
IFN beta-1b
6 MIU qw
IFN beta-1a
4.4 MIU tiw
IFN beta-1a
20 mg qd
8.8 MIU tiw
IFN beta-1a glatiramer acetate
*1 EDSS point sustained for 6 months in 6 MIU qw phase III trial and for 3 months
in all other phase III trials.
Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655
IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277
Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701
PRISMS Study Group. Lancet. 1998;352:1498
Summary
► Relapses and disability progression represent different but
complimentary aspects of MS natural history
► Relapse rate reduction and the mean change in EDSS are
the most sensitive clinical outcome measures in MS trials
► The generally accepted sustained change in EDSS measure
is not a reliable marker of long term disability
► Phase III trials results showed:

The interferons and glatiramer acetate modestly reduce the relapse rate

IFN beta-1a has a statistically significant impact on sustained disability
progression over two years

IFN beta-1a and glatiramer acetate have a statistically significant impact on
the mean EDSS over two year
Are direct comparator studies
needed in MS or can we make valid
conclusions from cross trial
comparisons?
Cross Trial Comparisons
Relative Efficacy (RR)
IFNβ-1a
30 µg
qw
IFNβ-1b,
250 µg
qod
IFN β-1a
44 µg
tiw
GA
20 mg
qd
Relapse rate (annualized)
-18%
-34%
-32%
-29%
Relapse-Free (2 years)
+42%
+95%
+100%
+36%
Progression free
-37%
-29%
-30%
-12%
New T2 Lesions
-36%
-83%
-78%
-38%
Gd+ Lesions
-42%
-
-88%
-33%
BOD
- 4%
-17%
-15%
-8%
The REGARD Trial
Time to First Relapse (1o endpoint)
Survival distribution function
1.00
672 days
(96 weeks)
IFNβ-1a
0.75
GA
Hazard ratio (95% CI):
0.943 (0.74, 1.21)
p = 0.643
0.50
0.25
0.00
0
100
200
300
400
500
Time to first relapse (days)
600
700
The BEYOND Trial
Relapse Risk (1o Endpoint)
►No
significant difference in relapse risk between any group
Sensitivity Analysis
(no major protocol violations,
100% of doses, post-hoc)
Primary Analysis
P-values
(one-sided)
P-values
(one-sided)
Interferon beta-1b 500
vs. Interferon beta-1b 250
Interferon beta-1b 250
vs. Glatiramer acetate
Interferon beta-1b 500
vs. Glatiramer acetate
0.5
1.0
P=0.16
P=0.29
P=0.73
P=0.30
P=0.43
P=0.18
1.5 0.5
1.0
1.5
What can be learned from
long-term follow up studies?
Long-Term Follow Up
►
Do long-term follow up studies adequately
address medication safety?
►
Do long-term studies adequately address
longitudinal efficacy?
►
Have methods of analysis for longitudinal
studies been optimized?
Sources of Bias in LTFU Studies
Bias
Impact
Strategy
Ascertainment
Modified therapeutic effect dependent
on characteristics of participating
patients.
F/U must be as complete as possible
Directly compare baseline and onRCT characteristics of those
patients in LTF to those not in LTF
Informed
Therapeutic
Decisions
Inflated estimate of therapeutic benefit
because patients doing well
continue therapy whereas failing
patients switch or stop therapy.
MPR: Use percent of total possible
time on therapy instead of
absolute time to assess exposure.
Treatment
Selection
Modified therapeutic effect dependent
on patient selection characteristics.
Propensity Scoring: Adjust for the
propensity (i.e., likelihood) that a
particular treatment will be
selected based on available
patient characteristics
Multiple Testing
Increased risk of Type 1 error from the
use of multiple predictor variables
and weighting schemes
Create a single model and apply
adjustments to p-values according
to the number of predictors tested
in the model.
Glatiramer Acetate 15 year LTFU
Ford C et al. Mult Scler. 2010;16:342-50.
Glatiramer Acetate 15 year LTFU
Ford C et al. Mult Scler. 2010;16:342-50.
Glatiramer Acetate 15 year LTFU
►
In a small cohort of patients followed for 15
years, glatiramer acetate was safe and well
tolerated
►
65% of continuously treated patients did not
progress to SPMS
►
41% of patients withdrawing from the study did
so because of disease progression
●
►
Propensity scores were used to try to adjust for
differences between ongoing and withdrawing
patients
EDSS at baseline predicts EDSS at 15 years
IFN β-1a (QW) LTFU Disposition
Complete 2-year follow-up
(n=172)
Unascertained
(n=36)
Able to locate,
Unable to contact
(n=13)
Unable to locate
(n=23)
Ascertained for ASSURANCE
(n=136; 79%)
Living
(n=122; 90%)
ICF and
question booklet
completed
Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]
Deceased
(n=14; 10%)
LOCF
IFN β-1a QW LTFU Outcomes
Currently receiving IM IFN ß-1a (n=56)
Not currently receiving IM IFN ß-1a (n=66)
P=0.006
P=0.062
P=0.114
Patients, %
Patients, %
P=0.326
EDSS Milestone
Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]
IFN β-1a QW LTFU Conclusions
►
79% of eligible patients were located for the 15 year
follow up
►
At 15 years, patients currently on IFN β-1a had less
progression in EDSS scores than patients not on IFN β1a
►
However, patients not currently on IFN β-1a had higher
baseline EDSS scores suggesting more severe baseline
MS
●
►
Propensity scores were used to adjust for these
differences
Inferences with regard to association with lower EDSS
and ongoing treatment were not made
Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]
IFN β-1b LTFU Design
Pivotal Study (n=372)
IFNβ-1b 250 µg
124
56
IFNβ-1b 50 µg
125
52
Placebo
123
58
1988 1990
Patients under regular medical care no trial
1993
Cross-sectional investigation of:
- clinical outcomes (disability, relapse rate)
- imaging (brain and spinal MRI)
- cognition and mood
- QoL, resource use
- lab parameter including NAb's and PgX
Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666
Ebers G et al. presented at AAN, October 2006: M-3
LTF
2005
Event Rates and Long-Term Efficacy
Clinical and Radiological Endpoints
1. Need to demonstrate that the short-term
event-rates are correlated with long-term
outcome.
2. Need to demonstrate that the short-term
event-rates contribute independently to
predicting outcome.
3. Need to demonstrate that therapies which
reduce the event-rates, are also associated
with improved long-term outcome.
Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666
Ebers G et al. presented at AAN, October 2006: M-3
IFN β-1b LTFU Adjusted OUtcome
Any Variable + Any Exposure Weighting – Any
Negative Outcome
1
EDSS
p<0.001
2
Exposure
p<0.001
Low
High
Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666
Ebers G et al. presented at AAN, October 2006: M-3
Event Rates and Long-Term Efficacy
Conclusions
1. The LTF study demonstrates that the short-term eventrate is correlated with long-term outcome.
2. The LTF study also demonstrates that the short-term
event-rate contributes independently to predicting longterm outcome.
3. The LTF study provides convincing evidence that early
initiation and sustained use of IFNβ-1b has a beneficial
impact on long-term outcome in MS.
4. The analysis strategy employed provides a
methodological framework for mitigating bias in assessing
long-term efficacy in other clinical trials having similar
non-randomized data.
Conclusions
► Disease modifying therapy seems favorably effect the
long-term course of MS
► Propensity score adjusted analysis and other statistical
methods for controlling biases inherent in long term,
unblinded studies are important statistical advances for
interpreting these studies
► Once the MS community agrees on the relevant
covariates, these methods can be used to sort out some
of these issues without the cost (and ethical dilemmas)
posed by long-term placebo-controlled trials.
Investigations • Innovation • Clinical Application
The Emergence of
Immunosuppressive Agents for MS
Safety, Efficacy, and Cautionary Notes—
Patient Monitoring, Risks for Infection, and
Mechanisms of Action
Mark J. Tullman, MD
Assistant Professor of Neurology
Director, Multiple Sclerosis Clinical Care Center
The Neurological Institute of New York
Columbia University Medical Center
New York, New York
Existing and Emerging MS Therapies
2005
2006
2007
2010
2013
BG12
BG12
Cladribine
Caldribine
Rebif
Rebif
Fingolimod
Betaseron
Teriflunomide
Teriflunomide
Ampyra
Ampyra
Copaxone
Laquinimod
Laquinimod
Extavia
Extavia
Avonex
Novantrone
2012
Oral
Injectables
IV
2011
Ocrelizumab
Ocrelizumab
Tysabri
Tysabri
IV
Generic
Generic
Mitoxantrone
Mitoxantrone
(oncology)
(MS)
(oncology)
MS
Alemtuzumab
Alemtuzumab
Approved
In phase II
In phase III
Filed
Efficacy in Recent Studies
►
Annualized relapse rate 0.29-0.36 over 2 years
►
58-61% relapse-free over 2 years
►
79-81% without disability progression over 2 years
►
88.3% without disability progression over 96 weeks
►
91.3% without disability progression over 96 weeks
►
74% without disability progression over 3 years
►
75% without EDSS progression 5 years after CIS
onset
►
13.3% reduction in MRI T2 lesion load over 3 years
►
All in placebo, interferon, or glatiramer acetatetreated patients
Kappos L, et al. Lancet Neurol 2009; 8: 987–97; Giovannoni G, et al. N Engl J Med. 2010;362:416-426; CAMMS223
Trial Investigators. NEJM 2008;359:1786-1801; Kappos L et al. N Engl J Med. 2006;355:1124-40; Mikol et al. Lancet
Neurol 2008; 7: 903–14
Prognostic Signs
►
Favorable Outcome
●
●
●
●
Female
Younger age at onset
Little disability 5 years
after onset
Optic neuritis as 1st
attack
►
Worse Outcome
●
●
●
●
●
●
●
●
Male
Older age at onset
Frequent attacks
Short interval between
1st 2 attacks
Incomplete recovery
from 1st attack
Cerebellar involvement
as 1st symptom
Rapidly accumulating
disability
Progressive disease from
onset
Baseline Brain MRI Lesion Number
20-Year Clinical Status
Fisniku LK. Brain 2008;131:808-817.
Baseline Brain MRI Lesion Number
20-Year Clinical Status
Fisniku LK. Brain 2008;131:808-817.
Disease Free State
Proportion Free of Clinical and MRI Activity
p < 0.0001
Natalizumab
Hardova E, et al. Lancet Neurol 2009;8:254-60.
Placebo
Alemtuzumab
►
Monoclonal humanized antibody directed against
CD52 antigen
●
●
CD52 antigen is a cell surface glycoprotein that is
present on >95% of T lymphocytes, B lymphocytes,
monocytes, and eosinophils
Results in prolonged depletion of B cells, T cells, and
monocytes
►
Within an hour following a single 5- to 10-mg dose,
lymphocytes and monocytes are no longer detectable
in circulation
►
FDA-approved for B-CLL
Muraro P, et al. Neurotherapeutics. 2007;4:676-692. Coles A, et al. J Neurol. 2006;253:98-108.
IFNβ-1a
44 mcg thw SC 107
95
Alemtuzumab
12 mg daily IV 108
66
80
24
102
92
101
77
Alemtuzumab
24 mg daily IV 108
22
105
92
104
88
Month 0
Month 12
CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.
Month 24
Month 36
Alemtuzumab CAMMS223: Co-Primary
Endpoints (36 months)
CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.
Alemtuzumab CAMMS223:
MRI Outcomes
Months 0-12
0-24
0-36
P=0.04
P=0.03
n=75
P=0.04
n=91
n=60
n=96
n=87
P=0.16
n=80
n=100
n=91
n=96
P≤0.03 for both doses of
alemtuzumab vs. IFN at
m 0-12 and 0-24. P=NS
at m 0-36
Months 0-36
CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.
12-36
Alemtuzumab CAMMS223: Safety
►
Principal AEs associated with alemtuzumab included:
●
Infusion reactions
●
Mild-to-moderate infections
●
Autoimmunity
• Immune thrombocytopenia in 6 of 216 patients (2.8%)
including one death
• Thyroid disorders (28% vs. 3% for IFNβ-1a)
• 1 case of Goodpasture’s syndrome
CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.
Alemtuzumab CAMMS223: Safety
IFN ß-1a
(n=107)
Alem
12 mg
(n=108)
Alem
24 mg
(n=108)
Upper resp. infection*
27.1
44.4
50.9
Lower resp. infection*
1.9
11.1
13.9
Herpes simplex
2.8
8.3
8.3
Herpes zoster
0.9
1.9
5.6
0
0
1.8
Infections, %
Meningitis**
* P<0.001 alemtuzumab vs. IFN
** Listeria or viral meningitis
CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.
Alemtuzumab:
Effects on the Immune System
►
B cells returned to
normal within 3-6
months
►
Median recovery time for
CD4+ T cells > 100
cells/µL = 3 months
►
6-9 months for CD4+ T
cells > 200 cells/µL
►
Median recovery time to
baseline levels of CD4+
T cells = 61 months
Thompson S, et al. J Clin Immunol 2010;30:99–105. Coles A, et al. J Neurol. 2006;253:98-108.
Cladribine
►
►
►
►
►
►
►
►
Synthetic purine nucleoside analogue prodrug
Accumulates and is incorporated into the DNA of lymphocytes as a result
of a high ratio of deoxycytidinekinaseto 5' nucleotidase activity
Selectively induces apoptosis in dividing and non-dividing lymphocytes
Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells
and B cells
Relatively transient effects on other immune cells such as neutrophils and
monocytes
Reduces levels of pro-inflammatory chemokines
Crosses the blood brain barrier - CSF concentration = 25% of plasma
(patients with no BBB compromise)
FDA-approved for hairy cell leukemia
Carson et al. Blood 1983;62:737–43; 2Beutler et al. Proc Natl Acad Sci USA 1996;93:1716–20. Rice et
al.Neurology 2000;54:1145–55. Szczucinski et al. Acta Neurol Scand 2007;115:137–46Bartosik-Psujek
et al. Acta Neurol Scand 2004;109:390–2. Liliemark.ClinPharmacokinet1997;32:120–3.
XXXX
XX
Placebo (n = 437)
1326
patients
XXXX
XX
Cladribine 3.50 mg/kg total dose; 4 courses (n = 433)
XXXX
XX
Cladribine 5.25 mg/kg total dose; 6 courses (n = 456)
–4
0 5 9
13 16
24
36
44 48 52
60
72
84
96 Time (weeks)
MRI
Neurological
examination
Dosing: 4-5 day courses at month 1 and 2 (3.50 mg/kg) or months 1-4 (5.25 mg/kg) and
2 additional monthly courses beginning at week 48
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
CLARITY: Clinical Outcomes
Annualized relapse rate (95% CI)
57.6%
0.33
(0.29-0.38)
0.14*
0.15*
(0.12-0.17) (0.12-0.17)
* P < 0.001
Percent of relapse-free patients at
98 weeks
54.5%
Placebo (n = 437)
Cladribine 3.50 mg/kg (n = 433)
Cladribine 5.25 mg/kg (n = 456)
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
Odds Ratio (95% CI)
2.43 (1.81-3.27)
Odds Ratio (95% CI)
2.53 (1.87-3.43)
79.7*
60.9
78.9*
CLARITY: Clinical Outcomes
Proportion with confirmed 3-month
EDSS progression (%)
25
Time to Confirmed EDSS Progression
20
Placebo
HR vs Placebo (95% CI)
Cladribine 3.50 mg/kg
0.67 (0.48-0.93); P = 0.02
Cladribine 5.25 mg/kg
0.69 (0.49-0.96); P = 0.03
15
10
5
0
0
12
24
36
48
60
72
333
364
375
315
355
363
84
96
Weeks
Placebo
3.50 mg
5.25 mg
437
433
456
424
424
447
399
407
425
373
389
404
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
355
379
388
304
347
350
304
347
350
CLARITY: MRI Outcomes
T1 GadoliniumEnhancing Lesions
Active T2-Weighted Lesions
Combined Unique Lesions
77.9%
76.9%
74.4%
mean ± SE lesions/patient/scan
73.4%
87.9%
1.72
1.43
85.7%
0.91
0.38
0.33
0.43
0.12
All P < 0.001
0.11
Placebo (n = 437)
Cladribine 3.50 mg/kg (n = 433)
Cladribine 5.25 mg/kg (n = 456)
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
0.38
CLARITY: Safety and Tolerability
Placebo
(n = 435)
Cladribine
3.5 mg/kg
(n = 430)
Cladribine
5.25 mg/kg
(n = 454)
Cladribine
overall
(n = 884)
Herpes zoster
0
8 (1.9)
11 (2.4)
19 (2.1)
Herpes zoster oticus
0
0
1 (0.2)
1 (0.1)
1 (0.2)
1 (0.2)
1 (0.2)
2 (0.2)
188 (42.5)
205 (47.7)
222 (48.9)
427 (48.3)
2 (0.5)
2 (0.5)
2 (0.4)
4 (0.5)
Preferred term, n (%) patients
Varicella
Any infection or infestation
Deaths
►
►
►
►
►
20 patients had 21 zoster events in the cladribine groups
All 21 cases were self-limiting and dermatomal; no cases were disseminated
3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study developed
zoster versus 1.8% of those that did not
70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia at the
approximate time zoster developed
Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic carcinoma;
cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrest
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
CLARITY: Safety and Tolerability
Malignancies
Placebo
(n = 435)
Cladribine
3.5 mg/kg
(n = 430)
Cladribine
5.25 mg/kg
(n = 454)
Cladribine
overall
(n = 884)
Melanoma
0
1(0.2)
0
1(0.2)
Ovarian
0
1(0.2)
0
1 (0.1)
Pancreatic
0
1 (0.2)
0
1 (0.1)
Cervix
0
0
1(0.2)
1(0.2)
0
0
1(0.2)
1(0.2)
Preferred term, n (%)
During Study
During post-study
surveillance
Choriocarcinoma
Giovannoni G, et al. N Engl J Med. 2010;362:416-426.
CLARITY: Effects on Lymphocyte Subsets
Maximum Effects on CD4 and CD 19 Counts*
Weeks 0-48
Weeks 48-96
3.5
5.25
3.5
mg/kg mg/kg mg/kg
Add Reference
CD4 (week)
Cells/µL
CD19 (week)
Cells/µL
16
391
9
18
16
209
16
14
72
275
52
27
5.25
mg/kg
72
207
52
31
*Median values
Rieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster #816.
Fingolimod (FTY720)
►
Sphingosine-1-phosphate (S1P) receptor modulator
►
Sequesters circulating lymphocytes into secondary
lymphoid organs
●
●
Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T
cells), CD45RO+ (memory T cells) and CD19+ cells
No effect on lymphocyte induction, proliferation,
or memory function
►
May inhibit the production of IL-17
►
S1P receptors located within the CNS
●
Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis
in EAE
1. Brown B, et al. Ann Pharmacother. 2007;41:1660-1668. 2. Kappos L, et al. N Engl J Med. 2006;355:1124-1140.
3. Mullershausen F, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 4. Miron VE, et al.
Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 5. Barske C, et al. Presented at: ECTRIMS;
October 11-14, 2007; Prague, Czech Republic.
Oral fingolimod 0.50 mg once daily (n = 425)
1272
patients
(1:1:1)
Oral fingolimod 1.25 mg once daily (n = 429)
Placebo once daily (n = 418)
Randomization
Month 6
Month 12
Month 24
MRI
Clinic visits
Kappos L, et al. N Engl J Med. 2010;362:387-401.
FREEDOMS: Primary Efficacy Endpoint
Annualized Relapse Rate at 24 months
Placebo
(n = 431)
Kappos L, et al. N Engl J Med. 2010;362:387-401.
-54% vs Placebo
p < 0.001
-60% vs Placebo
p < 0.001
Fingolimod
0.5 mg
(n = 429)
Fingolimod
1.25 mg
(n = 420)
Percent with 3-month confirmed
EDSS progression
FREEDOMS: Disability Data
30
FTY720 0.50 mg vs placebo HR 0.70
P = 0.02 in time to disability
Progression
Placebo (24%)
25
20
FTY720 1.25 mg vs placebo HR 0.68
P = 0.02 in time to disability
Progression
FTY720 0.50 mg (18%)*
15
FTY720 1.25 mg (17%)†
10
* P = 0.03 vs placebo
† P = 0.01 vs placebo
5
0
90
Number at Risk
FTY720 1.25 mg 429
FTY720 0.50 mg 425
Placebo
418
180
270
360
450
540
630
720
322
332
290
305
321
279
165
152
143
Days on study
401
416
391
373
388
371
356
370
341
Kappos L, et al. N Engl J Med. 2010;362:387-401.
344
354
320
332
340
308
FREEDOMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 24 Months
-82% P<0.001
-74% P<0.001
Kappos L, et al. N Engl J Med. 2010;362:387-401.
FREEDOMS: Brain Volume
P≤0.03 for both doses of fingolimod
vs. placebo at all time points
Kappos L, et al. N Engl J Med. 2010;362:387-401.
Optional
extension
phase
Oral fingolimod 0.5 mg once daily and matching
weekly placebo injection IM
Oral fingolimod 1.25 mg once daily and matching
weekly placebo injection IM
IFNβ-1a 30 µg IM once weekly and
matching daily oral placebo capsule
Assessments
MRI
EDSS
Clinical visit
Randomization
Month 6
Cohen J, et al. N Engl J Med. 2010;362:412-415.
Month 12
Ongoing
TRANSFORMS:
Primary Efficacy Endpoint
Annualized Relapse Rate at 12 months
IFNβ-1a 30 µg IM
once weekly
(n = 431)
Cohen J, et al. N Engl J Med. 2010;362:412-415.
-52% vs IFNβ-1a,
p < 0.001
-38% vs IFNβ-1a,
p < 0.001
Oral fingolimod
0.5 mg
(n = 429)
Oral fingolimod
1.25 mg
(n = 420)
TRANSFORMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 12 Months
-35% vs. IFNß-1a
P=0.004
-42% vs. IFNß-1a
P<0.001
-55% vs. IFNß-1a
P<0.001
-73% vs.
IFNß-1a
P<0.001
Cohen J, et al. N Engl J Med. 2010;362:412-415.
TRANSFORMS: Brain Volume
P < 0.001
Cohen J, et al. N Engl J Med. 2010;362:412-415.
Fingolimod: Safety
►
Transient reduction in heart rate on initiation of
treatment
►
Elevated blood pressure
●
►
Elevated liver enzymes
●
►
↑mean systolic BP (1.9 and 3.6 mm Hg for 0.5 mg and
1.25 mg, respectively) and diastolic BP (0.7 and 2.1
mm HG for 0.5 and 1.25 mg, respectively)
↑LFTs ≥ 3 x ULN 8% for FTY720 0.5 mg, 10% for
FTY720 1.25 mg, 1.2% for placebo, 2% for IFNß-1a
Macular edema
●
●
FREEDOMS - 7 cases in the 1.25 mg dose group
(1.6%) and none in the 0.5 mg dose group
TRANSFORMS – 6 cases (4 in the 1.25 mg dose group
(1%) and 2 in the 0.5 mg dose group (0.5%))
Kappos L, et al. N Engl J Med. 2010;362:387-401. Cohen J, et al. N Engl J Med. 2010;362:412-415.
Fingolimod: Safety
Malignancies and Herpes Infections
FTY720
0.5 mg
FTY720
1.25 mg
Placebo
IFNß-1a
(n = 854)
(n = 849)
(n = 418)
(n = 431)
Basal cell carcinoma
7(0.8)
3(0.4)
3(0.7)
1(0.2)
Melanoma
3(0.4)
1(0.1)
1(0.2)
0
Bowen’s Disease
1 (0.1)
0
0
0
46(5.4)
48(5.7)
33(7.9)
12(2.8)
AE, n (%)
Skin Cancers
Infections
Herpes infections
Kappos L, et al. N Engl J Med. 2010;362:387-401. Cohen J, et al. N Engl J Med. 2010;362:412-415.
Fingolimod: Safety
►
Two fatal infections in patients treated with
FTY720 1.25 mg
●
Herpes encephalitis
●
primary disseminated varicella
►
Hemorrhagic encephalitis in a patient treated
with FTY720 1.25 mg
►
Posterior reversible encephalopathy syndrome
in a patient treated with 5 mg in the phase 2
study
Cohen J, et al. N Engl J Med. 2010;362:412-415; Kappos L et al. N Engl J Med. 2006;355:1124-40;
Leypoldt F, et al. LK. Neurology 2009;72:1022-24.
FTY720 1.25 mg (n = 16)
Normal range
Treatment duration (yrs),
mean ± SEM
1.9 ± 0.2
-
Lymphocyte count (x 109/L),
mean ± SEM
0.4 ± 0.1
0.9-3.3
CD4 T cell count (cells/µL),
mean ± SEM
78 ± 5.6
700-1100
CD8 T cell count (cells/µL),
mean ± SEM
149 ± 7.4
500-900
Mehling M, et al. Neurology 2008;71:1261–1267
[PD5.006] Prolonged Reduction in Circulating Lymphocytes
after Discontinuation of FTY720 (Fingolimod): Possible
Relationship to Duration of Therapy
Mark R. Keezer, Yves Lapierre, Igor Shames, David Haegert,
Amit Bar-Or, Jack Antel, Montreal, QC, Canada
CONCLUSIONS/RELEVANCE: Peripheral lymphocyte counts
remained depressed beyond the currently expected time
period in 2 patients following cessation of long-term FTY720
therapy. Regional lymph node architecture was preserved in
the one available patient. Exploration of larger datasets will
determine the true incidence of prolonged lymphopenia and
whether time to recovery of circulating lymphocytes may
provide a potential biomarker for guiding continued therapy.
Category - MS and Related Diseases - Clinical Science
Presented at the AAN Annual Meeting 2010.
Emerging Therapies:
Trading Efficacy for Safety
►
? Impaired immune
surveillance and
opportunistic
infections
►
Viral and other
infections
►
? Malignancies
►
Long-lasting effects
►
Autoimmunity
►
Teratogenicity
►
Rare, but serious
infusion reactions
►
The Unknown
Natalizumab and the Risk of PML
►
Humanized monoclonal antibody directed against CD11a
affecting T-lymphocyte activation, migration, and
reactivation
►
Evaluated in 4 randomized, double-blind, placebocontrolled trials
►
FDA-approved for psoriasis in 2003
●
●
At the time of approval, 2764 patients had been treated
218 treated for ≥ 1 year
Nijsten T, et al. Arch Dermatol 2009;145:1037-39.
►
►
October 2008: Label update to include PML
February 2009:
• FDA issued a Public Health Advisory and changed the label to
include a “black box” warning for PML
– At the time, 48,000 patients treated with efalizumab, but only
14,000 for > 1 year, 5,100 for > 2 years, and 1,900 for > 3 years
• EMEA recommends suspension of marketing
• Health Canada suspends marketing
►
April 2009: Genentech announced plans for a voluntary
withdrawal from the U.S. market
Nijsten T, et al. Arch Dermatol 2009;145:1037-39.
Treatment Decisions:
Considering Benefits and Risks
Benefits
Risks
Meaningful impact
Short-term safety
Disease Course
Long-term safety
MRI
Pharmacovigilance
? Better than ABCR
Post-approval studies
? Window of opportunity
Pregnancy issues
Convenience
New Frontiers in Neurotherapy
The Long Haul: Optimizing Long-Term
Functional Status and Financial Outcomes in
RRMS with Immunomodulation Therapy
What Do The Trials Teach Us?
Guy J. Buckle, MD, MPH
Director of MS Clinical Care Partners Multiple Sclerosis Center
Brigham and Women’s Hospital
Assistant Professor of Neurology
Harvard Medical School
Boston, Massachusetts
Epidemiology of MS
►
The most common chronic disease affecting the CNS in young adults
►
Approximately 400,000 cases in the United States
●
Estimates range from 250,000 to 500,000
►
The chances of developing MS are 1:1000 in the general population
►
Estimated 2.5 million cases worldwide
►
Highest incidence in Caucasians
►
Higher incidence in women (approximately 3:1)
►
MS strikes individuals between the ages 20-50, normally a time of
peak productivity
CNS = central nervous system.
Compston A, et al. Lancet. 2002;359(9313):1221-1231. Frohman EM. Med Clin N Am. 2003;87(4):
867-897. Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9):871-878. National Multiple Sclerosis Society.
Who gets MS? http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed
January 8, 2009. Lage MJ, et al. Work. 2006;27(2):143-151.
Potential Triggers for MS
Infectious
Agent
Genetic
Predisposition
Abnormal Immunologic Response
Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):727-730.
Environmental
Factors
MS
Clinical Manifestations
►
Fatigue
►
Optic neuritis
►
Pain
►
Bladder dysfunction
►
Depression
►
Bowel dysfunction
►
Numbness/paresthesias
►
Cerebellar dysfunction
►
Cognitive dysfunction
►
Sexual dysfunction
►
Weakness
►
Gait abnormalities
►
Spasticity
►
Partial/complete
paralysis
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-knowabout-ms/symptoms/index.aspx. Accessed February 21, 2010.
Age of Onset of MS
Distribution of Patients According to
the Decade of Life of MS Symptoms Onset
35
Patients (%)
30
25
20
15
10
5
0
0-10
11-20
21-30
31-40
Years
Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):727-730.
41-50
51-60
Progression of Disability: EDSS
10.0 = Death due to MS
9.0–9.5 = Completely dependent
Increasing
disease
burden
8.0–8.5 = Confined to bed or chair
7.0–7.5 = Confined to wheelchair
6.0–6.5 = Walking assistance is needed
5.0–5.5 = Increasing limitation in ability to walk
4.0–4.5 = Disability is moderate
3.0–3.5 = Disability is mild to moderate
2.0–2.5 = Disability is minimal
1.0–1.5 = No disability
0 = Normal neurologic exam
EDSS = Expanded Disability Status Scale.
Kurtzke JF. Neurology. 1983;33:1444-1452.
Natural History of MS and Cost of MS
CIS
RRMS
SPMS
Clinical Threshold
$70,000
Atrophy and Axonal
Degradation
$60,000
$50,000
Predicted Cost
$40,000
Early
Intervention*
$30,000
MRI lesion
activity
$20,000
$10,000
$0
Mild EDSS < 4
Moderate EDSS 4-6
Severe EDSS > 6
*Curve is based on an estimation of the decrease in cost for early treatment of about 40% at each range of
EDSS
Burks J. J Manag Care Med. 2008;12(1):26-31. [Exhibit 8].
Comi G. Neurol Sci. 2006;27:S8-S12.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702.
US$ per Year
Pre-clinical
Early Relapses
Affect Long-term Disability
100
Low (0-1 attacks in 2 years)
Intermediate (2-4 attacks in 2
years)
High (≥5 in 2 years)
Patients (%)
80
60
40
20
0
0
10
20
30
40
50
Time from Onset of MS (years)
Actuarial analysis of disability—percentage of patients not having reached EDSS 6:
difference between the groups is significant (P < .0001).
Weinshenker BG, et al. Brain. 1989;112:1419-1428.
Relapses Can Result in
Residual Long-Term Disability
Net Change in EDSS Score from before a Relapse to after a Relapse*
100
42.4% increase 0.5 or more
Number of Subjects
86
80
28.1% increase 1 or more
60
40
32
33
20
20
1
3
-3.5
-2.5
7
4
14
8
8
5
1
2
3.5
4.0
0
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
42% of patients had a residual deficit ≥0.5 point
28% had a residual deficit ≥1.0 point
*In 224 placebo patients from the NMSS task force on clinical outcome assessment.
EDSS = Expanded Disability Status Scale; NMSS = National Multiple Sclerosis Society.
Lublin FD, et al. Neurology. 2003;61:1528-1532.
Long-term Study Design in RRMS
Copaxone® (glatiramer acetate injection)20,21
N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter
open-label extension, and 1 patient received 1 dose of COPAXONE® and never returned for
evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort
included 108 patients at 10 years and 100 patients at 15 years.
Avonex® (IFNβ-1a)9,23
Avonex®: N=301; 158 Avonex®, 143 placebo; subset (85 Avonex®, 87 placebo) followed for 2
years.
15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year
15.
Up to
2
Tysabri® (natalizumab)27
N=942; Tysabri® 300 mg (n=627) or placebo (n=315).
years
5
Betaseron®: N=372; 125 Betaseron® 1.6 MIU, 124 Betaseron® 8 MIU, 123 placebo.
16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but
included in the study as identified patients). LTFU data were obtained in an observational
study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients
were not taking Betaseron®.
N=560; 184 Rebif® 44 mcg, 189 Rebif® 22 mcg, 187 placebo; at end of year 2, 172 placebo
patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was
continued to year 4.
LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8
years after enrollment.
15
yrs
Betaseron® (IFNβ-1b)24,25
Rebif® (IFNβ-1a)26
15 years
16
yrs
4
yrs
3
yrs
years
7-8
years
Key
Prospective study design
Retrospective follow-up
9. Jacobs LD, et al. Ann Neurol. 1996;39:285-294. 20. Ford C, et al. WCTRIMS 2008. Abstract P44.
21. Ford CC, et al. Mult Scler. 2006;12:309-320.
23. Bermel RA, et al. WCTRIMS 2008. Abstract P14. 24. IFNβ Study Group. Neurology.
1995;45:1277-1285. 25. Ebers G, et al. AAN 2006. P01.079.
26. Kappos L, et al. Neurology. 2006;67:944-953. 27. O’Connor PW, et al. AAN 2007. P06.082.
Data Supporting
Long-Term Use of DMT
GA 15-year LTFU
High-dose IFNb-1a
PRISMS 8
IFNb-1b
16 Year(> 80)
Low-dose IFNb-1a
15-year
Disease
Duration
(Years)
Percentage
Reaching
EDSS 4
Percentage
Reaching
EDSS 6
>18.5
38%
18%
~13
26.8%
20%
~20
Not reported
~45%
14.3
64%
32%
Ryan M, et al. J Manag Care Pharm. 2009;15(1)(Suppl S-b):S1-S17.
Scope of QoL
►
Three important domains in life
●
●
●
Physical functioning
Psychosocial functioning
Symptom-related phenomenon
The Two Faces of Multiple Sclerosis
MS
Relapse
Progression
MRI
Symptoms
Mobility
Employment
Depression
Fatigue
Cognition
Mobility and HRQOL
►
Improvement in strength and mobility can
lead to improved social interaction and
emotional behavior
►
Improved fitness in MS is associated with
improved HRQOL
►
Physical activity is indirectly associated with
improved depression, fatigue, pain, in
individuals with MS
HRQOL = Health-related quality of life.
Petajan JH, et al. Ann Neurol. 1996;39(4):432-441. Motl R,W et al. Psychol Health Med. 2009;14(1)111-124.
Multiple Sclerosis
40
First Rank (%)
35
30
25
20
15
10
5
0
Heesen C, et al. Mult Scler. 2008;14(7):988-991.
MS <5 Years
MS >15 Years
Walking Impairment and
Quality of Life
64% of patients report difficulty walking
►
Impairment worsens with increasing EDSS severity
Percent Among Patients who
Reported Walking Impairment
►
Johanesson et al. J Neurol. 2007;254:767-773
Trends Across MS Clinical Trials
Annualized Relapse Rate (ARR)
Johnson
1995
Jacobs
1996
IFNβ-1b PRISMS-2 Kappos Polman
study
1998 TRANSFORMS 2006
group,1993
REGARD
2007
BEYOND
2007
BECOME
2007
CAMMS223
2008
3 years
HERMES
2008
48 weeks
FORTE
2008
1 year
CLARITY
2009
Cost of MS Relapse
►
Reducing relapses is key to reducing costs
• The number of relapses is a significant
predictor of total cost
►
Cost of treating a relapse is difficult to calculate
• Includes initial care, acute treatment costs,
post-discharge services, daily cost of
outpatient medications
►
►
In one study, using 2002 dollars, costs ranged from
$243 to $12,870, depending on level of
management needed
Cost estimates do not differentiate between the
different forms of MS
Morrow TJ. J Neurol Sci. 2007;256(supp 1):S39-S44.
Grudzinski AN, et al. J Manag Care Pharm. 2000;6:19-24.
O’Brien JA, et al. BMC Health Serv Res. 2003;3:17-29.
Medical Costs Per Relapse
$243
$1847
$12,870
Low-Intensity Episode
Initial Contact
Moderate-Intensity Episode
Initial Contact
High-Intensity Episode
Initial Contact
Usual care physician
Usual care physician
Usual care physician
ED
ED
IV Methylprednisolone
Hospital day case
Hospital Admission
Post Discharge Services
Home administration
Outpatient follow-up
Symptom-Related Medications
Rehabilitation
Home healthcare
Skilled nursing
Nursing home
Hospital readmissions
Follow-Up Office Visits
Symptom-Related Medications
Follow-Up Office Visits
Consults
Therapists
ED = emergency department; IV = intravenous.
O’Brien J, et al. BMC Health Serv Res. 2003;3(1):17-28.
Economic Implications
►
Annual cost of MS in the United States is estimated at
approximately $13.6 billion (in 1994 dollars)
►
Total lifetime direct and indirect costs per patient are estimated
at approximately $2.4 million (in 1994 dollars)
►
Mean annual direct and indirect costs per patient total an
estimated $47,215 (in 2004 dollars)
►
Mean direct healthcare costs incurred by insured patients with
MS are 2 to 3 times higher than those without MS
►
Direct correlation between cost (direct and indirect) and severity
of disease has been well-established
►
Therapeutics that modify MS activity and severity can result in
both clinical and economic benefits
Whetton-Goldstein K, et al. Mult Scler. 1998;4(5):419-425. Pope GC, et al. Neurology. 2002;58(1):37-43.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702. Patwardhan MB, et al. Mult Scler. 2005;11(2):232-239.
O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:918-926.
MS Cost Drivers
Informal Care (12%)
Sick Leave/Reduced Working Time (10%)
Adaptations (5%)
Services (2%)
Other Drugs (6%)
Early Retirement (34%)
DMTs (22%)
Tests (2%)
Ambulatory Care (4%)
DMT = disease-modifying therapy.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702.
Hospital Inpatient Care (3%)
Costs of MS by Disease Severity
70,000
60,000
Informal Care
Indirect Costs
Direct Costs
Other Drugs
DMTs
Cost ($)
50,000
40,000
30,000
20,000
10,000
0
Mild EDSS
<4.0
Moderate EDSS
4.0-6.0
DMTs = disease-modifying therapies.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702.
Severe EDSS
>6.0
All
Patients
Cost of Care
Cost and functionality
Approximate Mean Annual Cost*
EDSS Score
Medical
Unpaid
Caregiver
Time
Lost Work
Time
Total
Mild
$3,106
$932
$9,938
$13,976
Moderate
$5,100
$3,188
$22,950
$31,238
Severe
$12,524
$12,524
$21,291
$46,339
EDSS 0 - 3.5
EDSS 4.0 - 6.0
EDSS 6.5 - 9.5
* 2004 US Dollars Non-Drug Costs
Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.
DMT-Associated Costs
►
Approximately 65% of annual direct per patient healthcare costs
in MS are attributable to drug therapy
►
MS drugs represent 20.2% of specialty drug expenditures within
managed care plans
►
National trend in MS drug expenditures was +18.3% in 2008
●
►
23.5% increase in manufacturer pricing was primary driver of trend
Comparative AWPs of DMT options:
Agent
Dosage
AWP/day
AWP/year
Interferon beta-1b
0.25 mg SC every other day
$105.41
$38,475
Interferon beta-1a IM
30 mcg IM once weekly
$98.66
$36,010
Interferon beta-1a SC
44 mcg SC 3 times weekly
$106.20
$38,761
Glatiramer acetate
20 mg SC daily
$110.10
$40,187
AWP = average wholesale price.
Prescott JD, et al. J Manag Care Pharm. 2007;13(1):44-52. CuraScript 2008 Specialty Drug Trend Report.
April 2009. Red Book Update. Vol. 30(1). January 2010.
MS Consensus Guidelines
►
National MS Society Expert Consensus Statement (2007):
●
●
●
●
●
●
Initiate therapy as soon as possible following diagnosis of activerelapsing disease with an interferon beta agent or glatiramer
acetate
Drug therapy should also be considered in patients with first attack
at high risk of MS
Access to medications should not be limited by age, level of
disability, or frequency of relapses
Continue treatment indefinitely unless lack of benefit, intolerant
adverse effects, or better treatment becomes available
Ensure adequate accessibility of all FDA-approved drugs for MS
Change treatments only for medically appropriate reasons
National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus
Statement. 2007. http://www.nationalmssociety.org. Accessed February 10, 2010.
Factors Influencing
Adherence with DMT in MS
70
60
50
40
30
20
10
0
Total
*P<.05
†P<.01.
Treadaway K, et al. J Neurol. 2009;256(4):568-576.
Promoting Adherence to Therapeutic
Regimens in MS
►Starting
●
●
●
●
●
●
●
Therapy
Educate
Make a plan with the
patient
Reconfirm goals
Schedule proper
follow-up
Treat relapses
appropriately
Treat comorbid
conditions
Keep channels of
communication open
Establishing a
therapeutic
relationship
Managing
patient
expectations
Brandes DW, et al. Curr Med Res Opin. 2009;25(1):77-92. Figure 2.
Educating
patient and
family
Increased
adherence
to
treatment
Addressing
patient
concerns
Managing
adverse
events
Optimizing Treatment Outcomes
in MS Patients
Patient Education Is Essential
►
Understanding disease
►
Minimizing fear and anxiety
►
Clinical implications
►
Proper injection training
►
Rationale for treatment
►
Recognizing relapses
►
Reviewing treatment options
►
►
Setting realistic
goals/expectations
Tracking and reporting
symptoms/relapses/adverse
effects
►
Potential adverse effects
►
►
Ways to minimize and
manage adverse effects
Emphasizing importance of
adherence to therapy
Treadaway K, et al. J Neurol. 2009;256(4):568-576.
Challenges to Adherence
►
Cognition and physical limitations negatively impact
adherence
►
Up to half of patients reportedly discontinue because of an
AE or a lack of efficacy
►
Association of depression carried a 3-fold risk of
nonadherence
►
Third-party reimbursement challenges
●
●
►
Formulary status
Copays
Adherence tends to decrease over time due to a variety of
factors, such as “treatment fatigue,” loss of motivation,
and complacency
Rio J, et al. Mult Scler. 2005;11:306-309. Twork et al. Curr Med Res Opin. 2007;23(6):1209-1215.
O’Rourke KE, et al. Mult Scler. 2005;11(1):46-50. Ross AP. Neurology. 2008;71(Suppl 3):S1-S2. DiMatteo
MR, et al. Arch Intern Med. 2000;160:2101-2107.
Recent Analyses of the Economic
Impact of MS Treatment
►
In an analysis of an employer medical, drug and disability claims
database:
●
●
●
►
Baseline MS-related medical costs were higher for treated vs
untreated employees ($2520 vs $1012,P < 0.0001)
Risk-adjusted total annual medical costs ($4,393 vs $6,187) and
indirect costs ($2,252 vs $3,053) were significantly lower (P <
0.0001) for treated vs untreated employees with MS
Study limitation: lack of clinical detail on MS severity
Early use of DMTs in patients with CIS that delayed conversion to
CDMS provided a positive incremental cost-effectiveness ratio
(ICER) per patient-year compared with no treatment (Euros
2,574.94)
Birnbaum HG, et al. Curr Med Res Opin. 2009;25(4):869-877.
Lazzaro C, et al. Neurol Sci. 2009;30:21-31.
Rates of Unemployment in
Individuals with MS
Country
Duration of MS
Since Onset (Years)
Unemployment
Rate
Busche et al., 2003
Canada
14.8 (median)
(range 1-47)
Baseline: 49.9%
2.5 years later: 59.4%
Jackson and Quaal, 1991
Canada
> 5 in 80% of patients
76%*
Gronning et al., 1990
Norway
10 (mean)
(range 1-33 years)
72% of those
with definite MS
O’Connor et al., 2005
U.K.
Employed: 10 (mean)
64%
Beatty et al., 1995
U.S.
15.4 (mean)
60-66%
Kornblith et al., 1986
U.S.
13 (mean)
80%*
LaRocca et al., 1982
U.S.
13 (mean)
77%
Study
Unemployed: 15 (mean)
*Proportion of individuals unemployed during the study who had been employed at some time during his or
her lives.
Dennett SL, et al. Value Health. 2008.11(3):478-486.
Effect of IMT and Other Factors on
Employment Loss Time
►
Focus: factors that influence time missed from work
among individuals with MS (N = 284)
►
Records were examined for details of medical claims
►
Multivariate regressions were performed, controlling for
demographic characteristics, type of immunomodulatory
medication, and overall severity of illness
►
Looked at total number of days missed from work for any
reason and specifically due to absenteeism, short-term
disability, or workers compensation
►
Results indicate that lost work time is affected by severity
of illness and type of IMT
Lage MJ, et al. Work. 2006;27(2):143-151.
Effect of Immunomodulatory Therapy
on Employment Loss Time
60
(P = .003)
Fewer Days Absent
50
GA
INFbeta-1a
INFbeta-1b
40
(P = .04)
30
20
10
(P = .03)
(P = .18)
(P = .47)
(P = .09)
(P = .71)
(P = .33)
(P = .39)
0
-10
Short-term
Disability
Workers
Comp
Any
Reason
-20
Fewer days absent from work from 1999–2002 for individuals with MS treated with GA (n = 28), INFb1a (n = 74), or INFb-1b (n = 16) compared to untreated individuals with MS (n = 166)
Lage MJ, et al. Work. 2006;27(2):143-151.
Specialty Pharmacy Overview
►
Key Disease States Managed by a Specialty
Pharmacy
●
►
MS, RA, Hep C, hGH, Oral Oncolytics
The number of patients utilizing Specialty
Pharmacies continues to increase
●
Currently estimated to be 40% - 50% of MS
patients
SP Value Proposition
►
Compliance & Adherence
●
►
Typically 15% - 20% higher than retail*
Patient Education
●
Specially trained on rare diseases and
therapies
• Collaborate with manufacturers and MS
Specialists to assist with training
►
Patient Monitoring
●
●
●
Efficacy
Side effects
Co-Morbid Conditions
*2008 IMS Report
SP Value Proposition
►
Data Tracking and Monitoring
●
Compliance/Adherence
Efficacy
●
Side Effects
●
Co-Morbidities
●
Symptom Management
●
Appropriate and timely interventions
●
• Baseline
• Relapses
• EDSS
• Flu like symptoms
• Injection site reactions
• Asthma, Hypertension, diabetes
• Fatigue,
• Bladder
• Depression
Therapy OPtimization in MS
(TOP MS)
►
An Outcomes Study of disease
management (DM) for MS based in
Specialty Pharmacies who have
demonstrated commitment to DM:
•
•
•
•
•
•
Therapy Adherence and Compliance
Disease Characteristics
Relapses
Disability Progression
Quality of Life
Work / Usual Activity Productivity
Therapy OPtimization in MS
(TOP MS)
►
Brief Outline:
●
●
●
●
3 Specialty Pharmacies
~3,000 patients followed for 2 years
Patient-specific clinical reports to
physicians
De-identified data collected in a
research-quality database will be
available to address outcomes
research questions
Study Population
►
Subjects who are treated with glatiramer
acetate or interferon (IFN)-β and receive
their therapy from a Specialty Pharmacy:
• Copaxone®
• Avonex®
• Betaseron®
• Rebif®
• Extavia®
Study Objective
►
To demonstrate the benefits of
compliance and adherence to MS
therapy with patient outcomes:
●
●
●
●
Relapses
Disability progression
Quality of life
Work and usual activities productivity
Advocacy
►
Assist patients with resources and support
►
Assist patients with navigation of health care
system and insurance coverage
►
Speak with third-party payors to advocate for
coverage for all DMTs
►
Become involved with advocacy organizations
●
IOMSN
●
CMSC
●
NMSS
●
MSAA
●
MSF
• Educational activities for professionals
and patients
• Development of written materials
• Working at organizational level for FDA
approvals, third-party reimbursement
IOMSN = International Organization of MS Nurses; CMSC = Consortium of MS Centers; NMSS = National
MS Society; MSAA = MS Association of America.
Conclusion
►
MS is a chronic, debilitating, and progressive disease
►
Economic implications are significant and appear
directly correlated with disease severity
►
Although costly, long-term data and expert
consensus support the primary role of DMT in
managing disease progression
►
Optimal therapeutic benefit with DMT hinges
strongly on multidimensional support from the
healthcare system
►
Patient education and careful monitoring are key
factors driving success in MS therapy
Case Studies
Challenging Cases in the
Management of Multiple Sclerosis
Multiple Sclerosis Case #1
► 24-year-old female with diplopia on looking to the
right for a day or two – Austin ophthalmologist
found nothing unusual
► Back in Houston another ophthalmologist called it
‘some type of optic nerve inflammation’ and gave
her 5 days of oral steroids
► 2 weeks into symptoms seen by a pro who noted
skew deviation, marked asymmetric nystagmus
with torsion and jerk greater to the right, no INO,
no APD and normal VERs to go with complaints of
vertical diplopia and oscillopsia
UPIN 4804
06/06/08
UPIN 4804
06/06/08
Multiple Sclerosis Case #1
► 4 days later continued double vision on looking to
the right
► Extensive past history uncovered only one week
of nausea and vomiting about 4 months ago
attributed to food poisoning
► Nystagmus to right gaze of greater amplitude in
adducting eye with incomplete abduction of right
eye, remaining exam normal
► CSF with 10 lymphocytes, IgG index 1.15 and 3
OCBs
► Intravenous methylprednisolone course started
UPIN 4804
07/02/08
UPIN 4804
07/02/08
Multiple Sclerosis Case #1
The Issues
► The subject was born and raised outside of the
reach of the Scandinavian gene pool - is this
NMO, and how unusual is this?
► When you have CIS and can’t diagnose more
than suspect MS by McDonald’s or Swanton’s,
do you just treat, use Frohman?
► When asked about the familial risk of MS in the
company of the patients twin sister, what is the
best course?
Multiple Sclerosis Case #2
► 30-year-old Caucasian female presented initially
with right optic neuritis.
► Vision improved after high dose intravenous
methylprednisolone treatment
► T2-weighted MRI brain scan showed 2 areas of
abnormal signal in the periventricular and
subcortical white matter.
► No disease modifying therapy was started at that
time.
Multiple Sclerosis Case #2
► 1 year later- numbness and weakness of both legs, urinary
hesitancy, and increasing gait difficulties over several days.
► MRI cord -increased T2 signal at C8 with a corresponding
area of Gd enhancement on T1.
► MRI brain- one new periventricular white matter lesion
without enhancement in comparison to last year’s.
► Motor symptoms improved with high dose corticosteroid
therapy
► Residual numbness in the feet and bladder control
difficulties.
Multiple Sclerosis Case #2
► Given diagnosis of MS and therapy with once weekly
IM interferon beta was begun.
► 6 months later she complained of markedly increased
fatigue and “fuzzy thinking.”
► Brain MRI scan revealed several new T2 lesions in
both cerebral hemispheres and several new enhancing
lesions around the corpus callosum.
► Disease modifying therapy was changed to a high
dose subcutaneous interferon beta.
Multiple Sclerosis Case #2
► Over the next year, she had no new symptoms
and there were no new lesions seen on a repeat
MRI scan.
► After several months she complained of balance
difficulties, memory difficulties, and an increase in
fatigue.
► MRI scan showed additional Gd+ enhancing
lesions.
► A test for neutralizing antibody against interferon
beta (NAb) revealed a titer greater than 1:100.
Multiple Sclerosis Case #2
► The same interferon treatment was continued
but after several months she complained of
ongoing problems with memory.
► Several new enhancing lesions were again found
on MRI. A repeat NAb titer was unchanged.
Multiple Sclerosis Case #3
►
Student nurse falls hitting head on concrete
when obese patient she is transporting begins
to fall off litter. MRI shows pineal cyst.
►
18 months later, follow-up MRI shows
unchanged cyst but single periventricular nonenhancing white matter lesion.
►
Three yearly follow-ups show no new MRI
lesions, no symptoms and no neurologic
abnormalities.
Is it Multiple Sclerosis?
►
While hiking with physician husband on hot
afternoon, she notes numbness in left foot.
►
Spinal cord MRI shows enhancing lesion at
T17.
►
Is it MS?
►
Treatment recommendations?