2/16/2012
Recent Advances in Neurology
The Origins of Multiple Sclerosis
Multiple Sclerosis 2012 Lessons From the Bench and Bedside February 15, 2012
Stephen L. Hauser, MD Department of Neurology, University of California, San Francisco Conflicts of Interest: BioMarin, Receptos
Sir Augustus d’Este (1794-1848) Victoria and Albert Museum, London
Two Populations of MS Patients
Treatment of Multiple Sclerosis Harrison’s Principles of Internal Medicine 3rd Ed, 1958
Relapsing and Progressive 20
Minimal Cane Crutches Disability Benign Progressive MS Relapsing Remitting MS Gait Symptoms Nonambulatory Disturbance
10
0 0
1.5
2.5
3.5
4.5
5.5
Disability (EDSS)
6.5
7.5
The most that can be done is to reassure and encourage the patient through moderate exercise and supportive measures…during an acute episode it is surely preferable to assure the patient that he will recover and to preserve silence on the subject of relapse.
8.5 John N. Walton
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2/16/2012
Vesicular Demyelination in MS
The Therapeutic Landscape in MS (2011) Interferons
Interferon Omega Fc-IFß
Anti-proliferation agents
Interferon Tau
Phase II Lymphocyte trafficking
Phase III
Peg IFNß (BIIB017) Marketed Betaseron Avonex Teriflunomide Rebif Pixantrone
AJM-300 Firategrast
R1295
ATL-1102
Copaxone
Targeted Immune regulation
Laquinimod
Tovaxin
Cladribine
ATX-MS-1467
BG-12 Riluzole 683699(T-0047) Daclizumab
Sativex
PI2301 Ocrelizumab Campath Rituximab LY-2127399 Atacicept Ofatumumab
Targeted mAbs/Fc-Ab
TBC4746
MLN-0002
Tysabri Fingolimod
Novantrone Azathioprine
Vaccine, tolerization
A Pattern of Humoral Immune Pathology
Oral administration Injection
Phase I
Dalfampridine SR
MM-093 Nerispirdine
Symptomatic Tx
Courtesy of G. Giovannoni (modified)
Rituximab in Relapsing Remitting MS
Rituximab in Primary Progressive MS
Gadolinium-Enhancing Lesions from Baseline to Week 48
Time to Confirmed Disease Progression 70
All Intent-to-Treat Patients (N=439)
60
HR: 0.77 (95% Cl: 0.55 – 1.09) p-value=0.1442
2
50
P = 0.78
1.5 1
Proportion of Patients
Mean Number of Gd Lesions
2.5
P = 0.003 P < 0.001
0.5
P = 0.001
0 0
4
8
12
Weeks
16
20
24
28
32
36
40
44
48
* Missing values imputed by average of available data
40 30 20 10 0 0
12
Rituximab (N=66)
Rituximab
Placebo (N=35)
Placebo
Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A,..Smith CH. N Engl J Med: 358:676, 2008
24
36
48
60
72
84
96
108
Time to Confirmed Disease Progression (weeks)
Hawker et al, Ann Neurol 66:460, 2009
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2/16/2012
Rituximab in Primary Progressive MS
The Development of Anti-CD20 Therapy
Time to Confirmed Disease Progression Subgroup Analysis
Rituximab and Ocrelizumab
70 60
40
30
30
20
20
10
10
0
0 12
24
36
48
60
72
96
84
108
1986 Synthesis
HR: 0.33 (95% CI: 0.14-0.79) p=0.0088
50
40
0
Age 2
Treatment starting at day -21
Follicle-like aggregates Activated B cell
Bystander activation
MOG peptide
30 3
isotype
5
Isotype
2.5
α-hCD20
α-hCD20
4
EAE score
2
Mature naïve B cell
3 *
*
*
* *
20
* 1.5
*
2.5 isotype 2
α-hCD20
1
Potential sites of antigen recognition
1.5 1
0.5 0 2
4
6
8
10 11 12 13 15 16 19 21 23 26 28 30 33 35 37 41
Days after immunization Treatment starting at day -21
Courtesy of Christian vonBuedingen
1
0.5
0
Immature B cell
α-hCD20
10
0
* * *
2
0
pre-B
Isotype α-hCD20
40
Days after immunization
Days after immunization
Isotype
pro-B
0
50
0
0 0
Plasma cell (long lived)
Isotype α-hCD20
2 0 1 0
B cells per sq. mm
Spleen
3 0
total * 2
B cells per sq. mm
Bone marrow
42 49
0
2
4
6
8
10
11
12
13
15
17
19
25
28
31
33
35
38
0
Inflammation
Demyelination
Days after immunization Treatment starting at EAE > 2
Weber, MS et al. Ann Neurol 68:369, 2010
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2/16/2012
BLyS and APRIL bind to B cell-expressed receptors
BLyS and APRIL are B cell maturation & survival factors B cell division
Tumour environment
Ligands
BLyS
BLyS/APRIL heterotrimer
APRIL
B cell differentiation
Bone-marrow environment
Malignant B cell survival
APRIL
Class switch to IgA or IgG
BLyS
Receptors Resting B cell
B cell survival
Activated B cell T cell division
Antibody-producing plasma cell
BCMA BAFF-R
TACI Proteoglycans
B cell
(Enhanced antigen presentation)
Dillon S, et al. Nat Rev Drug Discov 2006;5:235–246
Lessons From the B-Cell Experience in MS
ATAMS: Atacicept in MS Atacicept: Recombinant fusion protein with immunomodulatory effects on B cells
ATAMS: 36-week phase II RCT of atacicept
•
The anti-CD20 trials have revealed that B-cells are central players in the pathogenesis of focal lesions in MS
•
The MOA is likely to involve interference with activation of pathogenic T-cells promoted by B-cells via APC or cytokine functions, but many questions remain
•
The attractiveness of B cell therapies for MS will likely be determined by their safety profile in phase 3 trials and beyond
•
These trials also set the stage for testing more selective therapies that target subsets of B-cells, B-cell growth/survival factors, or germinal center interactions
•
More than 15 years will have passed from the initial proposal to employ anti-CD20 therapy in MS to completion of the pivotal phase 3 trials!
P = 0.015 P = 0.042
25, 75, 150 mg vs placebo (PBO) in relapsing MS
Mean ARRs were greater in atacicept vs PBO arms (Figure)
Significantly more T1 Gd+ lesions were observed in atacicept 75 mg (2.64) vs PBO (1.14; P = 0.017) arm
Effects reversed after atacicept cessation in safety follow-up
Conclusion: Atacicept was associated with worse outcomes
Study stopped
Statistically significant results for 25 mg and 150 mg groups compared with placebo
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2/16/2012
Gene Discovery in MS
Will the Clinical Landscape of MS Look Different in 2016? • Many available therapies for RRMS
Whole genome sequencing of MS twins
First generation genome-wide linkage studies (400 markers)
• Aggressive early treatment is the norm
First reported association between MS and HLA
• Still no antigen-specific therapy on the horizon • Strategies for primary prevention available
First generation GWAS (1000 patients)
1972
1996
2005
2007
2009
IL2RA IL7R RPL5 CD58 CLEC16A EVI5
CD226 CD6 IRF8 TNFRSF1A TYK2
HLA
• Fewer patients with progressive MS A/A G/G
A/G
Separation from common ancestry Australopithecus Walking apes
Homo habilis stone tools
Homo ergaster communities
MS Susceptibility Genes in T Cell Activation Pathways
2010
GENES
• Biomarkers stratify patients for prognosis and treatment
• Treatment for the neurodegenerative component of MS remains a challenge
Meta-analysis of GWAS
STUDIES
• Exquisite imaging capabilities of the entire neuraxis
• Promising prospects for remyelination (anti-LINGO; Wnt pathway; retinoid X receptor [RXR-γ] signaling)
Second generation GWAS (10,000 patients)
Second generation genome-wide linkage study (5000 markers)
Homo erectus upright man
CLECL1 ZFP36L1 BATF GALC MALT1 TNFSF14 MPV17L2 DKKL1 MAPK1 SCO2 NFKB2 CXCR5 SOX8 RPS6KB1 TNFRSF6 CYP27B1 CYP24A1
VCAM PLEK MERT SP140 EOMES CD86 IL12B BACH2 THEMIS MYB IL22RA2 TAGAP ZNF767 MYC PVT1 HHEX Homo sapiens
Functional Studies of MS Variants
International Multiple Sclerosis Genetics Consortium Nature 476:214, 2011
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2/16/2012
A Disease-Focused Neuroscience Center at Mission Bay
Thank you!
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