2/16/2012

1

Multiple Sclerosis 2012Lessons From the Bench and Bedside

Recent Advances in Neurology

Stephen L. Hauser, MDDepartment of Neurology, University of California, San Francisco

Conflicts of Interest: BioMarin, Receptos

February 15, 2012

Sir Augustus d’Este (1794-1848)Victoria and Albert Museum, London

The Origins of Multiple Sclerosis

Two Populations of MS Patients

Relapsing and Progressive

0

10

20

0 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5

Disability (EDSS)

BenignSymptoms

MinimalDisability

Gait Disturbance

Cane Crutches

NonambulatoryRelapsing Remitting MS Progressive MS

Treatment of Multiple SclerosisHarrison’s Principles of Internal Medicine 3rd Ed, 1958

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.

John N. Walton

2/16/2012

2

Marketed

Phase III

Phase II

Phase I

The Therapeutic Landscape in MS (2011)

Anti-proliferationagents

Interferons

Vaccine, tolerization

Targeted mAbs/Fc-Ab Symptomatic Tx

Targeted Immuneregulation

Lymphocyte trafficking

Oral administration

Injection

Fingolimod

Firategrast

AJM-300

TBC4746

R1295

TysabriATL-1102

MLN-0002

Laquinimod

Cladribine

BG-12

Riluzole

683699(T-0047)Daclizumab

MM-093

Sativex

DalfampridineSR

Nerispirdine

OcrelizumabCampath

Rituximab

AtaciceptLY-2127399

Ofatumumab

Copaxone

Tovaxin

ATX-MS-1467

PI2301

NovantronePixantrone Azathioprine

Teriflunomide

BetaseronAvonex

Rebif

Peg IFNß(BIIB017)

Interferon Tau

Fc-IFß

Interferon Omega

Courtesy of G. Giovannoni (modified)

Vesicular Demyelination in MSA Pattern of Humoral Immune Pathology

Rituximab in Relapsing Remitting MSGadolinium-Enhancing Lesions from Baseline to Week 48

Weeks

Mea

n N

umbe

r of G

dLe

sion

s

0

0.5

1

1.5

2

2.5

0 4 8 12 16 20 24 28 32 4036 44 48

* Missing values imputed by average of available data

P = 0.78

P = 0.003

P = 0.001

P < 0.001

Rituximab (N=66)

Placebo (N=35)

Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A,..Smith CH. N Engl J Med: 358:676, 2008

Rituximab in Primary Progressive MSTime to Confirmed Disease Progression

Hawker et al, Ann Neurol 66:460, 2009

All Intent-to-Treat Patients (N=439)

Time to Confirmed Disease Progression (weeks)

Pro

porti

on o

f Pat

ient

s

0 12 24 36 48 60 72 84 108

HR: 0.77 (95% Cl: 0.55 – 1.09)p-value=0.1442

0

10

20

30

40

50

60

70

96

Rituximab

Placebo

2/16/2012

3

Rituximab in Primary Progressive MSTime to Confirmed Disease ProgressionSubgroup Analysis

HR: 0.63 (95% CI: 0.34-1.18)p=0.1427

HR: 0.33 (95% CI: 0.14-0.79)p=0.0088

Age <51Gd (+) at Baselinen=72

Age <51Gd (-) at Baselinen=143

Rituximab

Placebo

0 12 24 36 48 60 72 84 1080

10

20

30

40

50

60

70

96

Pro

porti

on o

f Pat

ient

s

0 12 24 36 48 60 72 84 1080

10

20

30

40

50

60

70

96

Time to Confirmed Disease Progression (weeks)

The Development of Anti-CD20 TherapyRituximab and Ocrelizumab

1995 Co-development

2003 Merger

2009 Merger

1986 Synthesis

Technological change moves faster than the pace of clinical experiments

SSSSSS

Constant region

Variable domains

CH1

SS

CH2

CH3

VH

V k

Ck

Fc

Heavy chain

Light chain

N-terminus

C-terminus

C

B B

PVP158

FCγRIIIa

PV

NK

ANP INIYNCEPANP

xx

X = mutation

V (ADCC) > P (ADCC)

Overlapping epitope

2 mutations in RTX reduce affinity for NK cells

Chimeric vs humanised VH/ VL

Ocrelizumab binds more strongly both forms of the Fc γRIIIa on NK cells

NK: natural killer cell

Ocrelizumab

Study Design for Ocrelizumab Phase II Trial

Design Randomized, double-blind, placebo-controlled ocrelizumab; blinded rater AvonexTM; 1:1:1:1 randomization stratified by geographical region

Sample Size / No. sites N = 200 planned (220 actual); ~100 sites European Union, United States, & Rest of World

PopulationRRMS, Expanded Disability Status Scale (EDSS) of 1.0–6.0, inclusive, At least two

documented relapses within last 3 years, at least one of which occurred within last year prior to screening, MRI evidence of disease burden

Schedule and dose

Placebo × 2 for Cycle 1 only �600 mg open-label ocrelizumab300 mg × 2 � by 600 mg q24 wks1000 mg × 2 �1000 mg q24 and 48 wks �600 mg q72 wksAvonexTM 30 µg IM qwk × 24 wks �600 mg open-label ocrelizumab

1°Endpoint Total number of Gd-enhancing lesions at Wks 12, 16, 20, and 24

2°Endpoint Annual relapse rate (ARR) by Wk 24; Proportion of patients relapse-free by Wk 24; total # new gadolinium (Gd)-enhancing lesions; change in total volume T2 lesions

Study duration 144 wks total = 96-week treatment period + 48 wks for follow-up

Double blind

Rater blinded

Screen (4 wks)

Treatment period (96 wks)

MRI

OCR / Pbo Infusion

-4 2 4 12 16 20 24 72 1440 8 9648

2/16/2012

4

Ocrelizumab in Relapsing Remitting MSPrimary Endpoint: Mean Gad+ Lesions Week 12 to Week 24

Weeks

Mea

n N

o. T

1 G

d-en

hanc

ing

Lesi

ons

0

1.0

2.0

3.0

4.0

0 4 8 12 16 20 24

*IFN beta-1a arm was open label, all efficacy comparisons were exploratory

Placebo (N=54)Ocrelizumab 600mg (N=51)Ocrelizumab 2000mg (N=52)IFN beta-1a (N=52)

Primary end point

P<0.0001 for both Ocrelizumab doses vs placebo

Lesions on MRI by week (ITT): average imputation

Kappos, Li, Calabresi, O’Connor, Bar-Or, Barkof,Yin, Leppert, Glanzman, Tinbergen, Hauser. Lancet 378:1779, 2011

A Fatality in the Ocrelizumab RRMS Trial!• 41 year old woman, disease duration 10 years, prior Rx IFN beta

• Randomized to OCR 2000 mg group

• At week 12, on day of routine blood and MRI follow-up studies (all unremarkable), developed delirium, thrombocytopenia and status epilepticus, then fever, and over the next 48 hrs a Systemic Inflammatory Response Syndrome (SIRS) with multiorgan dysfunction, brain edema

• Had sustained a bee sting on face 5 days earlier

• Multiple blood, CSF cultures (including viral PCR) negative for infection

• Treatment with platelets, IVIg, antibiotics to no avail; death on day 15• Pathology: severe cerebral ischemia with herniation; several

perivascular CNS hemorrhages; several septic emboli; multi-organ dysfunction; no evidence for TTP, DIC, or primary infection in brain or hepatic tissue

Ocrelizumab (OCR) Phase II Updated Results 96-Week ARR

Weeks 0-24 Placebo OCR 600 mg OCR 2000 mg IFN β-1a 30 mcg IMWeeks 24-48 OCR 600 mg OCR 600 mg OCR 1000 mg OCR 600 mg Weeks 48-72 OCR 600 mg OCR 600 mg OCR 1000 mg OCR 600 m gWeeks 72-96 OCR 600 mg OCR 600 mg OCR 600 mg OCR 600 mg

Ocrelizumab: 96 Week Data• There were 7 serious AEs in phase 2 RRMS trial: 1 in placebo; 1 in 600

mg; 3 in 2000 mg; 2 in IFNβ1a; no imbalance or increase over time

• Two serious AEs were thought to be infection-related: 1 in placebo; 1 in 2000 mg OCR

• No opportunistic infections were noted; no dropouts due to adverse events; no imbalance in infection rate during weeks 48-96

• Infusion-related reactions occurred after initial infusion (30-44%) and decreased on subsequent infusions; led to withdrawal in only 3 pts

• Through 96 weeks, with open-label Ocrelizumab 600 mg treatment:- No loss of efficacy; most patients had no clinical disease activity- No patient experienced a new or enlarging T2 lesion from Week 24 to Week 96- At the Week 96 MRI scan, no patient on Ocrelizumab experienced a Gd

enhancing TI lesion

2/16/2012

5

Ocrelizumab: The Path Forward

• Rheumatoid Arthritis (RA) phase 3 OCR program halted in May 2010 due to cases of serious/fatal opportunistic infections; dose, chronic GC use, co-morbid illness, Asian ancestry implicated as risk factors

• RA phase 3 trials: no increase in risk of opportunistic infections at 200 mg x2 dosing of OCR (>1500 pt/yrs)

• No cases of PML with OCR; with Rituxan (2 million Rx), PML noted in 6 RA (118,000 pts treated); 8 SLE; 6 other AID; 137 oncology; 0 MS cases

• Phase 3 OCR trials in MS launched in 2011: 2 in RRMS; 1 in PPMS

The Phase 3 Orchestra Trials of OcrelizumabORATORIO: Randomized, Double-Blind, Placebo-controlled Study in Primary Progressive MS`

OPERA I & II: Randomized, Double-Blind, Double-dummy Studies in Relapsing MS`vsIFN beta-1a (Rebif®)

B Cells and the brain

Bone marrow

Stem cell

pro-B

pre-B Immature B cell

CNS

Mature naïve B cell

SpleenSpleen

ActivatedB cell

Plasma cell(long lived)

Plasmablast

Plasma cell(long lived)

Plasmablast

Memory B cell

Potential sites of antigen recognition

Follicle-like aggregates

Bystander activation

Secondary lymphoid tissues

Lymph folliclewith germinal center

T

Courtesy of Christian vonBuedingen

Anti CD20 ameliorates MOG protein-induced EAE

0

10

20

30

B c

ells

per

sq.

mm

Isotypeα-hCD20

0

10

20

30

40

50

0

4

8

12

16

20Isotypeα-hCD20

parenchymalmeningeal

Isotypeα-hCD20

B c

ells

per

sq.

mm

total

0

1

2

3

4

5

0 2 4 6 8 10 13 15 17 22 25 27 29 36 39 41 43 49 51 56

Treatment starting at EAE > 2

Isotypeα-hCD20

Days after immunization

0

1

2

3

4

5

0 2 4 6 8 10 12 13 14 15 17 18 20 24 27 33 39 43 48 52 57 63

EA

E s

core

Treatment starting at day -21

Days after immunization

*

* * **

* **

*

**

Isotype

α-hCD20

MOG protein

0

1

2

3

4

5

0 2 4 6 8 10 11 12 13 15 16 19 21 23 26 28 30 33 35 37 41 42 49

EA

E s

core

Isotype

α-hCD20

Treatment starting at day -21

Days after immunization

*

* * * ** *

*

0

0.5

1

1.5

2

2.5

3

0 2 4 6 8 10 11 12 13 15 17 19 25 28 31 33 35 38

Treatment starting at EAE > 2

Isotype

α-hCD20

Days after immunization

**

0

0.5

1

1.5

2

2.5

Inflammation Demyelination

isotype

α-hCD20

0

10

20

30

B c

ells

per

sq.

mm

isotype

α-hCD20

MOG peptide

but exacerbates MOG peptide-induced EAE

Weber, MS et al. Ann Neurol 68:369, 2010

2/16/2012

6

BLyS and APRIL are B cell maturation & survival factors

Bone-marrowenvironment

Tumour environment

B celldifferentiation

APRIL

T cell divisionAntibody-producingplasma cell

ActivatedB cell

RestingB cell

Class switch to IgA or IgGBLyS

Dillon S, et al. Nat Rev Drug Discov 2006;5:235–246

MalignantB cell survival

(Enhanced antigen presentation)

B cellsurvival

B cell division

BLyS and APRIL bind to B cell-expressed receptors

BAFF-R

BCMA TACI

Proteoglycans

B cell

Ligands

Receptors

BLyS APRILBLyS/APRILheterotrimer

ATAMS: Atacicept in MS

� Atacicept: Recombinant fusion protein with immunomodulatory effects on B cells

� ATAMS: 36-week phase II RCT of atacicept25, 75, 150 mg vs placebo (PBO) in relapsing MS

� Mean ARRs were greater in atacicept vsPBO 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

P = 0.042

P = 0.015

Statistically significant results for 25 mg and 150 mg groups compared with placebo

Lessons From the B -Cell Experience in MS

• 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 initia l proposal to employ anti-CD20 therapy in MS to completion of the pivotal phase 3 trials!

2/16/2012

7

Will the Clinical Landscape of MS Look Different in 2016?

• Many available therapies for RRMS

• Aggressive early treatment is the norm

• Still no antigen-specific therapy on the horizon

• Strategies for primary prevention available

• Exquisite imaging capabilities of the entire neuraxis

• Biomarkers stratify patients for prognosis and treatment

• Fewer patients with progressive MS

• Promising prospects for remyelination (anti-LINGO; Wnt pathway; retinoid X receptor [RXR-γ] signaling)

• Treatment for the neurodegenerative component of MS remains a challenge

Gene Discovery in MS

A/A

G/G

A/G

First reportedassociation betweenMS and HLA

STUDIES

GENES1972

Separation from common ancestry

HLA

Meta-analysisof GWAS

2009

CD226CD6IRF8TNFRSF1ATYK2

Homo erectusupright man

First generationGWAS (1000 patients)

2007

IL2RAIL7RRPL5CD58CLEC16AEVI5

Homo ergastercommunities

Homo sapiens

VCAMPLEKMERTSP140EOMESCD86IL12BBACH2THEMISMYBIL22RA2TAGAPZNF767MYCPVT1HHEX

CLECL1ZFP36L1BATFGALCMALT1TNFSF14MPV17L2DKKL1MAPK1SCO2NFKB2CXCR5SOX8RPS6KB1TNFRSF6CYP27B1CYP24A1

Whole genomesequencingof MS twins

2010

Second generationGWAS (10,000 patients)

AustralopithecusWalking apes

First generation genome-wide linkage studies (400 markers)

1996

Second generation genome-wide linkage study (5000 markers)

2005

Homo habilisstone tools

MS Susceptibility Genes in T Cell Activation Pathwa ys

International Multiple Sclerosis Genetics Consortium Nature 476:214, 2011

Functional Studies of MS Variants

2/16/2012

8

A Disease-Focused Neuroscience Center at Mission Bay

Thank you!