Shifting the Treatment Paradigm

for Multiple Sclerosis: Advances in

Pathophysiology and Emergence of

Novel Disease-Modifying Therapies

Moderator

Edward Fox, MD, PhD

Director, Multiple Sclerosis Clinic

Central Texas Neurology Consultants

Round Rock, Texas

Faculty

Stephen Krieger, MD

Associate Professor of Neurology

Icahn School of Medicine

Corinne Goldsmith Dickinson Center for MS

Mount Sinai Medical Center

New York, New York

Clyde Markowitz, MD

Associate Professor of Neurology

Director, Multiple Sclerosis Center

Perelman School of Medicine

University of Pennsylvania

Philadelphia, Pennsylvania

Learning Objectives

• Describe the pathophysiology of MS as it relates to T-

and B-cell behavior and mechanisms of action of MS

therapies

• Assess mechanisms of emerging MS DMTs and how

to integrate these therapies into treatment regimens to

enhance patient outcomes

• Discuss how advanced understanding of MS

pathophysiology may translate into new and emerging

therapeutic options for progressive forms of MS

Please review the faculty disclosures

and accreditation information on the

accompanying webpage.

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Pathophysiologic

Mechanisms of MS

Paradigm Shifts in Understanding

of MS

• MS was thought to be primarily a T-cell disease;

we now recognize the importance of both B- and

T-cell mechanisms

• Recognition of a variety of immune cell types

involved in MS pathology offers potential for

more targeted treatments

• Understanding of immune-cell interaction in the

periphery and CNS suggests that triggering

activities may occur on both sides of the BBB

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CNS = central nervous system; BBB = blood-brain barrier.

Unanswered Questions in MS

Pathology

• What is the inciting event that leads to the

immune cascade resulting in MS?

• Does this occur in the CNS or periphery?

• Rather than activated immune cells crossing the

BBB, could an event originating in the meninges

trigger a breach in the BBB that allows immune

cells to cross over and interact with antigens?

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Activity of T Cells in Periphery and

CNS

DC = dendritic cell; Treg = regulatory T cell.

Fletcher JM, et al. Clin Exp Immunol. 2010;162(1):1-11. 6

T Cells in MS Pathogenesis

Th1 cells

• Promote cellular immunity directed against

intracellular pathogens

• Th1 ↑ during relapse (proinflammatory)

Th2 ↑ during remission (anti-inflammatory)

• T-cell subsets determine whether they will have

a helper or suppressor function

Amedei A, et al. Int J Mol Sci. 2012;13(10):13438-13460. 7

Th1 Mechanisms

IFN = interferon; Ig = immunoglobulin; IL = interleukin.

Mayer G, et al. Cell-mediated immunity: cell-cell interactions in specific immune responses. In: Hunt R.

(2011) Microbiology and Immunology. 8

T-Cell Subsets Driving Immune

Response

Th17 cells1:

• Distinct Th subset producing IL-17; critical role in autoimmune response

• Accumulation in MS vs controls: active MS lesions, CSF, peripheral circulation (esp. during acute relapse)

T-regulatory cells (Tregs)2:

• In non-MS: control autoreactive T cells; may have protective effect

• In MS: dysregulation or impaired maturation of Tregs

• Tregs, dendritic cells are potential therapeutic targets in MS

CSF = cerebrospinal fluid.

1. Amedei A, et al. Int J Mol Sci. 2012;13(10):13438-13460.

2. Zozulya AL, Wiendl H. Nat Clin Pract Neurol. 2008;4(7):384-398. 9

Personalized Medicine in MS

• Personalized medicine is desirable in MS

because it is a heterogeneous disease

• Expanding treatment armamentarium increases

opportunity to tailor therapy to patient

• Biomarkers are needed to better stratify patients

10 Derfuss T. BMC Medicine. 2012;10:116.

Role of B Cells in MS

Pathophysiology

B-Cell Mechanisms in MS

• Found mainly in active MS lesions

• Cytokine production:

– Activation/effector

– Proinflammatory, anti-inflammatory

– Regulatory

• Interaction with T cells:

– Presentation of antigen by B cells is necessary for

triggering autoimmunity against myelin

oligodendrocyte glycoprotein

von Büdingen HC, et al. Eur Neurol. 2015;73(3-4):238-246. 12

B-Cell Mechanisms in MS (cont’d)

BCR = B-cell receptor; LT = lymphotoxin; MHC = major histocompatibility complex; TCR = T-cell receptor;

TNF = tumor necrosis factor.

von Büdingen HC, et al. Eur Neurol. 2015;73(3-4):238-246. 13

Early Rituximab Data Established

Viability of B-Cell Depletion in MS

14 Hauser SL, et al. N Engl J Med. 2008;358(7):676-688.

0 4 8 12 16 20 24 28 32 36 40 44 48

Weeks

0.0

0.5

1.0

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2.0

2.5

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P=0.78

P=0.003 P=0.001

Placebo

Rituximab

P<0.001

0 4 8 12 16 20 24 28 32 36 40 44 48

1.0

1.5

No

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Weeks

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Rituximab

P<0.001

P=0.76 P=0.002

P<0.001

P values represent comparisons at baseline and 12, 16, 20, and 24 weeks

Does Depletion of B Cells “Reset”

Immune System in MS?

• Antigen presentation by B to T cells fosters

proinflammatory milieu associated with MS activity

• Bystander activation by B cells to T cells may

explain association between MS relapses and

systemic infections

• Goal of therapy is not just to reduce lymphocyte

counts but also to adjust immune balance

• Reset immune system toward an anti-inflammatory

environment by modulating B-cell activity

(“rebooting” immune system)

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Measuring Response to B-Cell

Therapies

With recovery1,2:

• Immature B cells predominate in periphery

• Proinflammatory Th1, Th17 responses

decreased in periphery and CSF

• Repopulated B cells do not appear to have

increased IL-6 expression

1. Lehmann-Horn K, et al. Ther Adv Neurol Disord. 2013;6(3):161-173.

2. von Büdingen HC, et al. Eur Neurol. 2015;73(3-4):238-246. 16

“Resetting” the Immune System:

B-Cell Depletion

With recovery:

• Depleting peripheral B-cell population maintains

immune surveillance

• Pro-B cells and antibody-producing

plasmablasts/plasma cells are unaffected by

CD20 depletion

Lehmann-Horn K, et al. Ther Adv Neurol Disord. 2013;6(3):161-173. 17

Newer and Novel

Mechanisms of MS Disease-

Modifying Therapies

Anti-CD20 Monoclonal Antibodies

• B-lymphocyte antigen CD20: glycoprotein on

surface of all B cells1

• 3 anti-CD20 monoclonal antibodies (mAbs)

under study for treatment of MS2:

• Rituximab (chimeric human/mouse IgG1)

• Ocrelizumab (humanized IgG1)

• Ofatumumab (fully human IgG1)

1. Lehmann-Horn K, et al. Ther Adv Neurol Disord. 2013;6(3):161-173.

2. von Büdingen HC, et al. Eur Neurol. 2015;73(3-4):238-246. 19

What Are the Goals of Induction

Therapies in MS?

• Rapid onset of action

• Significant impact on disease activity

• Durable mechanism of action

• Long-term influence on immune

regulation/modulation

• Acceptable safety profile with respect to immune

activity (fighting infections, viruses)

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Ocrelizumab Phase II Data

(Gd+ Lesions)

Gd+ = gadolinium-enhancing.

Kappos L, et al. Lancet. 2011;378(9805):1779-1787. 21

Placebo (n=54)

Ocrelizumab 600 mg (n=51)

Ocrelizumab 2000 mg (n=52)

Interferon-beta-1a (n=52)

0 4 8 12 16 20 24

Weeks

0

1

2

3

4

5

6

7

Mean T

1 g

adolin

ium

-enhancin

g lesio

ns

(95%

Cl)

Ocrelizumab: 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

• IFN-beta-1a 44 mcg SC 3 x weekly

• Primary outcome: annualized relapse rate at 96 weeks

ORATORIO2

• Primary progressive MS (N=732)

• Ocrelizumab 600 mg IV every 24 weeks vs placebo

• Age 18-55 years; EDSS 3.0-6.5, abnormal CSF

• Primary outcome: time to sustained progression

EDSS = Expanded Disability Status Scale.

1. Hauser S, et al. 31st ECTRIMS, 7-10 Oct., 2015. Barcelona, Spain. Abst. 190.

2. Montalban X, et al. 31st ECTRIMS, 7-10 Oct., 2015. Barcelona, Spain. Abst. 228. 22

Ocrelizumab Phase III Results

PPMS (ORATORIO)2 Reduced proportion of patients with:

• Confirmed disability progression at 12 weeks by 24% vs placebo (25% by 24 weeks, P=0.0365)

• Worsening on Timed 25-Foot Walk Test by 29% vs placebo (P=0.0404)

• Whole-brain volume loss over 120 weeks, by 17.5% vs placebo (P=0.0206)

PPMS = primary progressive MS; RRMS = relapsing-remitting MS.

1. Hauser SL, et al. Presented at ECTRIMS 2015; abstract 190 (OPERA).

2. Montalban X, et al. Presented at ECTRIMS 2015; abstract 228 (ORATORIO). 23

Study Interferon-β-1a Ocrelizumab Reduction P Value

Annualized relapse rate

OPERA I OPERA II

0.292 0.290

0.156 0.155

46% 47%

<0.0001 <0.0001

Gadolinium-enhancing lesions

OPERA I OPERA II

0.286 0.416

0.016 0.021

94% 95%

<0.0001 <0.0001

RRMS (OPERA I and II)1

Goals for Long-Term Follow-Up

Studies of CD20 Therapies

• Crossover trials will move patients into most

effective treatment group

• No long-term IFN comparator group

• Sustained benefits over time:

– Brain atrophy

– New lesion acquisition

– Relapse activity

– EDSS progression

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NEDA (“No Evidence of Disease

Activity”)

• Is NEDA an aspirational outcome?

• Useful outcome in clinical trials to show the

maximum potential efficacy of a therapy

• Percentage of patients achieving NEDA in a

real-world setting is unknown

Imitola K, Racke ML, JAMA Neurol. 2015;72:145-147. 25

Ofatumumab: Phase II Data

MIRROR Study

• RRMS, N=232

Subcutaneous dosing:

• Phase II study compared every 12 weeks and every 4 weeks

Overall Objective:

• Determine MRI efficacy and tolerability/safety of SC ofatumumab doses of 3, 30, and 60 mg vs placebo

Primary Endpoint:

• Cumulative number of new T1 Gd+ brain lesions over 12 weeks, vs placebo

Bar-Or A, et al. Neurology. 2014;82(10 Suppl):S23.006. 26

Ofatumumab: Cumulative T1

Lesions (Phase II)

Bar-Or A, et al. Neurology. 2014;82(10 Suppl):S23.006. 27

Wk 4 Wk 8 Wk 12 Wk 16 Screening Wk 20 Wk 24 Wk 36 Wk 48

0

1

2

Me

an

Nu

mb

er

of C

um

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3

4

5

6

7

8

9 Placebo (N=67)

Ofatumumab 3 mg q12w (N=32)

Ofatumumab 30 mg q12w (N=32)

Ofatumumab 60 mg q12w (N=32)

Ofatumumab 60 mg q4w (N=63)

Alemtuzumab: Anti-CD52

• CD52: glycoprotein present on surface of normal

T and B lymphocytes, monocytes, dendritic cells

• Alemtuzumab: humanized mAb directed against

CD52 cell-surface protein

• Depletes mainly T and B lymphocytes

• To a lesser degree, depletes monocytes,

macrophages, dendritic cells, NK cells

NK cells = natural killer cells.

Zhang X, et al. J Immunol. 2013;191(12):5867-5874. 28

Alemtuzumab: Anti-CD52 (cont’d)

• Rapid depletion of peripheral lymphocytes and

monocytes1

• Alemtuzumab depletes CD52-bearing T cells,

but does not affect hematopoietic stem cells2

• Monocytes return to pre-treatment levels within

1 month; B cells recover in 3 months1

• Potential for reconstitution of immune response

is preserved2

1. Freedman MS, et al. J Clin Cell Immunol. 2013;4(4).

2. Zhang X, et al. J Immunol. 2013;191(12):5867-5874 29

Months after alemtuzumab

T- and B-Cell Reconstitution After

Alemtuzumab

Thompson SA, et al. J Clin Immunol. 2010;30(1):99-105.

Months after alemtuzumab

30

*P<0.05; **P<0.01.

6-month SAD defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when baseline EDSS = 0).

1. Freedman M, et al. Presented at AAN 2013; abstract PO7.1111. 2. Coles AJ, et al. Lancet. 2012;380(9856):1829-1839. 31

Alemtuzumab Efficacy in MS

Alemtuzumab significantly reduced clinical disease activity in

patients who relapsed on prior therapy

• Alemtuzumab significantly reduced annualized relapse rate (ARR)1 and risk of 6-month sustained accumulation of disability (SAD)2 by an additional 49.4% and 42% beyond SC IFN-β-1a, respectively, in patients who relapsed on prior therapy

• Benefits on clinical disease activity were similar regardless of type, duration, or number of prior treatments1

alemtuzumab

IFN-β-1a

Targeting Therapeutic Selection

in MS

• How can we determine appropriate patient

selection for B-cell‒depleting therapies?

• Are there groups of patients who do not benefit

from these treatment strategies?

• Should we be treating earlier with more

aggressive therapies?

• Does stopping immune system activity early in

disease prevent long-term progression?

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ACR/EULAR Definition of Remission

in Rheumatoid Arthritis

• Boolean-based definition: At any time point, a

patient must satisfy all of the following:

– Tender joint count ≤1

– Swollen joint count ≤1

– CRP ≤1 mg/dL

– Patient Global Assessment ≤1

• Index-based definition: At any time point, a

patient must have:

– Simplified Disease Activity Index (SDAI) ≤3.3

ACR/EULAR = American College of Rheumatology/European League Against Rheumatism; CRP = C-reactive protein.

Bykerk VP, Massarotti EM. Rheumatology (Oxford). 2012;51(Suppl 6):vi16-vi20. 33

Treating Progressive

Forms of MS: Impact of

Newer Mechanisms

Active Disease Relapses, new/increasing neurologic

dysfunction, full or partial recovery

Progressive Disease Steadily increasing dysfunction or

disability without unequivocal recovery

Worsening Disease Documented increase in neurologic

dysfunction due to relapses or

progressive disease

Confirmed Progression or

Worsening

Increase of neurologic dysfunction

confirmed through a defined time interval

(eg, 3, 6, 12 months)

Revised Phenotype Classification

(Lublin 2013)

Lublin FD, et al. Neurology. 2014;83(3):278-286. 35

Determining Active vs Inactive

Inflammation in Progressive MS

• Disease burden may continue to advance in some people with MS despite lack of Gd+ lesion activity

• Some patients with progressive forms of MS have continued inflammatory activity

• This subpopulation of patients showed benefit from rituximab in early trials

• New data on B-cell therapies in patients with progressive MS will elucidate the role of lymphocyte depletion in these phenotypes

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Educating Patients About

Disease Mechanisms and

Management

Role of Patient Education on

Therapeutic Mechanisms

• Many MS patients are well informed; discussing pathophysiology/mechanism of action is increasingly important

• Risks of particular mechanisms are important part of discussion: – Importance of adherence to monitoring protocols

– Importance of follow-up to therapies

• Therapeutic decisions may be based on response to previous treatments and on individual perceptions of risk vs benefit

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This completes this activity, “Shifting the

Treatment Paradigm for Multiple Sclerosis:

Advances in Pathophysiology and Emergence

of Novel Disease-Modifying Therapies.”

Thank you for joining us. Please complete the

post-test and program evaluation to receive

Continuing Medical Education credit.

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