Update on Multiple Sclerosis

Aaron Miller, M.D.

Corinne Goldsmith Dickinson Center for Multiple Sclerosis

Icahn School of Medicine at Mount Sinai

New York, NY

.

Relevant Disclosures

Sources of Funding for Research: Acorda Therapeutics; Biogen Idec; Genzyme/sanofi-aventis; Novartis Pharmaceuticals Corp; Osmotica; Questcor, Roche.

Consulting Agreements: Acorda Therapeutics; Biogen Idec; EMD Serono;. Genzyme/sanofi-aventis; Glaxo Smith Kline; Novartis Pharmaceuticals Corp; Nuron Biotech; Questcor;

Speakers’ Bureau/Honorarium Agreements: None

Financial Interests/Stock Ownership: None

McDonald Criteria for MS (2005)

Determining Abnormal MRI

Three out of four of the following:

• 1 Gd+ lesion or 9 T2 hyperintense lesions

• 1 infratentorial lesion

• 1 juxtacortical lesion

• 3 periventricular lesions

(1 spinal cord lesion = 1 brain lesion)

After Barkhof et al and Tintore et al

Dublin Revision 2011

• For DIS: At least one T2 lesion in two of the following locations:

– Periventricular

– Juxtacortical

– Infratentorial

– Spinal cord

• For DIT: Any new lesion on any follow-up scan after a baseline scan done anytime after onset of CIS

Single Early MRI

• In CIS, a single MRI, even in 1st 3 months, with Gad enhancing lesion(s) and T2H has high specificity for development of CDMS

Radiologically Isolated Syndrome

• Lebrun 2009

– 70 patients, with mean F/U 5.2 years

– 23/70 convert to CIS at mean of 2.3 years

– 91% with dissemination in time by MRI

• Okuda 2009

– 44 patients; 30 with clinical F/U; 41 MRI F/U

– 10/30 convert to CIS at median time of 5.4 yrs

– 59% with MRI progression at median 2.7 yrs

Risk Factors for RIS to Convert to MS

• Okuda (2011): Asymptomatic spinal cord lesions are associated with conversion to MS

• 25/71 RIS patients had cord lesions

• 21 patients (84%) converted to CIS (19 ) or PPMS (2) in median time of 1.6 years

• Odds ratio 75.3 (CI=16.1—350.0)

Genetics

• HLA-DRB1*1501 remains most important MS risk locus

• Multiple genome wide association studies have identified > 50 risk loci

– Each locus has very low odds ratio (1.04-1.33)

– In total explain ~ 3% of total variance in MS risk

– Nearly all are implicated in immunologic function

Vitamin D: What’s New?

Nurses Health Study: High milk intake or vitamin D intake during pregnancy associated with 38% lower risk of MS in offspring

• Higher incidence of MS with births in spring

With each 10 ng/ml increase, 15% decrease in T2H, 32% decrease in Gad + lesions

Predictive correlation in CIS (ECTRIMS 2012)

Lower levels associated with more relapses

CLINICAL BENEFIT OF SUPPLEMENTATION UNCERTAIN

Smoking and MS

• Increased risk of MS (multiple studies)

• Handel (2011) meta-analysis of multiple studies:

– Increased relative risk of 1.48

– Increased risk of conversion to SPMS (1.88), just missed statistical significance (p=.06)

– Dose response for number of cigarettes smoked

• Passive exposure raises risk (ECTRIMS 2011)

• Doubles mortality rate (ECTRIMS 2012)

Update on EBV and MS

• Munger (2011) study of US veterans

– Largest study to date

– Increased risk of MS with increased titers of anti-EBNA complex IgG and anti-EBNA-1 IgG

• Very low odds ratio if EBV seronegative

Original Article Potassium Channel KIR4.1 as an Immune Target in

Multiple Sclerosis

Rajneesh Srivastava, M.Sc., Muhammad Aslam, Ph.D., Sudhakar Reddy Kalluri, M.Sc., Lucas Schirmer, M.D., Dorothea Buck, M.D., Björn Tackenberg, M.D., Veit Rothhammer, M.D., Andrew Chan, M.D., Ralf Gold, M.D., Achim Berthele, M.D.,

Jeffrey L. Bennett, M.D., Thomas Korn, M.D., and Bernhard Hemmer, M.D.

N Engl J Med Volume 367(2):115-123

July 12, 2012

Validation of KIR4.1 as the Target of the Serum IgG Reactivity in Patients with MS.

Srivastava R et al. N Engl J Med 2012;367:115-123

High-Titer Serum Reactivity to the KIR4.1 Protein in a Subgroup of Patients with MS.

Srivastava R et al. N Engl J Med 2012;367:115-123

“I look to the future because that’s where I’m going to spend

the rest of my life.” -George Burns

Predicting the Course of MS

• Clinical features of onset bout

– Motor worse than sensory

– Polyregional worse than monosymptomatic

– Early bladder involvement poor prognosis

• Incomplete recovery from initial attack

• Short interval between attacks

Prognosis(2)

Initial MRI

T2 lesion numbers

Median EDSS at 20 years = 6

for >10 T2 lesions

3 or 4 Barkhof criteria moderate correlation with EDSS at 5 years

0

10

20

30

40

50

60

70

0 1-3 4-9 ≥10

# of brain lesions

% p

ati

en

ts

EDSS > 3 EDSS ≥ 6

“The future ain’t what it used to be.”

Lawrence Peter “Yogi” Berra

Immunopathogenesis of MS (2012)

Ab+C9neo RNO

ROS

TNF

MMP

Courtesy of Suhayl Dhib-Jalbut, MD

B7

CD40 CD40L

CD28

Th1

Glutamate

gdT CD8

CTL

IFNg

TNF

MMP-2/9

B

Pl Oligo

BBB

MCP-1

MIP-1

IP-10

RANTES

Astrocyte

B

CD40L

CD28

CD40

IL-4 & IL-10

CD4 APC

Thp

B7

IFNg

TNF

LFA-1

Th1 VLA-4

ICAM-1 VCAM-1

IL-12

APC

Thp

CD4

Myelin Ag

Microbial Ag

HLA TCR

Tr1

Th2

Th3

IL-4

IL-5

IL-10

IL-13

TGF-b

IL-10

TGFb

Treg Foxp3

CD4+CD25+

Tr1

Th2

Th3

IL-6 & IL1-ß

APC

IL-23

IL-17

TGFß

IL-6

Treg Foxp3

Treg Foxp3

BAFF APRIL TACI

CD8p

EBV

FcR

CD8

Reg

CCR6

CCL20

DC

Th0

Th17

Th17

Th17

Neut

S1Pr

S1Pr

S1Pr

TLR

Fingolimod

IFNB

Natalizumab

GA

GA

Fampridine K+

IFNB

GA +

GA

Rituximab -

TF

TF TF

BG-12 BG-12

Existing and Emerging MS Therapies

2002 2011 2006 2008 2010 2013 2014

Injectables

IV

Generic

Mitoxantrone

(oncology) (MS)

Application Withdrawn

Approved Phase II

In phase III

Oral

IFNB-

1a SQ

IFNB-1b

Glatiramer

acetate IFNB-1a

IM

Mitoxantrone

Dalfampridine

Extavia

Natalizumab

BG-12 Cladribine

Fingolimod

Ocrelizumab

Teriflunomide

Laquinimod

Alemtuzumab

Firategrast

Ofatumumab

Daclizumab

IV

2015

Biogen Idec Announces Positive Top-Line

Results from Phase 3 Study of Peginterferon

Beta-1a in Multiple Sclerosis

– Every Two-Week and Every Four-Week Dosing

Demonstrate Significant Reductions in

Annualized Relapse Rate – [35.6% and 27.5%,

respectively]

–Secondary Endpoints on Reduction of Disability

Progression [Decreased 38% both doses],

Proportion of Patients Who Relapsed and MRI

Assessments Also Met

BiogenIdec Press Release, Jan. 24, 2013

0.505

0.331

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n = 461)

GA 40 mg tiw(n = 943)

AR

R ±

SE

M

GALA: ARR (Primary Endpoint)

ARR = annualized relapse rate.; SEM = standard error of mean

Khan O, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 166]

34.4% reduction, P < 0.0001

0.505

0.331

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n = 461)

GA 40 mg tiw(n = 943)

AR

R ±

SE

M

CombiRx • Combination of glatiramer acetate plus weekly IM IFNB-1a

vs either agent alone

• 3 year study of 1000 patients

• Primary endpoint: No significant difference in annualized relapse between combination and best performing single agent

• GA significantly better than IFNB-1a on ARR

• Combination better on some MRI end points

SAM Inhibition Implications for Multiple Sclerosis Therapy

Reduced

Leukocyte

Infiltration

and Brain

Inflammation

Leukocyte

Infiltration

and Brain

Inflammation

Leukocyte

Chemoattractant signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue VCAM-1

Leukocyte Chemoattractant Signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue VCAM-1

O’Connor P. Expert Opin Biol Ther. 2007;7:123-136.

19,600

26,100

33,500

41,400

50,300

60,300

72,400

104,300

Natalizumab Use in the Post Marketing Setting and PML Risk

224,718 patient-years of

natalizumab exposure

*As of October 22, 2012: 298 cases of natalizumab-associated PML have been reported; of these, 62 patients have died (22%)

Vermersch P, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 173]

≥ 36 Months

≥ 30 Months

≥ 24 Months

≥ 18 Months

≥ 12 Months

Overall

Exposur

e

≥ 42 Months

2.95

2.33

0.82

0.45

2.32

1.54

2.79

1.76

2.63

1.38

Number of infusions

0.11 0.02

≥ 48 Months

Patients

2.63

0.05

0.61

1.90

2.23

1.94

0

0.5

1

1.5

2

2.5

3

Post Marketing 1–12 13–24 25–36 37–48 49–60

Inc

ide

nc

e p

er

1,0

00 p

ati

en

ts

Natalizumab v Placebo Affirm Study (1801)

An

nu

aliz

ed R

elap

se R

ate

(95%

CI)

68%

P<0.0001

Placebo n=315

0.81

Natalizumab n=627

0.26

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Polman C et al. N Engl J Med. 2006;354:899-910.

Estimated Incidence of Natalizumab-Associated PML Stratified by Risk Factors

Natalizumab exposure

No Prior IS Use Prior IS Use

1–24 months 0.35/1000

95% CI: 0.190.60 1.2/1000

95% CI: 058–2.2

25–48 months 2.5/1000

95% CI: 1.8–3.4 7.8/1000

95% CI: 5.2–11.3

Bloomgren G, et al. Presented at ECTRIMS / ACTRIMS 2011; Amsterdam, Netherlands. [P995]

Anti-JCV Antibody Status

Negative Positive

Prior IS Use?

No Yes

≤ 0.11/1000

95% CI: 0-0.59

(based on 1 hypothetical

Anti-JCV antibody negative

PML case)

T cell FTY720-P

S1P receptor

FTY720 results in internalisation of the S1P1 receptor

This blocks lymphocyte egress from lymph nodes while sparing

immune surveillance by circulating memory T cells

LN

Prevents T cell invasion of CNS

FTY720 traps circulating lymphocytes in

peripheral lymph nodes

Fingolimod (FTY720): Mode of Action

FREEDOMS: Key Efficacy Results

CMSC. http://www.mscare.org/cmsc/Informs-Novartis-on-MS-therapy-FTY720.html

MRI: decreased number of new and enlarging T2H

and Gad + lesions (p<0.001)

Teriflunomide: a selective dihydro-orotate dehydrogenase inhibitor

A new oral disease-modifier for relapsing forms of MS (RMS)

Blocks de novo pyrimidine synthesis, reducing T- and B-cell proliferation and function in response to autoantigens

Preserves replication and function of cells (e.g. haemopoietic cells, memory T-cells) living on the existing pyrimidine pool (salvage pathway)

30 DHO-DH, dihydro-orotate dehydrogenase

DHO-DH, dihydro-orotate dehydrogenase;

Blasting lymphocyte

De novo pathway

DHO-DH

Pyrimidine pools Salvage

pathway

CTP-, UTP-sugars Nucleotides CDP lipids

Glycoproteins, Glycolipids RNA, DNA Phospholipids

Cell-cell contact

Adhesion and

diapedesis

Proliferation

Ig

secretion

Cell membranes

Second

messengers

Non-

lymphoid

cells

Resting lymphocyte

Teriflunomide

Teriflunomide for RRMS (Phase III TEMSO Study): Key Clinical Outcomes

31

RRR: 31.2%

P = 0.0002 RRR: 31.5%

P = 0.0005

RRR = relative risk reduction

O’ Connor P, et al. Presented at ECTRIMS 2010; October 13-16, 2010; Gothenburg, Sweden. [Abstract 79]

0

5

10

15

20

25

30 23.7%

P=0.0835 29.8%

P=0.0279

27.3

21.7 20.2

Placebo (n=363) 7 mg (n=365) 14 mg (n=358)

Annualized Relapse Rate EDSS 12 Week Sustained Change

Teriflunomide

Teriflunomide: Phase III TOWER Study

0.501

0.389

0.319

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n = 388)

Teriflunomide 7 mg(n = 407)

Teriflunomide 14 mg(n = 370)

AR

R

TOWER = Teriflunomide Oral in people With relapsing multiplE scleRosis; RRR = relative risk reduction

Kappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]

Primary Endpoint: ARR

RRR: 22.3%

P = 0.0183

RRR: 36.3%

P = 0.0001

Dimethyl Fumarate Has Shown Nrf2 Pathway Activation Activation

Keap1 ARE

Maf

Jun

ATF4

Nucleus

- Detoxification enzymes

- Antioxidant enzymes

- NADPH generating enzymes

- GSH biosynthesis enzymes

- Chaperones

- Ubiquitination/proteasome

- Detoxification

- Normalization of

energy metabolism

- Repair/degradation

of damaged proteins

Nrf

2

Cytoplasm

DMF=dimethyl fumarate; MMF=monomethyl fumarate.

Scannevin R, et al. Poster presented at ECTRIMS October 13–16, 2010. Gothenburg, Sweden. P887.

Feinstein D, et al. Poster presented at ECTRIMS October 13–16, 2010. Gothenburg, Sweden. P879.

O O

O

O DMF (BG-12)

O

O

O H

O MMF OR

Dimethyl fumarate: Pooled Efficacy Analysis of DEFINE and CONFIRM

Endpoint (at 2 years) Placebo BG-12 BID BG-12 TID

ARR

Reduction vs placebo

0.371 0.191*

49%

0.191*

49%

Time to 12-week confirmed disability

progression HR vs placebo

0.68*

0.70*

Time to 24-week confirmed disability

progression HR vs placebo

0.71*

0.68*

Mean number of Gd-enhancing lesions Reduction vs placebo

1.9 0.3* 83%

0.4* 70%

Mean number of new or enlarging T2 lesions Reduction vs placebo

16.8 3.7* 78%

4.5* 73%

Mean number of new T1 hypointense lesions Reduction vs placebo

6.3 2.2*

65%

2.3*

64%

*Statistically significant vs placebo.

Gold R, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 151]

Humanized mAb directed against CD52 (expressed on leukocyte surface)

Rapidly and profoundly depletes T cells, B cells, and monocytes through:

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Complement-mediated cytotoxicity (CDC)

CD4+ cells may take ~5 years to fully recover

Reconstituted lymphocytes appear to have regulatory properties

Jones JL, Coles AJ. Int MS J. 2009;16:77-81.

Alemtuzumab

CD52

B cell T cell

CARE-MS I: Annualized Relapse Rates

Coles A, et al. Presented at ECTRIMS / ACTRIMS 2011; Amsterdam, Netherlands. [Abstract 151]

0.46 0.29 0.390.22 0.13 0.180

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Year 0–1 Year 1–2 Years 0–2

Ad

juste

d A

RR

SC IFNβ-1a

Alem 12 mg/dayP < 0.0001

P < 0.0002

55% Rate Reduction

P < 0.0001

Drug Natalizumab Fingolimod Teriflunomide Dimethyl

fumarate

↓ ARR 68% 48-54% 31-36% 44-53%

Disability

Progress

0.58 0.70

0,83 (NS)

0.70

0.68

0.62

0.79 (NS)

MRI

↓ Gad lesions

92% 82% 80% 83%

Adverse

Events

PML

Hypersensitivity

Category C

Cardiac

Macular edema

???Infection

Category C

Hepatotoxicity

GI

Alopecia

Category X

Lymphopenia

GI

Flushing

Category C

Head-to-head None Better than IM

Weekly IFNB-1a

Equal to SC

IFNB-1a 3X/wk

Better than

Glatiramer

acetate

INSURANCE

Choice of Therapy

Aggressive Disease Aggressive Disease?

Yes No

JCV AB

Positive?

JCV AB

Negative

NTZ? Fingo

DMF NTZ

Safest Pregnancy? Non-injection

GA

IFN GA

Teri

DMF

?Fingo

?NTZ

Ocrelizumab* Phase II Study: Gd-Enhancing T1 Lesions

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

0 4 8 12 16 20 24

Weeks

Mean

Nu

mb

er

T1

Gd

-en

han

cin

g L

esio

ns

Placebo (n = 54)

Ocrelizumab 600 mg (n = 51)Ocrelizumab 2000 mg (n = 52)

IFNβ-1a (n = 52)

Kappos L, et al. Presented at ECTRIMS 2010; October 13–16, 2010; Gothenburg, Sweden. [Abstract 114]

*Humanized anti-CD20 mAb

IFNb-1a arm was open-label; all efficacy comparisons were exploratory

Lesions on MRI by Week (ITT)

↓ 89–96%, P < 0.0001 for

both ocrelizumab

doses vs placebo

Primary endpoint

Hypothesized Immunomodulatory Effect of Daclizumab Treatment

CD4

Anti-CD25

CD25

IL-2

CD4

TCR

TCR activation

NK

CD56hi

b g NK

CD56hi

NK

CD56hi

NK

CD56hi

IL-2 not

consumed by T cells NK cells are activated and expanded

by IL-2 binding to the intermediate-

affinity IL-2R

b g

TCR=T-cell receptor.

Bielekova B, Becker BL. Neurology. 2010;74:S31-S40.

DAC Treatment Increases CD56bright NK Cell Proliferation

and Cytotoxicity via Intermediate-Affinity IL-2 Signaling

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

Placebo DAC 150 mg DAC 300 mg

AR

R

54% Reduction in ARR (P<0.001)1

0.46

0.23

1. Biogen Idec Press Release, Aug. 9, 2011

2. Giovannoni G., et al. ECTRIMS 2011. Amsterdam, The Netherlands.

0.21

50% Reduction in ARR (P=0.002)1 ► Out of 600 enrolled, 559 patients

completed the study period (93%)2

► Relapse Free (P<0.001)2

► Risk of 3-month sustained disability progression compared to placebo2

150 mg DAC 300 mg DAC

57% (P=0.02) 43% (P=0.09)

150 mg DAC 300 mg

DAC Placebo

80% 81% 64%

Trials in Progressive MS

• Secondary Progressive MS

– ASCEND: Natalizumab v. Placebo

– Siponimod v. Placebo

• Primary Progressive MS

– INFORMS: Fingolimod v. Placebo

– ORATORIO: Ocrelizumab v. Placebo