slide 1 of 26 emerging therapies for multiple sclerosis

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Emerging Therapiesfor Multiple Sclerosis

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Newly Identified Players in the Pathophysiology of Multiple Sclerosis

Suhayl Dhib-Jalbut, MD

Professor and Chairman Department of Neurology

UMDNJ-Robert Wood Johnson Medical SchoolNew Brunswick, New Jersey

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Pathogenesis of MSOutline

• Genes

• Th17 cells

• B-cells

• CD8 and NK cells

• T-regulatory cells

• Mode of action of MS therapies

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MS LesionsAxonal Changes

Axonal Transection in MS Lesions

Trapp BD, et al. N Engl J Med. 1998;338:278. Copyright © [1998]. Massachusetts Medical Society. All rights reserved.

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Types of Cortical Lesions

Peterson JW, et al. In: Multiple Sclerosis as a Neuronal Disease. Elsevier Academic Press, 2005.165-184.

Type ILesion in white

matter and cortex

Type IIIntracortical lesions

Type IIILesions extending

into the cortex from the pial surface

Graphic courtesy of Dr. Suhayl Dhib-Jalbut.Graphic courtesy of Dr. Suhayl Dhib-Jalbut.

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Disease Heterogeneity by Cellular Pathology

Pattern I Pattern II Pattern III Pattern IV

Inflammation

CD3 T-cells +++ ++ ++ ++

Plasma cells/Ab ++ +++ ++ +

Complement (C9neo) - ++ - -

Macrophages ++ + + +++

Demyelination Perivenous Perivenous Ill-definedconcentric

Perivenous

Oligodendrocytes +++ +++ + +

DNA fragment/apoptosis +/- +/- ++ (Apo) -

Myelin loss Even Even MAG Even

Remyelination ++ ++ - -

Relative prevalence (???) ~12%–16% ~53%–60% ~25%–30% ≤4%

With permission from Lucchinetti C, et al. Ann Neurol. 2000;47:707-717.

Abbreviation: MAG, myelin-associated glycoprotein.

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Homogeneity of Active Demyelinating Lesions in Established MS

Complement, IgG, FcyR, and PLPCo-Localize to Phagocytic Macrophages

With permission from Breij ECW, et al. Ann Neurol. 2008;63:16-25.

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Multiple SclerosisAn Immunogenetic Disease

MS

Immune Dysregulation

Genetic Predisposition• Twins studies

• HLA-DR2 (DRß1*1501)(antigen presentation)

• IL-2R• (regulatory T-cells)

• IL-7R memory T-cells)

• ST8SIA1

Environmental FactorsDemographics/Epidemics

Microbial AgentsEBV

Vitamin D

Graphic courtesy of Dr. Suhayl Dhib-Jalbut.

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Pathogenic T-Cells

New Player: Th17

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Helper T-Cell Differentiation

TH0

IL-12/STAT4 IFN- Pro-inflammatoryTH1

TH2

IL-4

IL-5

IL-10

IL-13

Anti-inflammatory/

Allergy

IL-4/STAT6

IL-23

IL-17 Pro-inflammatoryTH17IL-6 + TGF-β

TGF-β RegulatoryTreg

TGF-β

TH0

Graphic courtesy of Dr. Scott Zamvil.

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IL-17 Expression in Acute and Chronic Active MS Plaques

With permission from Tzartos JS, et al. Am J Pathol. 2008;172:146-155.

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Immune Effects of IL-17 in MS

• Induces proinflammatory cytokines

• Induces chemokines

• Enhances dendritic cell maturation

• Promotes neutrophils function

Gold R, et al. Am J Pathol. 2008;172:8-10.

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Pathogenic B-Cells

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MS Is Not Necessarily a Th1-Driven Disease!

• No benefit from anti-CD4+ mAb treatment (phase II)

• No benefit from anti-IL12p40 (phase II x 2)

• Uncertain benefit from CD4+ T-cell vaccine trials including APL (disease worsened), anti-CD4v vaccine, and recent MBP peptide/CD4+ (phase II trials in SPMS)

• CTLA4-Ig first phase II modest benefit

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B-Cell Depletion with Rituximab in Relapsing-Remitting MS

• 48-week phase II study of 104 MS patients comparing 1000 mg IV rituximab with placebo

• Endpoint was number of gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24

• Rituximab significantly reduced the number of gadolinium-enhancing lesions and the number of new lesions

• Rituximab significantly reduced the relapse rate at week 24 (14.5% vs 34.5%) and week 48 (20.3% vs 40.0%)

• Results imply B-cell involvement in relapsing-remitting MS

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

of 26Hauser SL, et al. N Engl J Med. 2008;358:676-688. Copyright © [2008]. Massachusetts Medical Society. All rights reserved.

Relapsing-Remitting MSRituximab Versus Placebo

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The B-CellOld Player, New Position on the Team

McFarland HF, et al. N Engl J Med. 2008;358:664-665. Copyright © [2008]. Massachusetts Medical Society. All rights reserved.

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Uccelli A, et al. Trends Immunol. 2005;26:254-259.

How the CNS Fosters B-Cells in MS

• The CNS contains molecules that regulate B-cell homing and survival

• B-cell differentiation normally occurs in secondary lymphoid organs in response to antigen

– In some neuroinflammatory diseases, this process is replicated in the CNS

• Chronic inflammation can induce formation of ectopic lymphoid follicles in the meninges of MS patients

– May represent major source of B-cells and plasma cells that accumulate in MS lesions

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T-Regulatory Cells (Tregs)

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CD4+CD25+ Tregs in MS

• Have reduced suppressive function in MS

• Occur with no difference in frequency between MS and healthy controls

• Blocking IL-10, TGF- does not cause loss of suppressor function

Viglietta V, et al. J Exp Med. 2004;199:971-979.

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Induction of CD4+CD25+FOXP3+ Tregs During Glatiramer Acetate Treatment

0.0

2.5

5.0

7.5

10.0 CD4+CD25+FoxP3+

Mean GA-R

Pre-Rx 3mo 6mo 12mo 24mo

% G

ate

d i

n C

D4+

Ce

lls

0.0

2.5

5.0

7.5

10.0CD4+CD25+FoxP3+

Mean GA-HR/NR

Pre-Rx 3mo 6mo 12mo 24mo% G

ate

d i

n C

D4+

Ce

lls

With permission from Dhib-Jalbut S, et al. 23rd Congress of ECTRIMS, 12th Conference of Rehabilitation in MS; October 11-14, 2007; Abstract ID 52136.

Abbreviations: GA-R, glatiramer acetate-responder; GA-HR/NR, glatiramer acetate – hypo-responder/non-responder.Abbreviations: GA-R, glatiramer acetate-responder; GA-HR/NR, glatiramer acetate – hypo-responder/non-responder.

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Modulation of Tregs by Therapy in MS

With permission from Saresella M, et al. FASEB. 2008;22:3500-3508.

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CD8+ T-Cells in MS

• CD8 T-cells are a prevalent cell type in MS lesions

• In vitro tissue culture and in vivo animal models demonstrate both suppressive and pathogenic roles for the CD8 T-cells

• CD8 T-cells can transect axons, induce oligodendrocyte death, and promote vascular permeability, all of which are observed in MS lesions

• Conversely, CD8+ T-cells exhibit regulatory activity directed at suppression of effector CD4+ T-cells

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Natural Killer Cells

• NK cells are a subset of bone marrow–derived lymphocytes distinct from B and T lineage

• Innate response to kill microbe-infected cells and activate macrophages via IL-12 mediated pathways

• NK cells express CD16 (FcRIII), which binds to IgG opsonized cells and is lytic by ADCC-like mechanism

• In autoimmunity, NK cells may play opposing roles—they function as both regulators and inducers of disease relative to cytokine environment and cell:cell contact

• IL-15 appears to play pivotal role in the differentiation of NK cells from their progenitors, the maintenance of their survival, and their activation

Abbreviations: ADCC, antibody-dependent cell-meditated cytotoxicity; NK, natural killer.

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Loss of Natural Killer (NK) Functional Activity During Clinical Relapse

• Nine RRMS patients matched in age, sex, and NK responder status with controls

• No significant difference in average NK cell functional activity in the two groups

• Four clinical relapses in RRMS patients associated with novel NK valleys in functional activity– Observed in RRMS patients but not controls

– Preceded onset of clinical attacks

– Of greater depth and duration than cyclical valleys seen in controls and RRMS patients

– Suggests that RRMS patients are at greater risk for relapse during novel valleys in NK functional activity

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Immunopathogenesis of MS

Ab+C9neoNOOiTNFMMP

Graphic courtesy of Dr. Suhayl Dhib-Jalbut.

B7

CD40MicrogliaCD40L

CD28

Th1

Glutamate

TCD8CTL

IFNTNF

MMP-2/9

B

PlOligo

BBB

MCP-1MIP-1P-10RANTES

Astrocyte

B

CD40L

CD28

CD40

IL-4 & IL-10

CD4APCThp

B7

IFNTNFLFA-1

Th1VLA-4

ICAM-1VCAM-1

IL-12

APC

Thp

CD4

Myelin AgMicrobial Ag

HLATCR

Tr1Th2Th3

IL-4IL-5IL-10IL-13TGF-

IL-10TGF

TregFoxp3

CD4+CD25+

Tr1Th2Th3

CD40L

CD28

CD40

IL-6 & TGF-ß

CD4APCThp

B7

Th17

Th17

Th17

Th17

Th17

Th17

IL-23IL-17

TGFß

IL-6

TregFOXP3

TregFoxp3

BAFFAPRILTACI

CD8CTL

CD8p

NeutNeut

IL-17

EBV

FcR

CD8Reg

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Immunopathogenesis of the MS Lesion

Th2/Th3Tr1

MO

IL-4IL-5IL-6IL-13TGF

B

IL-12

APCThp

CD4CD40LCD40

IL-4 & IL-10

CD4APC

ThpCD28B7

Th2/Th3Tr1B7

CD40

MicrogliaCD40L

CD28

Th1/Th17

B

Glutamate

T CD8

MMP-2/9VCAM-1 VCAM-1

IFNTNF

IL-10TGF

Ab+CPl

IFNTNF

NO

VLA-4 VLA-4Th1Th17

Oligo

BBB

MCP-1MIP-1P-10RANTES B

IFN-ß

Rituximab

GA

Minocycline Statins, E2

Minocycline

Plasmaphoresis

MitoxantroneAlemtuzumabFingolimodLaquinimodTeriflunomideCladribineRapamycinDaclizumab

MemantineRiluzole

Antegren

Foxp3

IL-6/TGFß

Steroids

K-ChannelBlockers

Graphic courtesy of Dr. Suhayl Dhib-Jalbut.Graphic courtesy of Dr. Suhayl Dhib-Jalbut.

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Emerging Treatment Strategies for MS

Fred D. Lublin, MD

Saunders Family Professor of NeurologyThe Corinne Goldsmith Dickinson Center for Multiple Sclerosis

Mount Sinai School of MedicineNew York, New York

Tracy M. DeAngelis, MD

Assistant Professor of Neurology The Corinne Goldsmith Dickinson Center for Multiple Sclerosis

Mount Sinai School of MedicineNew York, New York

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Where We Are Now…

FDA-approved disease modifying agents

• Interferon beta– Interferon beta-1b (Betaseron®) 250 mcg qod

– Interferon beta-1a (Rebif®) 44 mcg SC TIW

– Interferon beta-1a (Avonex®) 30 mcg IM weekly

• Glatiramer acetate (Copaxone®)– 20 mg SC qd

• Mitoxantrone (Novantrone®)– 12 mg/m2 q3mo: lifetime max, 144 mg/m2

• Natalizumab (Tysabri®)– 300 mg IV monthly infusion

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Limitations of Current Therapies

• All are only partially effective

• All are injectable or IV and have side effects

• Risks vs benefits– Existing therapies have advantage of long-term safety data

• Difficulty predicting therapeutic response

• Expensive

• Goal: Individualized, more effective, safe medication(s) that are easier to administer and, ideally, less expensive

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Future Directions of MS Therapies

• Disease modification

– Building on existing therapies

– New immunotherapies

– Neuroprotection

– Remyelination and repair

• Symptomatic therapies

• Biomarkers of therapeutic response

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Building on Current Therapies

• Early initiation of therapy– Treating after clinically isolated syndrome

– BENEFIT, PRECISE, ETOMS, CHAMPS

• Combination therapies

• Double dosing – GA 40mg – double dose glatiramer acetate

– BEYOND trial – double dose interferon beta-1b

• Reformulations

• Induction therapies– ie, mitoxantrone, followed by disease-modifying agents,

interferon or glatiramer acetate

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Combination Therapies

• Approach used in other diseases – Rheumatologic disorders, cancers, HIV

– Ideal combination – synergistic, nonantagonistic

• Combination disease-modifying agents (DMA): Combi-Rx Trial– NIH multicenter study coordinated at Mount Sinai

Interferon beta-1a + glatiramer acetate vs interferon beta-1a alone vs glatiramer acetate alone

Fully enrolled, 1008 patients

• Combination: DMA + chemotherapeutic agents

• Combination: DMA + steroids

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Novel Therapies in Testing

• Parenteral (IV) drugs in phase II/III

– Monoclonal antibodies: rituximab/ocrelizumab, alemtuzumab, daclizumab

• Oral Drugs in phase III

– Fingolimod, cladribine, teriflunomide, fumarate, laquinimod

• Symptomatic therapies

– Fampridine (4-AP), nerispirdine

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Rituximab• Mechanism of action

– Chimeric human/murine mAb to CD20

– Depletes circulating B-cells

• Dosing– 2 doses given 2 weeks apart IV: 1 g on days 1 and 151

• Side effects– Infusion reactions, infections, hepatitis B reactivation, cases of progressive multifocal leukoencephalopathy in

systemic lupus erythematosus/cancer population

Approved by FDA for lymphomas, rheumatoid arthritis

• HERMES phase II study for RRMS1

• Randomized, 48 weeks, 104 patients with RRMS– Rituximab 1 g IV vs placebo on days 1 and 15

– 91% decrease in mean total Gd+ lesions Rituximab 0.5 ± 2.0; placebo 5.5 ± 15 (P <.0001)

– Relapses at 24 weeks Rituximab 14.5% vs placebo 34.3% (P = .02)

• Neuromyelitis optica/Devic’s open-label study2

• OLYMPUS trial phase II/III in PPMS – ineffective3

1. Hauser S, et al. N Engl J Med. 2008;358:676-688. 2. Cree BA, et al. Neurology. 2005;64:1270-1272. 3. Hawker KS, et al. Mult Scler. 2008;14:S299. Abstr 78.

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Alemtuzumab

• Mechanism of action– Anti-CD52 mAb to receptor on surface of T- and B-cells

FDA approved for chronic lymphocytic leukemia

• Dosing– Given IV for 3-5 days once yearly (produces rapid decrease in WBCs)1

• Alemtuzumab CAMSS223 Phase II trial 1

– 334 early RRMS patients randomized to alemtuzumab vs interferon beta-1a 2-year follow-up results

– Alemtuzumab group: 75% reduction in relapse rate vs interferon beta-1a– Significant reduction of risk of sustained disability

3-year follow-up– Maintained 71% and 74% reduction in risk of sustained disability and relapse rate,

respectively, vs interferon beta-1a 2 phase III trials (CARE-MS, CARE-MS2) now enrolling

• Serious adverse events– Infusion reactions– Idiopathic thrombocytopenic purpura (3%): total of 6 cases – 1st case was fatal– Grave’s disease – autoimmune thyroiditis (20%)

1. Coles, AJ. N Engl J Med. 2008;359:1786-1801.

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Daclizumab• Mechanism of action

– Anti-CD25 mAb targeting α chain of IL-2 receptor (IL-2Rα)

– Blocks the IL-2 “proinflammatory, ie, bad” cytokine receptor

– Prevents activation of sensitized T-cells

• Dosing– IV infusion every 2 weeks (high dose) or every 4 weeks (low dose)

Side effects – infections, cutaneous reactions

• FDA approved for graft versus host disease/kidney transplant rejection– CHOICE Trial – phase II results1

Randomized double-blind controlled trial Add-on to interferon in 230 patients with RRMS 3 arms: 2 doses of daclizumab and placebo added to interferon

– Results Decrease in new MRI lesions with higher dose vs interferon alone No significant difference in relapse rate 5.2% with significant infections, none life-threatening

– SELECT: phase II trial of daclizumab monotherapy – Ongoing

1. Montalban X, et al. Mult Scler. 2007;13:S7-S273. Abstr 50.

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FingolimodMechanism of action: Sphingosine 1-phosphate receptor analog which sequesters activated lymphocytes (T-cells) in lymph nodes preventing egress to central nervous system

• Dosing: once-daily pill

• Fingolimod phase II trial results1

– 255 patients with RRMS followed for 6 mo

– Arms: Placebo, 1.25 mg/d or 5 mg/d of fingolimod

– 43% (1.25 mg/d) and 61% (5 mg/d) decrease new MRI gad+ lesions

– 53% (5 mg/d) and 55% (1.25 mg/d) reduction in relapse rate 77% fingolimod patients were relapse-free

• Long-term (3-year) data from phase II2

– Of 173 RRMS patients receiving fingolimod for 3 y, 67% were relapse-free after 3 y, with an annual relapse rate of 0.2%

• Recent safety concerns in phase III– 2 cases of opportunistic infections:

– Herpes encephalitis (resulting in coma)

– Disseminated Varicella Zoster (fatal)

1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140.2. Kappos L, Radue E, O'Connor P, et al. Oral fingolimod (FTY720) inpatients with relapsing multiple sclerosis: 3 year results from a phase II study extension. Mult Scler. 2008;14(suppl 1):S50.

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Fingolimod

TRANSFORMS (phase 3) AAN 2009 update: primary endpoint reached

Outcome IFN beta-1aFingolimod (0.5 mg/d)

Fingolimod (1.25 mg/d)

ARR .33 .16 .20

% reduction vs IFN beta-1a

52% 38%

P value P <.001 P <.001

Cohen J, et al. AAN 61st Annual Meeting; June 25-May 2, 2009. Oral presentation.Graphic courtesy of Dr. Fred Lublin.

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Fingolimod

FREEDOMS (phase 3)Primary endpoint reached

Outcome PlaceboFingolimod

(0.5 mg/d)

Fingolimod (1.25 mg/d)

ARR .40 .18 .16

% reduction vs placebo

54% 60%

P value P <.001 P <.001Graphic courtesy of Dr. Fred Lublin.

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Cladribine

• Mechanism of action– Purine analog that semi-selectively blocks

lymphocyte and monocyte development

• Dosing– Oral medication given for 5 consecutive days for

2 cycles

• Side effects– Injection site reactions, neutropenia, muscle

weakness

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Cladribine

• CLARITY phase III trial results1,2

– 58% reduction in annualized relapse rate

– 2.5-fold better odds of remaining relapse-free

– ~30% relative reduction in risk of disability progression

• May be first oral MS disease-modifying drug to be FDA approved

• ORACLE: ORAL CLadribine in Early MS—a phase III 2-year, randomized, double-blind, placebo-controlled study of conversion to clinically definite MS in CIS patients

1. Vermersch P, et al. 19th Meeting of the European Neurological Society; June 20-24, 2009. Poster 700. 2. Giovannoni G, et al. 19th Meeting of the European Neurological Society; June 20-24, 2009.

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Teriflunomide

• Mechanism of action– Inhibits pyrimidine (DNA) synthesis in T-cells resulting in

destruction of immune cells• Dosing

– Once-daily pill• Side effects

– Well tolerated, adverse effects frequency similar to placebo• Results of phase II trial1: 36 weeks in 179 patients

– Teriflunomide (high dose and low dose) vs placebo– Significant (>61%) decrease in new MRI lesions in both doses– Decrease in disease progression (in high dose)– Trend towards lower relapse rate in high-dose group

• Phase III trial ongoing2-year trial in clinically isolated syndrome enrolling

1. O’Connor PW, et al. Neurology. 2006;66:894-900.

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Fumarate• Mechanism of action

– Oral formulation of dimethyl fumarate may exert a combination of anti-inflammatory and neuroprotective effects

• Dosing – thrice-daily pill

• Side effects– Hot flashes, GI events, nasopharyngitis, no effect on QTc

• Results of phase II trial1

– 257 RRMS patients

– Placebo vs 120 mg (once daily), 360 mg (3 divided doses), 720 mg (3 divided doses) for 24 weeks

– MRI outcomes Significant 69% decrease in Gd+ lesions with highest dose and 48% decrease in

new/enlarging T2 lesions

– Clinical outcomes 32% decrease in relapse rate Not significant compared with placebo

• 2 phase III trials under way comparing fumarate with placebo and glatiramer acetate

1. Kappos L, et al. Lancet. 2008;372:1463-1472.

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Laquinimod

• Mechanism of action– Immunomodulator that normalizes Th1:Th2 ratio

– Promotes regulation/suppression of inflammation

– Decreases number of infiltrating inflammatory cells into CNS

• Dosing– Oral once-daily dose

• Side effects– Liver toxicity, transient rise in inflammation in

bloodstream

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Laquinimod

• Phase IIa trial results1

– 209 patients enrolled

– Treatment arms: placebo, 0.1 mg/d, 0.3 mg/d for 24 weeks

– Significant decrease (44%) in new MRI lesions in high-dose group

– No difference in relapse rate or progression

• Phase IIb trial results2

– 306 patients enrolled

– Treatment arms: placebo, 0.3 mg/d, 0.6 mg/d for 36 weeks

– Significant decrease (40%) in new MRI lesions in 0.6 mg/d group

– Trend toward fewer relapses and greater time to first relapse in 0.6 mg/d group

• 2 phase III trials – 1 currently recruiting

1. Polman C, et al. Neurology. 2005;64:987-991. 2. Comi G, et al. Lancet. 2008;371:2085-2092.

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Symptomatic Therapies

• Fampridine (4-aminopyridine)– Mechanism: K+ channel blockade

Enhances axonal conduction

Side effects: seizures

– 2 recent phase III trials1,2

Significant improvement 25% in walking speed in responders after 14 weeks: 34.8% compared with 8.3%1

Submitted to the FDA for review

• Nerispirdine – currently enrolling– Activated Na+ channel blockade in addition to K+ channel

blockade, which may decrease risk of seizures1. Goodman AD, et al. Lancet. 2009;373:732-738.2. Goodman, AD, Scwid SR, Brown TR, et al, for Fampridine MS-F204 Investigators.

Sustained-release fampridine consistently improves walking speed and leg strength in multiple sclerosis: a phase 3 trial. Mult Scler. 2008;14:S295-S298.

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Future Directions

• Therapeutic research

• Genetic studies

• New MRI metrics

• Proteomics/genomics – biomarker fingerprints

• Neuroprotection strategies

• Regeneration and repair

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