Multiple Sclerosis:Clinical Treatment and Current Research

Walter Royal, III, MDAssociate Professor of NeurologyMaryland Center for Multiple SclerosisMultiple Sclerosis Center of Excellence - East

Social Security AdministrationMarch 16, 2011

Presentation Outline• MS Epidemiology, pathogenesis and clinical

features• General approaches to therapy• Currently approved disease modifying

therapies• Symptomatic therapies• Research underway at the Maryland Center

for MS

Multiple Sclerosis Risk and Geography

Wallin MT et al. Ann Neurol 2004;55:65-71.

MS is an Immune-Mediated Disease

BBB=blood-brain barrier; APC=antigen-presenting cell.Adapted from Miller et al. Continuum: Multiple Sclerosis (Part A). 1999;5:7.

The Immune Response in Multiple Sclerosis

Pathologic Features of Multiple Sclerosis

Gray Matter Lesions in MS

Amadio S et a. Cereb Cortex. 2010 Jun;20(6):1263.

Multiple Sclerosis Clinical Subtypes

Lublin FD et al. Neurology. 1996;46:907-911.

Relapsing-remitting

Primary-progressive

Dis

abili

ty

Time

Time

Dis

abili

ty

Secondary-progressive

Progressive-relapsing

Time

Time

Dis

abili

tyD

isab

ility

80% at diagnosis 50% of RR patients after 15 yrs

10-15% at diagnosis Rare

Diagnosis of Multiple Sclerosis• MRI • Revised McDonald Criteria

– Incorporates previous criteria– Address all MS types

• RRMS, SPMS• Monosymptomatic• Primary progressive

Magnetic Resonance Imaging in MS

Spinal cordOptic nerve

Brain

Spinal cordSpinal cordOptic nerveOptic nerve

BrainBrain

Magnetic Resonance Imaging in MS

Spinal cordOptic nerve

Brain

Spinal cordSpinal cordOptic nerveOptic nerve

BrainBrain

↔

What Causes MS?

• Genetics• Environmental

Major Gene Associations from GWAS Studies in MS

LocusHLADRB1*1501IL-2RA (CD25)*CD58 (LFA3)IL-7R (CD127)HLA-DRB5

Chromosome (Function)6p21.3 (antigen presentation)10p15 (development of Treg‡ cells)1p13 (binds CD2 on T cells)5p13 (T and B cell development)6p21.3 (decreases risk of SPMS)§

* Also associated with Graves Dis., IDDM and RA‡ Treg = regulatory T cells§ Based on data from small number of DRB5*null African American subjects

Epstein Barr Virus

Ascherio A and Munger K. Ann Neurol 2007;61:288–299

MS

Inci

denc

e R

ate

Age

Ser

um Ig

G L

evel

Currently Available MS Drug Therapies

• Drug – IFN-β1b (Betaseron®)– IFN-β1a (Avonex®)– Mitoxantrone (Novantrone®)– IFN-β1a (Rebif®)

– Natilizumab (Tysabri®)– IFN-β1b (Extavia®)– Fingolimod (Gilenya®)

• Approval Year– 1993– 1995– 2000– (2002; orphan drug

act)– 2005– 2009– 2010

Disease Modifying Therapies: Injections

Rebif®

8.8/22/44 μg SC

3x per week

Avonex®

30 μg IM

Weekly

Interferon -1a

Betaseron®/Extavia®

250 μg SC

Every other day

Interferon -1b

Copaxone®

20 mg SC

Daily

Glatiramer acetate

Humanized Monoclonal Antibody Therapies – IV Infusions

• Natalizumab (Tysabri®)– 4 Integrin (T cells®)

• Rituximab (Rituxin®) – CD20 (B) cells;

• Alemtuzamab (Campath®)§

– CD52 (T+B cells, monocytes)• Daclizumab (Zenapax®)§

– CD25, CD40 ligand (T cells; NK cells)§ Not currently FDA approved

Mechanisms of Action of Injectable Drugs

• Interferons (IM, SC)– Induction of Interferon-responsive genes

• Glatiramer acetate (SC)– ↑ numbers of suppressor cell phenotypes– Neuroprotection via BDNF induction (?)

• Monoclonal antibodies (IV)– Physical interactions → functional inhibition

• Oral agents– Inhibition by small molecules

Impact of Approved MS Therapies on Annualized Relapse Rate

0 20 40 60 80

Betaseron

Avonex

Glatiramer Acetate

Novantrone

Rebif

Tysabri

Extavia

Gilenya

% Decrease in Annualized Relapse Rate

What Works Best? • High vs Low Dose IFN-

– High dose was superior

• IFN- Low Dose vs Double-dose x 2– No difference

• IFN- vs Glatiramer acetate– No difference

• IFN- vs Glatiramer acetate vs IFN+GA– Results pending

• Approved drug as comparator– E.g., Natalizumab and fingolimod vs IFN- (natalizumab was

superior)

More Aggressive Therapies in MS: Efficacy at a Price

• Higher dose IFN-β: ↑Injection frequency; ↑ side effects (?)

• Natalizumab: PML• Rituximab: Rarer reports of PML • Alemtuzamab: ITP; Graves disease• S1P1 antagonists: cardiopulmonary, infectious• More potent immunomodulation → increased risk of

malignancy?

Progressive MS• No treatments available• Recent, current and pending studies

– Fingolamod® (FTY-720; PPMS)– MIS416 (used for pathogen-specific immunization)– Lipoic acid (neuroprotection)– Simvastatin (SPMS)– Mesenchymal stem cell transplantation

(autologous; SPMS)

Treatment of MS Symptoms (*New Agents)

• Fatigue: *Armodafinil (Nuvigil®)• Poor ambulation: *Dalfampridine (Ampyra®)• Pain• Spasticity• Pseudobulbar affect:

*Dextromethorphan/Quinidine sulfate (Nuedexta®)

• Psychological problems• Urinary dysfunction• Sexual dysfunction• Cognitive impairment

Maryland Center for MS: Active Clinical Drug Studies

MS Clinical Trials at the Maryland Center for Multiple Sclerosis Active Studies Sponsor

1. A Phase II, Randomized, Double-blind Parallel-group, Placebo-controlled, Multicenter Study to Evaluate the Safety and Efficacy of Abatacept in Adults with Relapsing-Remitting Multiple Sclerosis

Immune Tolerance Network; NIAID/NIH

2. FTY720 in Patients With Primary Progressive Multiple Sclerosis Novartis 3. JCV Antibody Program (STRATIFY-2) Biogen-Idec 4. Prospective Observational Long-term Safety Registry of Multiple Sclerosis

Patients Who Have Participated in Cladribine Clinical Trials EMD Serono

5. Efficacy and Safety Study of Oral BG00012 With Active Reference in Relapsing-Remitting Multiple Sclerosis (CONFIRM)

Biogen-Idec

6. TYSABRI® Global Observational Program in Safety (TYGRIS) Biogen-Idec 7. BRAVO (A multinational, multicenter, randomized, parallel-group study performed

in subjects with relapsing-remitting multiple sclerosis (RRMS) to assess the efficacy, safety and tolerability of laquinimod over placebo in a double -blind design and of a reference arm of interferon ß -1a (Avonex), in a rater-blinded design

Teva Neurosciences

8. A Study to Evaluate the Long-term Safety, Tolerability and Effect of Daily Oral Laquinimod 0.6 mg on Disease Course in Subjects With Relapsing Multiple Sclerosis

Teva Neurosciences

9. RGC-32 as a Potential Marker of Relapses and Response to Glatiramer Acetate in Multiple Sclerosis

Teva Neurosciences

10. COMBIRX (A Multi-Center, Double-Blind, Randomized Study Comparing the Combined Use of Interferon Beta-1a and Glatiramer Acetate to Either Agent Alone in Patients with Relapsing Remitting Multiple Sclerosis)

NIH/NINDS

11. Long Term Follow of Copaxone Teva 12. Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting

Multiple Sclerosis Novartis

13. An Extension Protocol for Multiple Sclerosis Patients Who Participated in Genzyme-Sponsored Studies of Alemtuzumab

Genzyme

14. Telephone Interview of Patients That Participated in the Pivotal Betaferon MS Trial Bayer

Maryland Center for MS: Pending Clinical Drug Studies

MS Clinical Trials at the Maryland Center for Multiple Sclerosis Pending Studies

1. Study Evaluating Rebif, Copaxone, and Tysabri for Active Multiple Sclerosis Biogen-Idec 2. AB Science AB Science 3. A 6-month, Randomized, Open-label, Patient Outcomes, Safety and Tolerability

Study of Fingolimod (FTY720) 0.5 mg/Day vs. Comparator in Patients With Relapsing Forms of Multiple Sclerosis

Novartis

4. Generic Copaxone 5. Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting

Multiple Sclerosis Novartis

Other MS Research at the Maryland Center for Multiple Sclerosis

• MS Biomarkers– T cell markers (Naïve, memory T cells; CXCR3)– Genetic markers (Response Gene to Complement 32; RGC-32)

• Vitamin D• Cigarette smoke and MS• Potassium channels and immune modulation• Models of bone marrow transplantation therapy• Neuroprotection

Maryland Center for Multiple Sclerosis

• Christopher Bever, MD• Kenneth Johnson, MD• Walter Royal, III, MD• Horea Rus, MD• Robert Shin, MD

• Kerry Naunton, RN• Elizabeth Wheeler, RN• Valerie Wells, BA• Cynthia Dorsey