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