Mitzi Joi Williams, MD Neurologist MS Center of Atlanta Atlanta, GA

Transcription

1 Mitzi Joi Williams, MD Neurologist MS Center of Atlanta Atlanta, GA Disclosures Consultant and Speaker Bureau member for Biogen-Idec, Pfizer, TEVA Neuroscience, Bayer, EMD Serrono, Questcor, Novartis, Genzyme, Accorda 2 1

2 Therapy Four Tiered Approach Acute Therapy for Exacerbations Disease Modifying Therapy Symptomatic Management Rehabilitation MS Attack The development of neurologic symptoms likely caused by an inflammatory demyelinating lesion, lasting at least 24 hours and supported by objective findings. Can also include repeated attacks of paroxysmal symptoms lasting >24hrs. 2

3 Acute Relapse Should be distinguished from a pseudorelapse related to: Infection Increased Body temperature Treatment of Acute Relapse Oral Methylprednisolone -500mg po q daily x 5 days IV Methylprednisolone -1 gram IV q daily x 3-5 days Dexamethasone ACTH -80 units sc or im q daily x 5 days Side effects include: Insomnia, fluid retention, blood sugar elevation GI upset, irritability 3

4 Other Therapies for Acute Relapse Plasma exchange life threatening relapse No response to high dose IV steroids IVIG 0.4mg/kg Severe DM Poor tolerance of steroid therapy Case 1 30 y.o. woman with a 5 year history of MS presents with a recurrence of blurred vision in her right eye. She had right optic neuritis when diagnosed. This has been present for the past 2 days. She also has a fever, nasal congestion and cough for 3 days. WOULD YOU TREAT THIS PATIENT FOR AN MS RELAPSE? 4

5 Our Current State of Affairs The 10 FDA Approved Treatments for MS are indicated for: Clinically Isolated Syndrome AND/OR Relapsing Forms of Multiple Sclerosis Exception: Mitoxantrone for Secondary Progressive MS Disease Modifying Therapies Glatiramer Acetate (Copaxone)- 20mg SQ daily, 40mg 3 x weekly Interferon Beta Avonex (1a) 30 µg IM weekly Rebif (1a) 22 or 44 µg SQ 3 x weekly* Betaseron (1b) 250 µg SQ QOD* Extavia (1b) 250 µg SQ QOD* 5

6 Oral Therapies Fingolimod Dose: 0.5mg daily AE: macular edema, bradycardia Dimethyl Fumerate Dose: 240mg BID AE: flushing, GI upset Teriflunomide Dose: 7mg or 14 mg daily AE: teratogenicity, elevated LFT s, hair thinning Infusion Therapies Natalizumab (Tysabri) Dosing: 300mg IV once monthly AE: PML Mitoxantrone (Novantrone) Dosing: 10-20mg IV every 3 months AE: Cardiotoxicity, leukemia 6

7 Around the Corner Two therapies are currently submitted for FDA approval Pegylated Interferon Alemtuzumab Therapies awaiting FDA Approval: Alemtuzumab Dosing: 12mg/day IV for 3-5 days once a year Indications: RRMS MOA: monoclonal antibody to CD 52 Prior Uses: Chronic Lymphocytic Leukemia 7

8 Alemtuzumab Phase III: Alemtuzumab vs Interferon Beta 1a (SC) CARE MS I 55%% reduction in relapse rate Change in EDSS not statistically significant Cohen, JA., et al. Alemtuzumab versus interferon beta 1a as a first line treatment for patients with relapsing-remitting multiple sclerosis: a radomized controlled phase 3 trial. Lancet CARE MS II 49% reduction in relapse rate over 2 years 42% reduction in sustained disability Coles, Alasdair J., et al. "Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial." The Lancet (2012). Therapies awaiting FDA Approval: Alemtuzumab Adverse Effects Profound Lymphopenia Autoimmune thyroid disease Immune Thrombocytopenic Purpura Infusion Reaction Increased Susceptibility to Infections 16 8

9 Pegylated Interferon Beta 1-a Dosing: 125mcg SC every 2 or 4 weeks Study Population: Relapsing MS MOA: reduces pro-inflammatory cytokines Inhibits T cell migration PHASE III Studies ADVANCE Pegylated Interferon Beta 1a 2 week dosing 4 week dosing ARR: 35.6% decrease ARR: 27.5% decrease New or enlarging T2 lesions: 67% decrease New or enlarging T2 lesions: 28% decrease Gd+ lesions: 86% decrease Gd+ lesions: 36% decrease Data presented at AAN March 20,2013 Calabresi et al. 9

10 Pegylated Interferon B 1-a Common Adverse Events Flu-like symptoms Injection Site Reactions Fever Headache Case 2 51 yo man 20 year history of MS Therapy: Interferon SC every other day EDSS 2.0 Clinical status and MRI s stable Pt is having some injection fatigue, but feels he is doing well on his current therapy 10

11 Case 2 Which therapy may be a good choice for this patient? Further Down the Road 11

12 Daclizumab Dosing: 150mg vs 300mg q4w MOA: Binds to CD25 decreasing activated T cells Study Population: Relapsing MS Prior Uses: Rheumatoid Arthritis, Kidney Transplant PHASE II STUDIES - DACLIZUMAB SELECT: ARR: 50-54% decrease Confirmed Disability: 43-57% decrease New Gd+ lesions: 79-86% reduction New or enlarging T2 lesions: 70-79% reduction SELECTION (extension study) ARR: 59% decrease Confirmed Disability: 54% decrease New T2 MRI lesions: 74% decrease Gd+ lesions: 86% decrease 12

13 Daclizumab Adverse Events Increased risk of infection Abnormal liver function tests Diarrhea Constipation Swelling of the extremities Rituximab Dosing: 1000mg at wk1 and wk3 q 6 months Studied in RRMS, SPMS MOA: monoclonal antibody to CD20, depletes B lymphocytes Previous Uses: B-cell malignancies Phase II studies showed 56% decrease in relapse rate and 91% decrease in active MRI lesions at 24 and 48 wks 26 13

14 Ocrelizumab Dosing: 600mg or 2,000mg Study Population: RRMS, PPMS MOA: Anti Cd20 (more humanized antibody) Also being studied in Rheumatoid Arthritis Ocrelizumab Phase II studies showed ARR decreased by 73% (2,000mg) and 80% (600mg) Phase II studies showed 89% (600mg) and 96% (2000mg) decrease in Gd+ enhancing lesions compared to placebo Adverse Events Infusion related reactions Possible Increased risk of infection One death from systemic inflammatory response of unknown cause Kappos, Ludwig, et al. "Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial." The Lancet (2011)

15 Case 3 45 yo woman 3 year history of MS Previous therapies: glatiramer acetate Recently diagnosed with B cell lymphoma EDSS of 3.5 Pt is clinically stable and MRI s are stable. Case 3 Which therapy would be most appropriate for this patient? 15

16 What s on the Horizon? Other Drugs in earlier phases of Research Relapsing MS Ofatumumab S1P Receptor Modulators Tcelna Statins Antibiotics Vitamin D3 Progressive MS S1P Receptor Modulators Mastinib Ibudilast 16

17 Potential Future Therapies Continued studies of drugs and mechanisms for myelin repair ANTI- LINGO 1 Stem Cell Therapies Hormone Therapy Estrogens Testosterone Other Avenues of Research Gene and DNA studies Personalized medicine and biomarkers Monitoring progression of disease 17

18 I m Thinking We Injected You with the Wrong Stem Cells. Future Questions? Safety Non neurologic Side Effects Sequencing of therapies 36 18