1. Emerging MS Therapies

2. 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 Goal: Individualized, more effective, safe medication(s) that are easier to administer

3. 1. Carroll WM. N Engl J Med. 2010;362:456-458. Two Oral Therapies Have Completed Phase III Studies Fingolimod Cladribine 3 important questions to ask 1 –How do they compare with current therapies? –Are all of the long-term safety issues known? –What do they tell us about MS and our treatment goals?

4. Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457. Pinschewer DD, et al. J Immunol. 2000;164:5761- 5770. Chiba K, et al. J Immunol. 1998;160:5037-5044. Fingolimod Modulates sphingosine-1-phosphate receptors –Receptors play a role in egress of lymphocytes out of lymph nodes Fingolimod sequesters lymphocytes in lymph nodes Fingolimod crosses blood-brain barrier and may have neuroprotective properties Dosing: once-daily pill Status: 2 phase III trials completed; pending FDA review

5. Kappos L, et al. N Engl J Med. 2010;362:387-401. Placebo-controlled FREEDOMS II study is ongoing. Fingolimod reduced relapse rate by 54% to 60% vs placebo and reduced risk of disability progression Fingolimod FREEDOMS, 24-Month Study

6. Cohen JA, et al. N Engl J Med. 2010;362:402-415. Fingolimod reduced relapse rate by 38% to 52% versus IFN beta-1a but was not significantly different with regards to effect on disability Fingolimod TRANSFORMS, 12-Month Study

7. Cohen JA, et al. N Engl J Med. 2010;362:402-415. Kappos L, et al. N Engl J Med. 2010;362:387-401. Fingolimod Safety Common: nasopharyngitis, infections, cough/dyspnea, fatigue, headache, back pain, diarrhea, nausea, and elevated ALT levels Malignancies (skin cancer, breast cancer) Bradycardia/atrioventricular block –Requires 6-hour first-dose monitoring with hourly ECGs –Bradycardia persisting >6 hours requires continued monitoring –Break in therapy >2 days requires repeat first-dose monitoring; therefore, not good choice for nonadherent patients Severe herpes infections (some fatal) Disseminated Varicella Zoster (fatal) Macular edema requiring ophthalmology screening Reduction in FEV1 —PFTs and HRCT required in phase III studies Lower dose has fewer side effects

8. Sipe JC. Expert Rev Neurother. 2005;5:721-727. Cladribine Results in selective long-term depletion of CD4+ and CD8+ T cells FDA approved for treatment of hairy-cell leukemia Dosing: given orally for 5 consecutive days for 2 cycles, 1 month apart Status in MS –Fast-tracked by the FDA –Phase III study completed –FDA issued “refuse to file” letter Nov. 30, 2009 –NDA will be resubmitted as soon as FDA’s concerns can be addressed

9. Giovanni G, et al. N Engl J Med. 2010;362:416-426. Oral cladribine reduced the relapse rate by 54.5% to 57.6% and the risk of sustained disability progression at 3 months by about one third compared with placebo. Oral Cladribine CLARITY

10. Giovanni G, et al. N Engl J Med. 2010;362:416-426. Cladribine Safety Common adverse effects: headache, nasopharyngitis, upper respiratory tract infection, nausea Infections/infestations –Herpes zoster –Primary varicella Benign uterine leiomyomas Malignancies (melanoma, pancreatic, ovarian, cervical) Decreased lymphocyte counts/severe aplastic anemia

11. Carroll WM. N Engl J Med. 2010;362:456-458. Do We Have the Answers to the Three Questions? Fingolimod and cladribine are likely to be at least as effective as available treatments –Fingolimod > IFN beta-1a IM in TRANSFORMS –IFN beta-1a IM was the least effective of available therapies in prior head-to-head trials Fingolimod and cladribine may have greater safety issues –Severe herpes infections, malignancies, lymphocytopenia (both fingolimod and cladribine) –Macular edema, bradycardia/AV block (fingolimod) –Higher discontinuation rates than available therapies It is not yet clear whether these therapies can prevent immune- mediated injury

12. Additional Oral Small-Molecule MS Therapies in Late-Stage Development Fumarate (BG00012) Teriflunomide Laquinimod

13. Emerging Monoclonal Antibodies Rituximab Ocrelizumab Alemtuzumab Daclizumab

14. Future Directions Therapeutic research Genetic studies New MRI metrics Proteomics/genomics – biomarker fingerprints Neuroprotection strategies Regeneration and repair