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Emerging MS Therapies

Emerging MS Therapies. 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

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Emerging MS Therapies

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  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. Two Oral Therapies Have Completed Phase III Studies Fingolimod Cladribine 3 important questions to ask1 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? 1. Carroll WM. N Engl J Med. 2010;362:456-458.

  4. 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 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.

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

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

  7. 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 Cohen JA, et al. N Engl J Med. 2010;362:402-415. Kappos L, et al. N Engl J Med. 2010;362:387-401.

  8. 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 Sipe JC. Expert Rev Neurother. 2005;5:721-727.

  9. Oral CladribineCLARITY 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. Giovanni G, et al. N Engl J Med. 2010;362:416-426.

  10. 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 Giovanni G, et al. N Engl J Med. 2010;362:416-426.

  11. 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 Carroll WM. N Engl J Med. 2010;362:456-458.

  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

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