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

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

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?

1. Carroll WM.

N Engl J Med.

2010;362:456-458.

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.

Fingolimod

FREEDOMS, 24-Month Study

N = 1272 RRMS n = 425 n = 429 n = 418 0.18

0.16

0.40

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.

Fingolimod

TRANSFORMS, 12-Month Study

N = 1292 RRMS randomized n = 429 n = 420 n = 431 0.16

0.20

0.33

94.1% 93.3%

P = .50 vs IFN

92.1% 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.

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.

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.

Oral Cladribine

CLARITY

N = 1326 RRMS n = 433 0.14

n = 456 0.15

n = 437 0.33

No disability progression at 3 months: 79.4% P=.02 vs placebo P=.03

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.

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.

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.

Additional Oral Small-Molecule MS Therapies in Late-Stage Development

• Fumarate (BG00012) • Teriflunomide • Laquinimod

Emerging Monoclonal Antibodies

• Rituximab • Ocrelizumab • Alemtuzumab • Daclizumab

Future Directions

• Therapeutic research • Genetic studies • New MRI metrics • Proteomics/genomics – biomarker fingerprints • Neuroprotection strategies • Regeneration and repair