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

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 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?

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

Kappos L, et al. N Engl J Med. 2010;362:387-401.

Placebo-controlled FREEDOMS II study is ongoing.

No disability progressionat 3 months: 82.3%P = .03 vs placebo

Annualized relapse rate0.18

P < .001 vs placebo

Fingolimod 0.5 mg QDn = 425

No disability progressionat 3 months: 83.4%P = .01 vs placebo

Annualized relapse rate0.16

P < .001 vs placebo

Fingolimod 1.25 mg QDn = 429

No disability progressionat 3 months: 75.9%

Annualized relapse rate0.40

Placebon = 418

N = 1272 RRMS

Fingolimod reduced relapse rate by 54% to 60% vs placebo and reduced risk of disability progression

Fingolimod FREEDOMS, 24-Month Study

No disability progression94.1%

P = .25 vs IFN

Annualized relapse rate0.16

P <.001 vs IFN

Fingolimod 0.5 mg QDn = 429

No disability progression93.3%

P = .50 vs IFN

Annualized relapse rate0.20

P < .001 vs IFN

Fingolimod 1.25 mg QDn = 420

No disability progression92.1%

Annualized relapse rate0.33

IFN beta-1a 30 mcg IM Qn = 431

N = 1292 RRMS randomized

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

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

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

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

No disability progressionat 3 months: 85.7%P=.02 vs placebo

Annualized relapse rate0.14

P<.001 vs placebo

Cladribine 3.5 mg/kgn = 433

No disability progressionat 3 months: 84.9%

P=.03

Annualized relapse rate0.15

P<.001 vs placebo

Cladribine 5.25 mg/kgn = 456

No disability progressionat 3 months: 79.4%

Annualized relapse rate0.33

Placebon = 437

N = 1326 RRMS

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 CladribineCLARITY

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

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

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