Multiple Sclerosis: Emerging Therapies

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1 Multiple Sclerosis: Emerging Therapies Bruce Cree, MD, PhD, MCR Conflicts of Interest EMD Serono: Grant support ovartis: Adviser, Clinical Trial Participant What are the Future Considerations for MS Therapies? Treatments for PPMS and SPMS remain a significant unmet need Reduced dosing frequency, or a less invasive delivery method, will significantly increase patient compliance Improved diagnosis rates will allow treatment to commence earlier Identification of biomarkers will result in a more targeted therapeutic approach atalizumab safety issues will affect approval of other agents Dimethyl Fumarate Laquinimod Teriflunomide Alemtuzumab Daclizumab Ocrelizumab Estimated Study Completion Dates for Phase III Trials of Emerging MS Therapies TRASFORMS ov 2008 CLARITY Dec 2008 FREEDOM-1 placebo Sep 2009 The MS Pipeline DEFIE placebo Dec TEMSO Oct 2010 FREEDOM-2 placebo Mar 2011 COFIRM Vs. GA Apr 2011 ALLEGRO placebo Feb 2011 TOWER Sep 2011 CARE-MS1 May 2011 BRAVO ov 2011 TEERE Oct 2011 CARE-MS2 Sep 2011 ORACLE CIS placebo Oct 2012 TOPIC CIS Placebo Oct 2012 IFORMS PPMS placebo Dec 2013 Daclizumab Jan 2014 Ocrelizumab 2014? 1

2 HO OH H2 Background and Mechanism of Action Derivative of a fungal metabolite Sphingosine 1-phosphate (S1P) modulator Initially investigated to prevent renal allograft rejection sequesters circulating lymphocytes into secondary lymphoid organs Peripheral reduction of lymphocytes o effect on lymphocyte induction, proliferation, or memory function Crosses blood brain barrier May have neural protective properties Baumraker T, et al. Expert Opin Investig Drugs. 2007;16: Mandala S, et al. Science. 2002;296: Pinschewer D, et al. J Immunol. 2000;164: Brinkmann V, et al. Trends Pharmacol Sci. 2000;21: Budde K, et al. Am J Transplant. 2003;3: versus Inteferon β-1a TRASFORMS: TRial Assessing injectable interfero (30mg IM Q week) vs FTY720 Oral in versus Interferon β-1a 0.35 Results: Primary Endpoint Active comparator study, and IFβ-1a 1-year, randomized, double-dummy, double-blind, parallel-group trial comparing 0.5 mg/day or 1.25 mg/day of to IFβ-1a Primary endpoint: annualized relapse rate Subjects (=1292):, baseline EDSS=2.2, 1 relapse in prior year, or 2 relapses in prior 2 years Annualized 0.2 Relapse Rate % 52% p<.001 P<.001 IF B-1a Cohen JA. EJM 1/20/2010 Cohen JA. EJM 1/20/2010 2

3 : FREEDOMS 1 FREEDOMS: Research Evaluating Effects of Daily Oral therapy in MS 2-year, randomized, multicenter, double-blind, placebo-controlled, dose-comparison study (0.5 mg and 1.25 mg ) Primary endpoint: relapse rate at 24 months Subjects (=1272): baseline EDSS=2.4 versus Placebo Annualized Relapse 0.25 Rate Results: Primary Endpoint % p< % P< Placebo Kappos L. EJM 1/20/2010 Kappos L. EJM 1/20/2010 Safety and Tolerability Discontinuation rates 12% IFβ-1a 21% placebo 10-13% fingolimod (0.5 mg) 15-22% fingolimod (1.25 mg) AEs Transient heart rate reduction Blood pressure increase (minor) Liver enzyme elevations Macular edema 2 Fatal SAEs HSV1 encephalitis Disseminated zoster with fulminant hepatic failure Control =849 =1992 Basal Cell 4.7/ /1000 Squamous Cell 0 1.5/1000 Melanoma 1.2/ /1000 Breast Cancer 3.5/ /1000 3

4 Score Card Efficacy Excellent Tolerability Safety Good Qualified H 2 HO Cl O HO Background and Mechanism of Action CLARITY - Treatment Regimen is a lymphocyte-depleting agent CD4 > CD8 T > B cells Pro drug metabolized into active drug by deoxycytodine kinase that is expressed at high levels in lymphocytes Allows for more targeted lymphocyte depletion Mean reduction of 40% to 45% in lymphocyte counts from baseline CSF concentration = 25% of plasma (patients with no blood brain barrier compromise) FDA approved for hairy cell leukemia Sipe J. Exper Rev eurotherapeutics. 2005;5: Leist T, Vermersch P. Curr Med Res Opin. 2007;23: Kopadze T, et al. Eur J eurol E-pub ahead of print. Stelmasiak Z. eurology. 2008;70:A86. Presented at: AA; April 12-19, 2008; Chicago, IL. [P02.143]. Annual short-course treatment Screening Each course = 1 2 tablets (10 mg) daily for 4 or 5 consecutive days per month Courses given for 2 or 4 consecutive months in Year 1 and for 2 consecutive months in Year randomized (1:1:1) Giovannoni G. EJM First 48 weeks X X X X Placebo X X Second 48 weeks X X tables: 4 courses, total dose 3.5 mg/kg tables: 6 courses, total dose 5.25 mg/kg X Placebo course course 4

5 Clarity: Relapse Rate Clarity: Disability Progression Annualized Relapse 0.2 Rate % p< % P< % 33% Reduction Placebo 3.5 Caldribine 5.25 Giovannoni G. EJM : CLARITY (Phase III) Adverse Events Score Card Adverse Events 1 : Overall, frequencies of AEs were reported to be low in the cladribine tablet groups and comparable to the placebo group Lymphopenia was the most reported AE in the cladribine groups Other than lymphopenia, the most frequently reported AEs in the three study groups were headaches and nasopharyngitis Four malignancies were reported in the cladribine treatment groups (none in the placebo group: one case each of cervical, ovarian, and pancreatic cancer, as well as a single case of melanoma One death, respiratory arrest, tuberculosis In hairy cell leukemia, cladribine is associated with increased risk of secondary malignancies 2 1. Giovannoni G. EJM Else M. Br J Haematol 2009;145: Efficacy Tolerability Safety Very Good Excellent Compromised 5

6 4-Amino Pyridine-SR 4-Amino Pyridine-SR H 2 4-amino pyridine SR 10 mg twice daily Central Potassium Channel Blocker Improves conduction across demyelinated axons 4-Amino Pyridine-SR: Trial Design Outcome measure: timed 25 walk, assessed at 8 time points 4-Amino Pyridine Results: responder analysis 4-AP SR 4-AP SR 4 amino pyridine SR 10 mg twice a day A timed walk responder was defined as a patient with a faster walking speed for at least three of the four visits during the double-blind blind treatment period (visits 3,4,5,6) than the maximum speed for any of the five off-drug visits (visits 0, 1, 2, 7, 8) Goodman A. Lancet 2009; 373: % of 4-AP SR treated patients were responders vs. 8% of placebo treated patients Goodman A. Lancet 2009; 373:

7 4-Amino Pyridine-SR Conclusions 4-Amino Pyridine-SR Score Card 4-amino pyridine SR improved walking speed by 25% on the timed 25 foot walk test in 35% of patients (responder analysis) This result was replicated in a second Phase III trial 4-amino pyridine SR was US FDA approved for treatment of MS in January amino pyridine SR is a medication for symptomatic management in MS and does not alter the disability progression Although reasonably safe and well tolerated compounded 4-amino pyridine has been caused seizures in some patients particularly with incorrect dosing Efficacy Tolerability Safety Modest Good Reasonable ext Generation MS Therapeutics Agent Alemtuzumab Route IV (1 x year) MOA Anti-CD52 Lymphocyte depleting Phase III Program (completion date) 2011 Fumarate Oral TID Immunomodulator 2011 Oral, two weeks/year Oral QD Immunosuppressive 2008/2012 S1P agonist/ Immunosuppressive 2009/2011 Laquinimod Oral QD Immunomodulator 2011 Ocrelizumab IV? x year Anti-CD20 (B-cell depleting) 2014? Teriflunomide Oral QD Immunosuppressive 2011/ amino pyridine Oral BID Kv Channel Blocker FDA Approved 7