Summary Clinical Evaluation of Carisbamate for Adjunctive Use in Treatment of Partial Onset Seizures J&J Pharmaceutical R&D Antiepileptic Drug Trials XI April 27 2011
Summary of Past Development Efficacy in preclinical models and Phase 2 clinical trials provided evidence that carisbamate (CRS) has anticonvulsant effects that might extend across a broad range of seizure types CRS was in licensed from SK Life Sciences and J&J PRD commenced its full development as an adjunctive treatment of partial onset seizures in adults 4 randomized double blind placebo controlled trials were executed between Feb 2005 and Dec 2009 CRS failed to demonstrate a consistent pattern of superior efficacy across the dosage ranges studied in this group of patients, and further development in this indication was discontinued by J&J PRD 2
Current Status of Carisbamate Carisbamate has been returned to SK Life Science SK will continue the development of CRS in epilepsy and in other indications SK will continue to supply 3 subjects remaining in an expanded access program 3
Carisbamate Efficacy in Phase 2 = p<0.05 4
Efficacy in Two Trials in a Lower Dose Range = p<0.05 5
Efficacy in a Higher Dose Range = p<0.05 6
Efficacy by Induction Status EPY 2003 EPY 3001/3002 EPY 3013 Induced = receiving Barbiturate, Phenytoin, or Carbamazepine 7
Design of Clinical Trials EPY 2003 EPY 3001 EPY 3002 EPY 3013 Dosages Pbo, 100, 300, 800, 1600 mg/d Pbo, 200, 400 mg/d Pbo, 200, 400 mg/d Pbo, 800, 1200 mg/d N Subjects 537 565 562 547 Titration 4w None None 2w Maintenance 12w 12w 12w 12w Age >18, <70 >16 >16 >16 Min Prior AED 3 1 1 1 Max Concom AED Other Excl 3 2 2 3 >100 sz/m at BL 8
Demographics EPY 2003 EPY 3001 EPY 3002 EPY 3013 Regions NA, SA, EU NA, SA, EU, AS NA, SA, EU, AS NA, EU, AS, AUS # Sites 101 91 83 106 N Subjects 537 565 562 547 Male, n (%) 48 50 48 49 Race White 95 61 53 53 Black 3 1 <1 1 Asian >1 36 4 43 Other 2 1 <1 4 Age, Median (Range) 37 (17 69) 33 (16 75) 34 (16 74) 36 (16 73)
Baseline Disease Characteristics EPY 2003 EPY 3001 EPY 3002 EPY 3013 Years Since Diagnosis, Median (Range) 21 (0 58) 19 (1 57) 15 (1 62) 18 (1 61) Prior AEDs, Median (Range) 6 (2 18) 5 (1 24) 4 (1 17) 6 (1 22) Baseline Monthly POS, Median (Range) 10.5 (3 445) 9 (2 614) 7 (2 274) 8 (3 110) Number of Co AEDs, % One Two Three 14 50 36 23 77 1 31 69 0 14 47 39 % Induced 61 56 61 54 Syndrome, % Symptomatic Cryptogenic Undetermined 46 45 9 57 43 <1 47 53 <1 50 40 9 10
Factors Examined in Relation to Efficacy Age and Gender Geographic Region Duration of Epilepsy Number of Prior AEDs Number of Concurrent AEDs Etiology (Symptomatic/Cryptogenic) Baseline Seizure Rate 11
Baseline Factors Not Predictive of Placebo Response STUDY ID EPILEPTIC SYNDROMES CLASS UNIQUE SITE NAME CP SEIZURES PRESENT IN BASELINE SIZE OF STUDY SITE SPM SEIZURES PRESENT IN BASELINE RECURITMENT RATE AT SITE SECONDARY GEN SEIZURES PRESENT COUNTRY GTC SEIZURES PRESENT IN BASELINE OTHER SEIZURE TYPES PRESENT AGE in YEARS BASELINE POS RATE BODY MASS_INDEX RACE HADS BASELINE ANXIETY SCORE SEX HADS BASELINE DEPRESSION SCORE WEIGHT QOLIE 31 BASELINE TOTAL SCORE SZ SEVERITY BASELINE RECOVERY SCORE AGE IN YEARS AT EPILEPSY DIAGNOS IS THERE FAMILY HISTORY OF EPILEPSY DATE OF RANDOMIZATION HAS SUBJECT EVER HAD STATUS EPILEPTICUS SUBJECT DB PHASE COMPLETION EPILEPSY SURGERY IN PRIOR HISTORY NUMBER OF PRIOR REPORTED AEDS PHENOBARBITAL IN PRIOR HISTORY CARBAMAZEPINE IN PRIOR HISTORY 12
Past Performance Was Not Predictive Only the best sites in Phase 2 were invited to participate in Phase 3
Seizure Reduction for Carisbamate not Related to Placebo Response Sites Grouped in Order of Placebo Response Quartile Pooled Studies EPY 3001+3002
EPY 2003 ITT: Median Percent Reduction From Baseline Over Time in POS Frequency Observed Cases 300mg 100mg Placebo
EPY 3001 ITT: Median Percent Reduction From Baseline Over Time in POS Frequency Observed Cases 400mg 200mg Placebo
EPY 3002 ITT: Median Percent Reduction From Baseline Over Time in POS Frequency Observed Cases 400mg 200mg Placebo
EPY 3013 ITT: Median Percent Reduction From Baseline Over Time in POS Frequency Observed Cases Median Percent Reduction from Baseline 1200mg 800mg Placebo Week of DB Phase 18
Why is it so difficult to develop an AED as an adjunct in the treatment of partial onset seizures? STRICTLY CONFIDENTIAL 19
Some Basic Requirements Subjects Sites Sponsors STRICTLY CONFIDENTIAL 20
Requirements: the Subject Must have epilepsy Must have POS Must know when he has had a seizure Must record seizures consistently over 5+ months Must take study drugs Must report other meds 21
Requirements: the Investigator Must be able to diagnose and classify seizures Must recognize the capable subject Must assure continuity and consistency of assessors Must provide appropriate support and encouragement to the subject Must comply with the protocol, report data accurately and in a timely manner 22
Requirements: the Sponsor Must choose appropriate sites and investigators Must communicate the key requirements of the protocol and answer the investigators questions promptly Must monitor: Site compliance, especially early in trial Individual and tabulated summary data in real time 23