29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 1 Roger J. Porter, M.D. Consultant Adjunct Professor of Pharmacology, USUHS Adjunct.

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29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 1 Roger J. Porter, M.D. Consultant Adjunct Professor of Pharmacology, USUHS Adjunct Professor of Neurology, Univ. of Pennsylvania Former Deputy Head, CR&D, Wyeth-Ayerst Research Former Deputy Director, NINDS, NIH Pipeline Presentation ASENT: March 6, 2009 RETIGABINE

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 2 Conflict of Interest Statement Roger J. Porter, MD Consultant to Valeant Consultant to Valeant Consultant to GSK Consultant to GSK (relevant to discussions of retigabine)

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 3 DRUG PRODUCT FLOW Lead Finding IND Track Phase I Phase II Phase III Registration Development Discovery

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 4 Retigabine F HHN N NH 2 O O Retig

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 5 Retigabine is Effective in the Following Models of Epilepsy: 1. Maximal electroshock 2. Pentylenetetrazol 3. Picrotoxin 4. Kainate 5. Audiogenic 6. Corneal kindling 7. Cortical penicillin 8. Kindling development 9. Fully-kindled Retigabine is Ineffective in the Following Models of Epilepsy: 1. Voltage-dependent sodium channels 2. Calcium channels Retig

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 6 RETIGABINE OPENS KCNQ2/3 POTASSIUM CHANNELS Rundfeldt and Netzer, Neuroscience Letters (17Mar2000) 282: Retigabine shifts the KCNQ2/3 activation V 1/2 ~ -20 mV.

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 7 Retigabine Phase I Results Desired Pharmacologic Effect Mechanism of action less well defined Mechanism of action less well defined Cannot measure either seizure frequency or a surrogate in normal volunteers. Cannot measure either seizure frequency or a surrogate in normal volunteers. Only reliable measure of the desired pharmacologic effect (efficacy) is RCCT. Only reliable measure of the desired pharmacologic effect (efficacy) is RCCT. Phase I cannot contribute data to support the desired pharmacologic effect (efficacy) in this case Phase I cannot contribute data to support the desired pharmacologic effect (efficacy) in this case

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 8 Retigabine Phase I Results Pharmacokinetics Pharmacokinetics well defined Rapid and almost complete absorption Rapid and almost complete absorption Dose proportional Dose proportional No self induction or inhibition No self induction or inhibition T 1/2 of 6-8 hours T 1/2 of 6-8 hours Oral clearance of 0.7L/hr/kg Oral clearance of 0.7L/hr/kg No significant drug interactions No significant drug interactions

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 9 Phase II Controlled clinical trials (randomized, blinded, etc) Controlled clinical trials (randomized, blinded, etc) Typically patients with disorder Typically patients with disorder Biggest goal is proof of concept Biggest goal is proof of concept Second biggest goal is dose determination Second biggest goal is dose determination Critical are the categorization of the adverse effects Critical are the categorization of the adverse effects Also: dosing schedule Also: dosing schedule

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 10 Baseline TitrationRetigabine Monotherapy MTD Add-on Retigabine Background Medication Carbamazepine, Phenytoin, Topiramate or Valproate. PK Tapering Background Medication Retigabine Phase IIA Study : 60 pts., Open Label—for MTD and DDI

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 11 Retigabine Phase IIB Study Three doses versus placebo Three doses versus placebo Add-on to other drugs Add-on to other drugs 397 patients randomized 397 patients randomized 400 mg t.i.d. maximum dose 400 mg t.i.d. maximum dose

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media Screening Seizure Baseline Titration Maintenance Taper Interim Optional Long- Term extension study or Tapering mg Days Placebo EU/AU/US : Study Design

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 13 Overall difference across treatment arms: p<0.001; overall difference across RTG arms: p=0.05 (closed-test procedure for dose response) *p<0.05 vs. placebo, rank ANCOVA Intent-to-treat Retigabine Phase IIb Study: Dose-Related Efficacy as Adjunctive Therapy Placebo RTG, mg/day Porter RJ et al. Neurology 68: 1197, 2007 Median % Seizure Reduction

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 14 Phase III Controlled clinical trials Controlled clinical trials Larger number of patients Larger number of patients - Sometimes May involve hospitals, clinics, physician offices Object: Confirm effectiveness & confirm knowledge of adverse effects

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 15 Study 301 Study Design Baseline (8 wks) Titration (6 wks) Maintenance (12 wks) 18-Wk Double-Blind Phase RTG 1050 mg/day RTG 1200 mg/day Randomization Placebo Transition* (6 wks) Open- Label Extension *Patients not entering extension tapered over 3 wks Start RTG 300 mg/day (increase 150 mg/day every wk)

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 16 Study 302 Study Design Baseline (8 wks) Titration (4 wks) Maintenance (12 wks) 16-Wk Double-Blind Phase RTG 900 mg/day Randomization Start RTG 300 mg/day (increase 150 mg/day every wk) Placebo Transition* (4 wks) Open- Label Extension RTG 600 mg/day *Patients not entering extension tapered over 3 wks

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 17 Patients with >50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance) Intent-to-treat Study 302Study 301 *p<0.005 **p<0.001 Fisher’s exact test % Patients Placebo Placebo1200 RTG RTG

29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 18 NDA FOR RETIGABINE 1 ST -2 nd Q ST -2 nd Q 2009