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Pipeline Presentation ASENT: March 6, 2009 RETIGABINE

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.

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Pipeline Presentation ASENT: March 6, 2009 RETIGABINE

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  1. Roger J. Porter, M.D.ConsultantAdjunct Professor of Pharmacology, USUHSAdjunct Professor of Neurology, Univ. of PennsylvaniaFormer Deputy Head, CR&D, Wyeth-Ayerst ResearchFormer Deputy Director, NINDS, NIH Pipeline Presentation ASENT: March 6, 2009 RETIGABINE

  2. Conflict of Interest StatementRoger J. Porter, MD • Consultant to Valeant • Consultant to GSK (relevant to discussions of retigabine)

  3. DRUG PRODUCT FLOW Discovery Development Lead Finding IND Track Phase I Phase II Phase III Registration

  4. H H N N O F O NH2 Retigabine Retig--13008

  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 channels2. Calcium channels Retig--13004

  6. RETIGABINE OPENS KCNQ2/3 POTASSIUM CHANNELS Retigabine shifts the KCNQ2/3 activation V1/2 ~ -20 mV. Rundfeldt and Netzer, Neuroscience Letters (17Mar2000) 282: 73-76.

  7. Retigabine Phase I ResultsDesired Pharmacologic Effect Mechanism of action less well defined Cannot measure either seizure frequency or a surrogate in normal volunteers. 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

  8. Retigabine Phase I ResultsPharmacokinetics Pharmacokinetics well defined Rapid and almost complete absorption Dose proportional No self induction or inhibition T 1/2 of 6-8 hours Oral clearance of 0.7L/hr/kg No significant drug interactions

  9. Phase II • Controlled clinical trials (randomized, blinded, etc) • Typically 100-500 patients with disorder • Biggest goal is proof of concept • Second biggest goal is dose determination • Critical are the categorization of the adverse effects • Also: dosing schedule

  10. Retigabine Phase IIA Study :60 pts., Open Label—for MTD and DDI Background Medication Carbamazepine, Phenytoin, Topiramate or Valproate. Baseline PK Tapering Background Medication Retigabine PK PK PK PK PK Titration MTD Add-on Retigabine Monotherapy

  11. Retigabine Phase IIB Study • Three doses versus placebo • Add-on to other drugs • 397 patients randomized • 400 mg t.i.d. maximum dose

  12. mg 205-EU/AU/US : Study Design 1200 1200 Optional Long- Term extension study 1100 1100 1050 1000 1000 or 900 900 800 800 Tapering 750 700 700 600 600 500 500 450 400 400 300 Placebo 0 113 148 -56 1 8 15 22 29 36 43 50 57 168 Days Screening Seizure Baseline Taper Titration Interim Maintenance

  13. Retigabine Phase IIb Study: Dose-Related Efficacy as Adjunctive Therapy Median % Seizure Reduction 99 95 96 106 Placebo 1200 600 900 RTG, mg/day 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 Porter RJ et al. Neurology 68: 1197, 2007

  14. Phase III Controlled clinical trials Larger number of patients • Sometimes 1000-5000 May involve hospitals, clinics, physician offices Object: Confirm effectiveness & confirm knowledge of adverse effects

  15. Study 301 Study Design RTG 1200 mg/day Open- Label Extension RTG 1050 mg/day Randomization Placebo 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Baseline (8 wks) Transition* (6 wks) Titration (6 wks) Maintenance(12 wks) 18-Wk Double-Blind Phase Start RTG 300 mg/day (increase 150 mg/day every wk) *Patients not entering extension tapered over 3 wks

  16. Study 302 Study Design RTG 900 mg/day Open- Label Extension Randomization RTG 600 mg/day Placebo Baseline (8 wks) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Titration (4 wks) Maintenance (12 wks) Transition* (4 wks) 16-Wk Double-Blind Phase Start RTG 300 mg/day (increase 150 mg/day every wk) *Patients not entering extension tapered over 3 wks

  17. Patients with >50% Seizure Reduction in Overall Treatment Period(Titration + Maintenance) Study 302 Study 301 % Patients 179 181 178 152 153 600 900 Placebo 1200 RTG Placebo RTG *p<0.005 **p<0.001 Fisher’s exact test Intent-to-treat

  18. NDA FOR RETIGABINE • 1ST-2nd Q 2009

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