Presentation is loading. Please wait.

Presentation is loading. Please wait.

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.

Published byGeorgiana McCormick Modified over 9 years ago

Similar presentations

Presentation on theme: "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."— Presentation transcript:

1 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

2 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)

3 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

4 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--13008

5 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--13004

6 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: 73-76. Retigabine shifts the KCNQ2/3 activation V 1/2 ~ -20 mV.

7 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

8 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

9 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 100-500 patients with disorder Typically 100-500 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

10 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

11 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

12 29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 12 1200 900 600 300 1815222936435057 113 -56 Screening Seizure Baseline Titration Maintenance 0 148 Taper Interim 600 500 400 900 800 700 1200 1100 1000 Optional Long- Term extension study or Tapering mg Days Placebo 450 750 1050 168 205-EU/AU/US : Study Design 500 400 800 700 1100 1000

13 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 600 900 1200 RTG, mg/day Porter RJ et al. Neurology 68: 1197, 2007 Median % Seizure Reduction 96 9995 106

14 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 1000-5000 May involve hospitals, clinics, physician offices Object: Confirm effectiveness & confirm knowledge of adverse effects

15 29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 15 Study 301 Study Design 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) 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)

16 29052-PorterJ32.ppt 5/7/2015 9:56:12 AM /xx/fh/BF/ms/gb/SSKMulti-Media 16 Study 302 Study Design 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 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

17 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 179181178152153 Placebo 600900Placebo1200 RTG RTG

18 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 2009 1 ST -2 nd Q 2009

Download ppt "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."

Similar presentations

Design of Dose Response Clinical Trials

Design of Dose Response Clinical Trials
J. Stephen Huff, MD, FACEP Critical Issues in the Evaluation and Management of Adult Patients Presenting to the ED with Seizures: The 2004 ACEP Clinical.

J. Stephen Huff, MD, FACEP Critical Issues in the Evaluation and Management of Adult Patients Presenting to the ED with Seizures: The 2004 ACEP Clinical.
Integration of Taxanes in the Management of Breast Cancer

Integration of Taxanes in the Management of Breast Cancer
Palumbo A et al. Proc ASH 2013;Abstract 536.

Palumbo A et al. Proc ASH 2013;Abstract 536.
An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures Mark Versavel MD, PhD, MBA Vice President, Clinical Research.

An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures Mark Versavel MD, PhD, MBA Vice President, Clinical Research.
Fig.3 Adverse effects of antiepileptic therapy in children: poly-therapy vs mono-therapy In-Service, Problem-Based Pharmacotherapy Teaching and Clinical.

Fig.3 Adverse effects of antiepileptic therapy in children: poly-therapy vs mono-therapy In-Service, Problem-Based Pharmacotherapy Teaching and Clinical.
Basic Design Consideration. Previous Lecture Definition of a clinical trial The drug development process How different aspects of the effects of a drug.

Basic Design Consideration. Previous Lecture Definition of a clinical trial The drug development process How different aspects of the effects of a drug.
Journal Club Alcohol, Other Drugs, and Health: Current Evidence March–April 2014.

Journal Club Alcohol, Other Drugs, and Health: Current Evidence March–April 2014.
Farxiga™ - Dapagliflozin

Farxiga™ - Dapagliflozin
Pharmaceutical Development and Review Process Rev. 10/21/2014 APGO Interaction with Industry: A Medical Student Guide.

Pharmaceutical Development and Review Process Rev. 10/21/2014 APGO Interaction with Industry: A Medical Student Guide.
Results of a Phase 2 Randomised, Open- Label, Study of Lower Doses of Quizartinib (AC220; ASP2689) in Subjects with FLT3-ITD Positive Relapsed or Refractory.

Results of a Phase 2 Randomised, Open- Label, Study of Lower Doses of Quizartinib (AC220; ASP2689) in Subjects with FLT3-ITD Positive Relapsed or Refractory.
INVESTIGATIONAL DRUG SERVICES IN THE HOSPITAL Sheree Miller, Pharm.D. University of Washington Medical Center 1-13-04.

INVESTIGATIONAL DRUG SERVICES IN THE HOSPITAL Sheree Miller, Pharm.D. University of Washington Medical Center
Study 307- Long term open label extension data Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, Laurenza A Perampanel,

Study 307- Long term open label extension data Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, Yang H, Gee M, Zhu J, Laurenza A Perampanel,
CE-1 CRESTOR ® Clinical Development Efficacy James W. Blasetto, MD, MPH Senior Director, Clinical Research.

CE-1 CRESTOR ® Clinical Development Efficacy James W. Blasetto, MD, MPH Senior Director, Clinical Research.
Role of Rosuvastatin in the Treatment of Dyslipidemia

Role of Rosuvastatin in the Treatment of Dyslipidemia
ATLAS Clinical Trial Commentary Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and.

ATLAS Clinical Trial Commentary Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and.
CME Disclosure Statement The North Shore LIJ Health System adheres to the ACCME's new Standards for Commercial Support. Any individuals in a position.

CME Disclosure Statement The North Shore LIJ Health System adheres to the ACCME's new Standards for Commercial Support. Any individuals in a position.
305 Study Randomised, Double Blind, Placebo Controlled Phase III Safety and Efficacy Study (8 and 12 mg OD) Conducted in Europe, Asia, North America, Australia,

305 Study Randomised, Double Blind, Placebo Controlled Phase III Safety and Efficacy Study (8 and 12 mg OD) Conducted in Europe, Asia, North America, Australia,
2010 ASENT Conference March 2010. Highlights A novel mechanism of action and a new class of therapy in a large marketplace where existing mechanisms leave.

2010 ASENT Conference March Highlights A novel mechanism of action and a new class of therapy in a large marketplace where existing mechanisms leave.
Jasper Ogwal-Okeng Gulu University Research Workshop 3 rd -6 th March 08.

Jasper Ogwal-Okeng Gulu University Research Workshop 3 rd -6 th March 08.

Similar presentations

Ads by Google