29052-porterj32.ppt 5/7/2015 9:56:12 am /xx/fh/bf/ms/gb/sskmulti-media 1 roger j. porter, m.d....
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Roger J. Porter, M.D.Roger J. Porter, M.D.ConsultantConsultant
Adjunct Professor of Pharmacology, USUHSAdjunct Professor of Pharmacology, USUHSAdjunct Professor of Neurology, Univ. of PennsylvaniaAdjunct Professor of Neurology, Univ. of Pennsylvania
Former Deputy Head, CR&DFormer Deputy Head, CR&D, , Wyeth-Ayerst ResearchWyeth-Ayerst ResearchFormer Deputy Director, NINDS, NIHFormer Deputy Director, NINDS, NIH
Pipeline PresentationPipeline Presentation
ASENT: March 6, 2009ASENT: March 6, 2009
RETIGABINERETIGABINE
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Conflict of Interest StatementConflict of Interest StatementRoger J. Porter, MDRoger J. Porter, MD
• Consultant to ValeantConsultant to Valeant
• Consultant to GSKConsultant to GSK
(relevant to discussions of retigabine)(relevant to discussions of retigabine)
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DRUG PRODUCT FLOWDRUG PRODUCT FLOW
Lead Lead FindingFinding
IND IND TrackTrack
Phase Phase II
Phase Phase IIII
Phase Phase IIIIII
RegistrationRegistration
DevelopmentDevelopmentDiscoveryDiscovery
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RetigabineRetigabine
FF
HH HH
NNNN
NHNH22
OO
OO
Retig--13008Retig--13008
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Retigabine is Retigabine is EffectiveEffective in the Following Models in the Following Models
of Epilepsy:of Epilepsy: 1. Maximal electroshock1. Maximal electroshock2. Pentylenetetrazol2. Pentylenetetrazol3. Picrotoxin3. Picrotoxin4. Kainate4. Kainate5. Audiogenic5. Audiogenic6. Corneal kindling6. Corneal kindling7. Cortical penicillin7. Cortical penicillin8. Kindling development8. Kindling development9. Fully-kindled9. Fully-kindled
Retigabine is Retigabine is IneffectiveIneffective in the Following Models in the Following Models of Epilepsy: of Epilepsy:
1. Voltage-dependent sodium channels1. Voltage-dependent sodium channels2. Calcium channels2. Calcium channels
Retig--13004Retig--13004
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RETIGABINE OPENS KCNQ2/3 RETIGABINE OPENS KCNQ2/3 POTASSIUM CHANNELSPOTASSIUM CHANNELS
Rundfeldt and Netzer, Rundfeldt and Netzer, Neuroscience Letters (Neuroscience Letters (17Mar2000) 282: 73-76.17Mar2000) 282: 73-76.Rundfeldt and Netzer, Rundfeldt and Netzer, Neuroscience Letters (Neuroscience Letters (17Mar2000) 282: 73-76.17Mar2000) 282: 73-76.
Retigabine shifts the KCNQ2/3 activation VRetigabine shifts the KCNQ2/3 activation V1/21/2 ~ -20 mV. ~ -20 mV.Retigabine shifts the KCNQ2/3 activation VRetigabine shifts the KCNQ2/3 activation V1/21/2 ~ -20 mV. ~ -20 mV.
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Retigabine Phase I ResultsRetigabine Phase I ResultsDesired Pharmacologic EffectDesired Pharmacologic Effect
• Mechanism of action less well definedMechanism of action less well defined
• Cannot measure either seizure frequency Cannot measure either seizure frequency or a surrogate in normal volunteers.or a surrogate in normal volunteers.
• Only reliable measure of the desired Only reliable measure of the desired pharmacologic effect (efficacy) is RCCT.pharmacologic effect (efficacy) is RCCT.
• Phase I Phase I cannot contribute datacannot contribute data to support to support the desired pharmacologic effect (efficacy) the desired pharmacologic effect (efficacy) in this casein this case
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Retigabine Phase I ResultsRetigabine Phase I ResultsPharmacokineticsPharmacokinetics
Pharmacokinetics well definedPharmacokinetics well defined
•Rapid and almost complete absorptionRapid and almost complete absorption
•Dose proportionalDose proportional
•No self induction or inhibitionNo self induction or inhibition
•T 1/2 of 6-8 hoursT 1/2 of 6-8 hours
•Oral clearance of 0.7L/hr/kgOral clearance of 0.7L/hr/kg
•No significant drug interactionsNo significant drug interactions
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Phase IIPhase II
• Controlled clinical trials (randomized, blinded, etc)Controlled clinical trials (randomized, blinded, etc)
• Typically 100-500 patients with disorderTypically 100-500 patients with disorder
• Biggest goal is Biggest goal is proof of conceptproof of concept
• Second biggest goal is Second biggest goal is dose determinationdose determination
• Critical are the categorization of the Critical are the categorization of the adverse effectsadverse effects
• Also: dosing scheduleAlso: dosing schedule
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BaselineBaseline Titration Retigabine Monotherapy
MTDAdd-on
Retigabine
Background MedicationCarbamazepine, Phenytoin, Topiramate or Valproate.
PK
PK
PK
PK
PK
PK
TaperingBackgroundMedication
Retigabine Phase IIA Study :Retigabine Phase IIA Study :60 pts., Open Label—for MTD and DDI60 pts., Open Label—for MTD and DDI
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Retigabine Phase IIB StudyRetigabine Phase IIB Study
• Three doses versus placeboThree doses versus placebo
• Add-on to other drugsAdd-on to other drugs
• 397 patients randomized397 patients randomized
• 400 mg t.i.d. maximum dose400 mg t.i.d. maximum dose
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1200
900
600
300
1 8 15 22 29 36 43 50 57 113-56
ScreeningSeizure Baseline
Titration Maintenance
0
148
TaperInterim
600
500
400
900
800
700
1200
1100
1000
Optional Long-Term extensionstudyor
Tapering
mg
Days
Placebo
450
750
1050
168
205-EU/AU/US : Study Design205-EU/AU/US : Study Design
500
400
800
700
1100
1000
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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 ANCOVAIntent-to-treat
23%
29%*
35%*
13%
0
10
20
30
40
50
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 99 95 106
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Phase IIIPhase III
Controlled clinical trialsControlled clinical trials
Larger number of patientsLarger number of patients- Sometimes 1000-5000Sometimes 1000-5000
May involve hospitals, clinics, physician officesMay involve hospitals, clinics, physician offices
Object: Object: Confirm effectivenessConfirm effectiveness & & confirm knowledge of confirm knowledge of adverse effectsadverse effects
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Study 301 Study DesignStudy 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 24Baseline(8 wks) Titration
(6 wks)Maintenance(12 wks)
18-Wk Double-Blind Phase
RTG 1050 mg/day
RTG 1200 mg/dayR
and
om
izat
ion
Placebo
Transition*(6 wks)
Open-LabelExtension
*Patients not entering extension tapered over 3 wks
Start RTG300 mg/day(increase 150 mg/day every wk)
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Study 302 Study DesignStudy 302 Study Design
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20Baseline(8 wks) Titration
(4 wks)Maintenance(12 wks)
16-Wk Double-Blind Phase
RTG 900 mg/dayR
and
om
izat
ion
Start RTG300 mg/day(increase 150 mg/day every wk)
Placebo
Transition*(4 wks)
Open-LabelExtensionRTG 600 mg/day
*Patients not entering extension tapered over 3 wks
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Patients with >50% Seizure Reduction in Overall Treatment
Period (Titration + Maintenance)
44%**
18%
39%**
31%*
17%
0
10
20
30
40
50
60
Intent-to-treat
Study 302 Study 301
*p<0.005 **p<0.001 Fisher’s exact test
% P
atie
nts
179 181 178 152 153
Placebo 600 900 Placebo 1200 RTG
RTG
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NDA FOR RETIGABINENDA FOR RETIGABINE
• 11STST-2-2ndnd Q 2009 Q 2009