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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