Download No Slide Title

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
29052-PorterJ32.ppt
5/23/2017 6:20:21 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
1
Conflict of Interest Statement
Roger J. Porter, MD
• Consultant to Valeant
• Consultant to GSK
(relevant to discussions of retigabine)
29052-PorterJ32.ppt
5/23/2017 6:20:22 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
2
DRUG PRODUCT FLOW
Discovery
Lead
Finding
29052-PorterJ32.ppt
IND
Track
Development
Phase
I
Phase
II
5/23/2017 6:20:22 AM
Phase
III
Registration
/xx/fh/BF/ms/gb/SSK
Multi-Media
3
Retigabine
H
H
N
N
F
NH2
29052-PorterJ32.ppt
Retig--13008
5/23/2017 6:20:23 AM
/xx/fh/BF/ms/gb/SSK
O
O
Multi-Media
4
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
29052-PorterJ32.ppt
Retig--13004
5/23/2017 6:20:23 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
5
Retig
abineOpensOPENS
KCNQ2/3
Potassium
RETIGABINE
KCNQ2/3
Channels
POTASSIUM CHANNELS
Concentration-Response
5.0
-fold)
Retigabine 10M
4.0
0.5nA
1s
Inducedcurrent (x
3.0
2.0
1.0
EC50 =1.7µM
0.0
CHOcells expressing KCNQ2/3, voltageclamped at -50 mV.
0.1
1
10
100
Retigabine[µM]
RetigabineshiftstheKCNQ2/3activationV1/2 ~-20m
V.
Retigabine shifts the KCNQ2/3 activation V1/2 ~ -20 mV.
Rundfeldt and Netzer, Neuroscience Letters
(17Mar2000)
282:
Ru
ndfeldt andNe
tzer,73-76.
NeuroscienceLetters (17Mar2000) 282: 73-76.
29052-PorterJ32.ppt
29052-PorterJ32.ppt
28
5/23/2017 6:20:24 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
6
Retigabine Phase I Results
Desired 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
29052-PorterJ32.ppt
5/23/2017 6:20:25 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
7
Retigabine Phase I Results
Pharmacokinetics
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
29052-PorterJ32.ppt
5/23/2017 6:20:26 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
8
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
29052-PorterJ32.ppt
5/23/2017 6:20:27 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
9
Retigabine Phase IIA Study :
60 pts., Open Label—for MTD and DDI
Background Medication
Carbamazepine, Phenytoin,
Topiramate or Valproate.
PK
Retigabine
PK
Tapering
Background
Medication
PK
PK
PK
PK
Baseline
29052-PorterJ32.ppt
Titration
MTD
Add-on
5/23/2017 6:20:28 AM
/xx/fh/BF/ms/gb/SSK
Retigabine
Monotherapy
Multi-Media
10
Retigabine Phase IIB Study
• Three doses versus placebo
• Add-on to other drugs
• 397 patients randomized
• 400 mg t.i.d. maximum dose
29052-PorterJ32.ppt
5/23/2017 6:20:29 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
11
205-EU/AU/US : Study Design
mg
1200
1200
Optional LongTerm extension
study
or
1100
1050
1000
900
900
800
750
700
600
600
Tapering
500
450
400
300
Placebo
0
-56
1
Screening
Seizure Baseline
29052-PorterJ32.ppt
8 15
22
29 36
Titration
43
50
113
57
Maintenance
5/23/2017 6:20:29 AM
/xx/fh/BF/ms/gb/SSK
148
Interim
Multi-Media
168 Days
Taper
12
Retigabine Phase IIb Study:
Dose-Related Efficacy as Adjunctive Therapy
Median % Seizure Reduction
50
40
35%*
29%*
30
23%
20
13%
10
0
96
99
95
106
Placebo
600
900
1200
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
Porter RJ et al. Neurology 68: 1197, 2007
Intent-to-treat
29052-PorterJ32.ppt
5/23/2017 6:20:30 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
13
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
29052-PorterJ32.ppt
5/23/2017 6:20:30 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
14
Study 301 Study Design
RTG 1200 mg/day
OpenLabel
Extension
Randomization
RTG 1050 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 21 22 23 24
Transition*
Titration
Maintenance
(6 wks)
(6 wks)
(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
29052-PorterJ32.ppt
5/23/2017 6:20:31 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
15
Randomization
Study 302 Study Design
RTG 900 mg/day
OpenLabel
Extension
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
Maintenance
Transition*
(4 wks)
(12 wks)
(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
29052-PorterJ32.ppt
5/23/2017 6:20:32 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
16
Patients with >50% Seizure
Reduction in Overall Treatment
Period (Titration + Maintenance)
Study 302
60
Study 301
% Patients
50
44%**
39%**
40
31%*
30
20
18%
17%
10
0
179
181
178
152
153
Placebo
600
900
Placebo
1200 RTG
RTG
Intent-to-treat
29052-PorterJ32.ppt
*p<0.005
**p<0.001
Fisher’s exact test
5/23/2017 6:20:32 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
17
NDA FOR RETIGABINE
• 1ST-2nd Q 2009
29052-PorterJ32.ppt
5/23/2017 6:20:32 AM
/xx/fh/BF/ms/gb/SSK
Multi-Media
18