Retigabine
Summary:
Retigabine works through a new mechanism of action: the potassium channel. Animal models offer the promise that it may be effective against a broad spectrum of seizure types. Two large scale phase III studies showed high median percent seizure reductions with an increase in dropout rates at higher doses in a population of patients with refractory partial onset seizures. The large phase II study indicated statistically significant but modest responder rates and seizure reduction, but took place in a difficult to treat patient population and so efficacy in general use could be better than this study might suggest. Based on the animal studies and because it works through a novel mechanism of action, Retigabine is an exciting potential new aed and add-on therapy.
This is a first draft, work in progress entry which needs to be updated to reflect data presented from the two phase III Restore trials in full. Please help us build out this pipeline entry. wl 4/18/09.
Community Ranking: (patient impact, prob of success, time to market , overall assessment)
Therapy description:
Retigabine is the first member of a new class of drugs that act through the potassium channel, potentiate GABA, and exhibit broad-spectrum anticonvulsant activity.
Sponsor:
Retigabine will be marketed by a Valeant Pharmaceuticals, GlaxoSmithKline partnership.
Valeant Pharmaceuticals, Aliso Viejo, CA USA
www.valeant.com
GlaxoSmithKline,
www.gsk.com, Registered office: 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
Status:
Pivotal clinical trials complete and awaiting submission.
Pharmacokinetics:
Retigabine is absorbed rapidly after oral administration (Tmax =1.5 hours; T1/2 =8 hours).
Dosing:
The phase III Restore 1 trial evaluated placebo against a dose of 1200 mg tid.
The phase III Restore 2 trial evaluated placebo against 600 and 900 mg tid.
Formulations Under Development: The sponsor has discussed developing a sustained release formulation.
Indications:
Epilepsy: Sponsor indicates that they will pursue the following indications for initial submission to regulatory agencies in the US and Europe and contemplate post-approval studies also in these populations. Sponsor plans to submit for monotherapy as well as add-on use in Europe but only for add-on use in the United States.
Other: Retigabine is in Phase II trials for Pain (? needs update)
Estimated arrival in market:
Pivotal trials complete. Data not yet submitted. Perhaps a late 2010, early 2011 release.
Trial data:
1350 patients exposed, > 700 over 6 months, 350 > 12 months, subset 7 years.
Phase 3
Completers 83% placebo, 76% at 600 mg, 69% at 900 mg and 61% at 1200.
Phase 2 trials, meant to determine dosing, were placebo controlled and included more than 600 patients. In the studies, the compound appeared to demonstrate a 23-35% reduction in monthly seizure rates when used as adjunctive therapy in patients with partial seizures. (footnote)
Phase 1 summary (footnote)
Adverse events:
The most common adverse events in the Phase 2 trials were somnolence, speech disorder and ataxia.
Animal data:
Retigabine blocked seizures in the MES (maximal electroshock) model as well as the PTZ (pentylenetetrazole) induced seizure model.
Retigabine effectively suppressed sound induced seizures in audiogenic seizure-susceptible DBA/J2 mice and GEPR rats. However, retigabine was more effective against the seizures of GEPR-3 rats (moderate) than the seizures of GEPR-9 rats (severe).
Retigabine was also very effective in the amygdale kindling model. At doses of 0.01 mg/kg, the compound increased the electrical threshold for induction of afterdischarges (which indicates antiseizure activity). At doses of 5 mg/kg, retigabine increased the induction threshold by 450%, as well as reducing seizure severity and duration.
Retigabine was also active in hippocampal kindling in rats and corneal kindling in mice.
Additional Sponsor Detail:
New York Stock Exchange (symbol VRX)
Market Capitalization as of May 7, 2007 $1.6 billion
2006 Revenues, profits, cash flow:
Revenues: $907.2 million; 2006 product sales totaled $826.0 million.
Cash flow from operations (Net income + depreciation and amortization): $15,311,000
Net cash (debt): $326,002,000
Other CNS Products Marketed by Sponsor
Zelapar (Parkinson’s), Diastat AcuDial, Migranal, Mestinon (myasthenia gravis), Tasmar (Parkinson’s)
Other CNS Products in Sponsor Pipeline
Retigabine IR, Cesamet, Retigabine IR, Diastat IN, Retigabine Follow-On
Partnership Status, Commercial Strategy (This to be a commentary by epilepsy tdp, David/Warren)
Development History of Compound
Retigabine was first developed at the University of Koln and licensed to Wyeth which completed phase II studies in
Publications: (from PubMed)
1:
Smith MD, Adams AC, Saunders GW, White HS, Wilcox KS.
Related Articles
Phenytoin- and carbamazepine-resistant spontaneous bursting in rat entorhinal cortex is blocked by retigabine in vitro.
Epilepsy Res. 2007 Mar 27; [Epub ahead of print]
PMID: 17395429 [PubMed - as supplied by publisher]
2:
Bu W, Nguyen M, Xu C, Lin CC, Yeh LT, Borges V.
Related Articles, Links
Determination of N-acetyl retigabine in dog plasma by LC/MS/MS following off-line muElution 96-well solid phase extraction.
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Feb 17; [Epub ahead of print]
PMID: 17350902 [PubMed - as supplied by publisher]
3:
Hryhorov OO, Moskaliuk AO, Fedulova SA, Veselovs'kyi MS.
Related Articles, Links
[Voltage-activated potassium channels of the inhibitory interneurons of the hippocampus in culture]
Fiziol Zh. 2006;52(6):35-44. Ukrainian.
PMID: 17333621 [PubMed - indexed for MEDLINE]
4:
Hu H, Vervaeke K, Storm JF.
Related Articles, Links
M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region.
J Neurosci. 2007 Feb 21;27(8):1853-67.
PMID: 17314282 [PubMed - indexed for MEDLINE]
5:
Miura Y.
Related Articles, Links
[A new aspect in the research on antiepileptic drugs]
Nippon Yakurigaku Zasshi. 2007 Feb;129(2):111-5. Review. Japanese. No abstract available.
PMID: 17299237 [PubMed - indexed for MEDLINE]
6:
Yaari Y, Yue C, Su H.
Related Articles, Links
Recruitment of Apical Dendritic T-Type Ca2+ Channels by Backpropagating Spikes Underlies de novo Intrinsic Bursting in Hippocampal Epileptogenesis.
J Physiol. 2007 Feb 1; [Epub ahead of print]
PMID: 17272342 [PubMed - as supplied by publisher]
7:
Jensen HS, Grunnet M, Olesen SP.
Related Articles, Links
Inactivation as a new regulatory mechanism for neuronal kv7 channels.
Biophys J. 2007 Apr 15;92(8):2747-56. Epub 2007 Jan 19.
PMID: 17237198 [PubMed - in process]
8:
Porter RJ, Nohria V, Rundfeldt C.
Related Articles, Links
Retigabine.
Neurotherapeutics. 2007 Jan;4(1):149-54.
PMID: 17199031 [PubMed - in process]
9:
Hirano K, Kuratani K, Fujiyoshi M, Tashiro N, Hayashi E, Kinoshita M.
Related Articles, Links
Kv7.2-7.5 voltage-gated potassium channel (KCNQ2-5) opener, retigabine, reduces capsaicin-induced visceral pain in mice.
Neurosci Lett. 2007 Feb 14;413(2):159-62. Epub 2006 Dec 20.
PMID: 17184917 [PubMed - in process]
10:
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T.
Related Articles, Links
Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII).
Epilepsy Res. 2007 Jan;73(1):1-52. Epub 2006 Dec 8.
PMID: 17158031 [PubMed - indexed for MEDLINE]
Commentary: (Epilepsy TP SAB, BAB, community)
Metanotes: Publication section, how best to populate it?
Tab?
Auto search on PUBMED and display top ten results by date?
Similar search for secondary indications???

warren7

Created by warren7 04/18/2009 at 12:32pm

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Edited by admin 08/16/2010 at 02:26pm