GSK and XenoPort's Horizant fails in Phase IIb for migraine prophylaxis
This article was originally published in Scrip
GlaxoSmithKline and XenoPort's new formulation of gabapentin, Horizant (gabapentin enacarbil, GSK1838262/XP13512), has failed to meet the primary endpoint in a Phase IIb study of improvement over placebo as a prophylactic treatment for migraine headaches, with or without aura. GSK told Scrip that it was probably not going to progress Horizant to Phase III for this indication.
This is not the first blow for the product, which is in development for a number of indications. It was filed in the US for moderate-to-severe primary restless legs syndrome (RLS), but received a complete response letter in February, in which the agency expressed concerns over pancreatic acinar cell tumours in rats that it said were sufficient to preclude US approval (scripintelligence.com, 22 February 2010).
The companies met the FDA in May for an end of review meeting, in which the agency suggested additional data and analysis that it wants for the complete response in RLS. GSK said that it was currently evaluating the extra work and also undertaking a epidemiology study of cancer risk in patients taking gabapentin that are registered on the General Practice Research Database (GPRD). It expects to submit its complete response in the second half of this year.
For the migraine indication, XenoPort's chief executive Dr Ronald Barrett said he was disappointed by the results, especially by the high placebo response rate, which may have impacted the ability of the trial to detect the potential benefit of GSK1838262.tsWe remain committed to working with our partners and regulatory authorities to make this product candidate available to patients with unmet medical needs."
The failed Phase IIb migraine study was 30 weeks long and enrolled 526 patients who were randomised to twice daily doses of Horizant (1,200mg, 1,800mg, 2,400mg or 3,000mg) or placebo. The primary endpoint was the change from baseline in the number of migraine headache days during the last four weeks of the treatment prior to taper, but was not met.
Horizant is a pro-drug of gabapentin, a GABA analogue that has been marketed since 1993 as an anti-epileptic and as a treatment for neuropathic pain. GSK and XenoPort have said that Horizant is designed to provide a dose-proportional and sustained exposure of gabapentin by taking advantage of high-capacity transport mechanisms in the gastrointestinal tract. The drug is also in Phase II development for post-herpetic neuralgia and neuropathic pain; although GSK told Scrip it was undecided whether to continue the drug's development in the latter indication.
It has not been linked with pancreatic cancer in humans, based on analysis of spontaneous reports in the adverse event reporting system but the US FDA said this is not a reliable indicator of absence of risk.
Horizant has had several other setbacks in its RLS setting. These include a PDUFA date delay to view a risk evaluation and mitigation strategy (REMS) that had been added to the submission package (scripintelligence.com, 10 November, 2009), and in 2008, the companies decided to withdraw and resubmit the [RLS] NDA after the FDA requested that the data of one of three pivotal Phase III trials be re-formatted (scripintelligence.com, 22 November, 2008).
GSK licensed the product in 2007 for co-development and co-commercialisation worldwide except in certain Asian countries, where it was already licensed to Astellas. The product has also been filed in Japan by XenoPort and Astellas for RLS.
Also in the clinic, XenoPort has a GABA agonist, XP19986 (the R-isomer of baclofen), which is in Phase II development for gastroesophageal reflux disease and spasticity. The company has said that its carcinogenic studies have been completed and no cancer safety signals were detected.