The big decision day is drawing near for XenoPort Inc.'s (XNPT) restless leg syndrome drug candidate gabapentin enacarbil, known in the United States by the trade name Horizant extended-release tablet, which is at the regulatory altar for the second time.
Horizant extended-release tablet is a modified version of gabapentin, an epilepsy drug that has been sold by Pfizer Inc. (PFE) as Neurontin since 1993 and is currently sold as a generic drug by a number of companies. In December 2005, XenoPort licensed rights to develop and commercialize Horizant to Astellas Pharma Inc. in Japan and five Asian countries, and licensed the rights to GlaxoSmithKline plc. (GSK) in the U.S. and all other regions of the world in February 2007. Last November, XenoPort reacquired all rights to Horizant outside of the United States that were previously granted to GlaxoSmithKline (which excludes the Astellas territory).
For Horizant , this is its second go-around with the FDA. Last February, Horizant was issued a complete response letter in which the FDA indicated that a preclinical finding of pancreatic acinar cell tumors in rats was of sufficient concern to preclude approval of Horizant for restless leg syndrome, or RLS, at that time.
In October 2010, GlaxoSmithKline responded to the complete response letter for Horizant and submitted new data from nonclinical studies of the drug candidate and two epidemiology studies, exploring gabapentin use and cancer based on the UK General Practice Research Database. The resubmission also included a final safety update that provided updated or new safety information on patients in clinical studies who have been treated with Horizant. In order for the FDA to be able to consider published gabapentin nonclinical data in their assessment of Horizant, GlaxoSmithKline amended the New Drug Application for Horizant from a 505(b)(1) to a 505(b)(2) application.
Under the 505(b)(1) regulatory pathway, a drug candidate is required to demonstrate clinical meaningful treatment benefits and statistically significant safety and efficacy objectives and endpoints and is a new chemical entity, with a new indication. However, the 505(b)(2) regulatory pathway allows a sponsor to rely, at least in part, on the FDA's findings of safety and/or effectiveness for a previously approved drug (the "reference drug").
The resubmission of the NDA, which was accepted by the regulatory agency last November, was designated as a Class 2 response with a new Prescription Drug User Fee Act goal date of April 6, 2011.
In Japan, Astellas is seeking Pharmaceuticals and Medical Device Agency, or PMDA, approval of gabapentin enacarbil as a potential treatment for restless legs syndrome. Astellas estimates that there are approximately 3.9 million patients with restless legs syndrome in Japan.
Restless legs syndrome, or RLS, is a neurological condition that is characterized by an irresistible urge to move the legs to relieve unpleasant feelings such as creeping, crawling, pulling, itching, tingling or burning sensations.
According to the National Institute of Neurological Disorders and Stroke, as many as 10 percent of the U.S. population may have RLS. About 2-3 percent of adults (more than 5 million individuals) are said to have moderate to severe RLS. An additional 5 percent appears to be affected by a milder form.
Dopamine agonists, which are the most common form of medication to treat restless legs syndrome, account for more than 90% share of the prescription, while gabapentin account for less than 5% share.
However, dopamine agonists are associated with some side effects including nausea, dizziness, compulsive behavior and augmentation, which results in worsening of the symptoms.
Ropinirole, marketed as Requip by GSK, a dopamine agonist, approved in 2005, was the first FDA-approved drug for RLS. A year later - in 2006, Pramipexole, developed by Boehringer Ingelheim and marketed as Mirapex, was approved by the FDA and the EU for the treatment of restless legs syndrome. Requip's patent lapsed in May of 2008 and its generic versions have also been approved to treat RLS. In Japan, Pramipexole was approved in 2010 for the treatment of restless legs syndrome.
Horizant is also being evaluated by GlaxoSmithKline for the potential treatment of post-herpetic neuralgia, or PHN, a chronic type of neuropathic pain that can follow the resolution of shingles, and Horizant has successfully completed several Phase 2 clinical trials for the management of PHN in the United States.
In addition, GlaxoSmithKline evaluated Horizant for the potential treatment of diabetic peripheral neuropathy, or DPN, and as a potential prophylactic therapy for migraine headaches. However, Horizant did not show statistically significant separation from placebo in the primary endpoints of these trials.
Xenoport's other clinical drug candidates include, Arbaclofen placarbil, which is in phase II clinical development for the potential treatment of patients with spasticity, and XP21279, which is also in phase II clinical development as a potential treatment for Parkinson's disease.
The company expects to begin phase III efficacy trial of Arbaclofen placarbil as a potential treatment of spasticity in multiple sclerosis patients by mid-year. Arbaclofen placarbil was also being evaluated as a potential adjunctive therapy in patients with gastroesophageal reflux disease or GERD. However, the company has stopped testing Arbaclofen placarbil for GERD after it failed in a mid-stage study, the results of which was reported earlier in the week.
The upcoming regulatory decision on Horizant is a significant catalyst for XenoPort. Will the drug pass muster with the FDA this time? Stay tuned...
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