Inching closer to a market that, until recently, was virtually untapped, XenoPort Inc. proved in a Phase IIb trial that its restless leg syndrome candidate, XP13512, was significantly better than placebo in relieving patient symptoms.
The Santa Clara, Calif.-based company now plans to design its first Phase III trial, to begin in the first half of 2006. If all goes well, the company expects to file a new drug application based on two pivotal trials, leading to a potential launch in 2009.
Restless leg syndrome (RLS) is a neurological disorder in which patients feel urges - a burning, creeping, tugging or tingling - in their legs, forcing them to move them in order to alleviate the discomfort. The urges are at their worst during inactivity and they often disrupt sleep.
"This was a disease that was very frustrating for patients because there wasn't an official diagnosis up until recently," said Ronald Barrett, CEO of XenoPort.
With no official diagnosis, few pharmaceutical or biotech companies worked to find a treatment because of the difficulties in defining the patient population. There also were no established ways of measuring the efficacy of a drug used to treat the disorder.
But that changed in May, when London-based GlaxoSmithKline plc received FDA approval of Requip, currently the only available treatment for patients with moderate to severe primary RLS.
"One of the positive things about the approval of Requip is the fact that it sets a blueprint for how to get approval from the FDA for restless leg syndrome," Barrett told BioWorld Today.
In addition to RLS, Requip is indicated to treat Parkinson's disease. While GSK conducted three Phase III RLS trials - two 12-week efficacy studies, and a longer-term relapse prevention study - XenoPort could get approval of XP13512 with only two trials. The company is talking with the FDA to map out a plan for registration.
In January, results from a Phase IIa trial of 38 patients showed a statistical improvement in objective sleep measures with XP13512. In that trial, patients received an 1,800-mg dose each day, one-third taken at 5 p.m. and two-thirds at one hour before bed. However, the Phase IIb trial has established efficacy of a lower, more convenient dose of 1,200 mg taken once a day at an evening meal.
"We believe that that will be more convenient for patients," Barrett said.
The Phase IIb trial enrolled 95 patients diagnosed with RLS. The patients were randomized to receive either placebo, 600 mg of XP13512 or 1,200 mg of the drug. While the higher dosage demonstrated significant benefits over a 14-day period (p<0.0001) as measured by the International Restless Legs Scale (IRLS) score, the lower 600-mg dosage showed little difference from placebo.
A statistically significant improvement in the IRLS score also was seen after one week of 1,200 mg of treatment, and XP13512 reached statistical significance based on both patient and investigator clinical global impression (CGI) of change scales (both p<0.0001). According to investigator CGI, about 81 percent of patients receiving 1,200 mg of the drug were "much improved" or "very much improved," as compared to 48 percent of those receiving placebo.
The treatment also resulted in statistically significant improvements in overall sleep quality, the number of awakenings per night, and the number of hours awake per night, due to RLS symptoms. And it demonstrated a significant reduction in the severity of symptoms in the evening. The drug was generally well tolerated with no serious adverse events. The most common side effects were somnolence and dizziness, which previously were seen in patients receiving gabapentin - the active ingredient in XP13512.
While potential competitors target a dysfunction involving dopamine, XP13512 is a transported prodrug of gabapentin.
"This is not a terribly crowded field at this point," Barrett said, "and '512 is the only compound that works by this non-dopamine mechanism that I'm aware of."
Other companies working in the RLS field include Newron Pharmaceuticals SpA, of Milan, Italy; Schwarz Pharma AG, of Monheim, Germany; and Boehringer Ingelheim, of Ingelheim, Germany. Schwarz Pharma licensed its dopamine agonist, rotigotine, from Aderis Pharmaceuticals Inc., of Hopkinton, Mass. Phase III trials of rotigotine were slated to begin this year. Newron's safinamide, an inhibitor of monoamine oxidase, which is used in conjunction with a dopamine agonist, is in Phase II testing. And Boehringer Ingelheim recently completed a 345-patient trial of its dopamine agonist pramipexole.
Barrett said the potential advantages of XP13512 relate to overall efficacy, improved tolerability and side effects. Gapapentin is sold as a generic drug and was first marketed as Neurontin in 1993 by New York-based Pfizer Inc. XP13512 uses high-capacity transport mechanisms so the drug is well absorbed in the small and large intestines and converted to gabapentin. Phase I data have shown that XP13512 produced higher levels of gabapentin in the blood for a longer period of time when compared with Neurontin.
While nobody knows for sure how many people suffer from RLS, experts believe that 10 percent of the general population has symptoms. About 2 percent to 3 percent of those people experience a lower quality of life as a result. With Requip new to the RLS market, it should shed light on the sales potential of a product such as XP13512.
"Up until recently, there were no approved drugs," Barrett said.
XenoPort priced its $53 million initial public offering in June. (See BioWorld Today, June 3, 2005.)
Its stock (NASDAQ:XNPT) rose 43 cents Tuesday to close at $12.83.