Washington Editor

Phase III has begun for another product for restless legs syndrome (RLS), XenoPort Inc.’s XP13512, a potential entry into that somewhat newly defined market.

"RLS is categorized as a disorder that disrupts sleep," XenoPort CEO Ronald Barrett told BioWorld Today, "but it hasn’t received a lot of attention from pharmaceutical companies to date."

That dynamic has changed, though, partly due to the advent of a standard diagnostic and the acceptance of a validated measure for the disorder about five years ago.

More recently, the market garnered attention when GlaxoSmithKline plc’s Requip (ropinirole) received FDA approval in May for treating RLS, which is characterized by an urge to move one’s legs and frequently accompanied by sensations of burning, creeping, tugging or tingling.

Since then, Barrett noted, "prescriptions for Requip have taken off substantially." Initially indicated for Parkinson’s disease, the drug sold $94 million through September of last year, an increase over the nine-month period in 2004, and fourth-quarter sales in 2005 totaled $75 million. Requip is a dopamine agonist, as is another Parkinson’s disease product being positioned for RLS treatment, Mirapexin (pramipexole, from Boehringer Ingelheim GmbH).

But XP13512 could represent the first new mechanism of action for treating RLS, a condition that impacts 2 percent to 3 percent of the general population severely enough to warrant treatment, Barrett said. He added that Requip’s early RLS sales are "really just the start" of a large market opportunity with room for several players.

Beginning XP13512’s pivotal development triggered a $10 million milestone payment to XenoPort from Astellas Pharma Inc., its partner for Japan and five other Asian countries. XenoPort, of Santa Clara, Calif., had $91.9 million in cash reserves at the end of last year and expects to burn $60 million to $65 million this year as its broad pivotal program for XP13512 gets under way in earnest.

The first trial is Study XP052, a randomized, double-blinded, placebo-controlled trial designed to evaluate the safety and efficacy of a once-daily, 1,200-mg dose of XP13512 for 12 weeks. It is expected to enroll about 200 patients at multiple U.S. sites, with top-line results expected in the first half of next year.

A second randomized trial, Study XP053, will begin later this year to evaluate once-daily doses of 600 mg and 1,200 mg for the same length of time. The lower dose, which was not effective after two weeks in Phase IIb testing, is expected to provide information on the drug’s pharmacokinetic and pharmacodynamic relationship in those patients.

XP13512 is a transported prodrug of gabapentin, a generic compound primarily used to treat neuropathic pain. But Barrett noted that XP13512’s pharmacokinetic profile is different and maintains therapeutic levels of the drug for a longer period of time, from when it is taken in the evening and throughout the night. So its profile in treating patients both awake and asleep "really makes ‘512 unique in its ability to treat these compendia of symptoms in RLS patients," he said.

The studies’ co-primary endpoints track changes from baseline in two measures, the International Restless Legs Syndrome rating scale and the Clinical Global Impression of Improvement at the end of treatment. Secondary endpoints include onset of efficacy and subjective sleep, pain, mood and quality-of-life assessments.

A third clinical trial, Study XP060, also will begin later this year to evaluate XP13512’s long-term efficacy using a placebo-controlled, randomized withdrawal design to evaluate relapse of restless legs syndrome symptoms in XP13512-treated or placebo-treated patients who had previously achieved clinical improvement while taking 1,200 mg of XP13512 for 24 weeks. XenoPort also plans to conduct an open-label safety study to test the treatment for up to a year.

The results of all the studies are intended to meet the International Committee for Harmonization guidelines for safety assessment, and form the safety and efficacy basis to support a new drug application slated for submission in the second half of 2008.

Before then, XenoPort will seek a partnership for territories not covered in its deal with Astellas, of Tokyo. That arrangement, potentially worth more than $85 million, provided a $25 million up-front payment when it was reached at the end of last year.

Barrett said XenoPort would like to maintain co-development and co-commercialization rights in the U.S., in which the company would seek to reach specialists through an internal sales force, while a partner would handle primary care sales and other such efforts abroad. (See BioWorld Today, Dec. 2, 2005.)

Beyond RLS, XenoPort is planning XP13512’s development in neuropathic pain. A Phase II study in postherpetic neuralgia demonstrated the drug’s efficacy over placebo and also showed that its use on top of gabapentin proved superior to gabapentin alone. XP13512’s use in another type of neuropathic pain, painful diabetic neuropathy, also is to be explored.

In addition, the company’s other clinical compound, XP19986, is due to produce Phase IIa results in this half of the year in patients with gastroesophageal reflux disease. That product is a transported prodrug of R-baclofen.

On Tuesday, XenoPort’s shares (NASDAQ:XNPT) gained 53 cents to close at $19.71.