Shares of XenoPort Inc. leaped 44 percent on news that its gabapentin prodrug, XP13512, met its endpoints in the first of three Phase III studies in restless legs syndrome (RLS).

The drug demonstrated statistically significant improvements over placebo in both of the trial's co-primary endpoints: the change from baseline for the International RLS (IRLS) rating scale score at the end of the 12-week treatment period and the percentage of patients demonstrating significant improvement on the Clinical Global Impression of Improvement (CGI-I) scale at the end of treatment.

Top-line results from the 222-patients study showed that those treated with 1,200 mg of XP13512, given daily, showed an improvement of -13.2 in IRLS rating score vs. -8.8 in the placebo group. And 76 percent of XP13512-treated patients were reported as "much improved" or "very much improved" on the CGI-I scale compared to 39 percent receiving placebo.

"It's gratifying to see the drug work and to see these kinds of results," XenoPort CEO Ronald Barrett told BioWorld Today, and Wall Street seemed equally pleased. The Palo Alto, Calif.-based firm's stock (NASDAQ:XNPT) gained $12.70 Wednesday to close at $41.56.

The company did not disclose information on the trial's secondary endpoints, which are expected to include onset of efficacy and subjective sleep, pain, mood and quality-of-life assessments. Barrett told investors during a conference call Wednesday morning that those results would be revealed at a future conference or held for publication. In the meantime, XenoPort is finishing up two additional Phase III studies of XP13512 in RLS, including a second 12-week study with the same co-primary endpoints. The other study is assessing the drug's long-term efficacy. Data from both trials are expected later this year, and the company aims to "be in a position to file for approval in the second half of 2008," Barrett said.

Regulatory filing is the responsibility of XenoPort's partner, London-based GlaxoSmithKline plc, which gained worldwide rights to the product in RLS and neuropathic pain, except for certain Asian territories, in February in exchange for up to $640 million in up-front and milestone payments. Barrett said terms of the deal precluded XenoPort from disclosing whether the recent top-line data triggered a milestone payment, though he acknowledged that the agreement included up to $65 million in milestones relating to the "progression of our RLS development program." (See BioWorld Today, Feb. 9, 2007.)

He did, however, say that a $5 million milestone is due from Japanese partner, Tokyo-based Astellas Pharma Inc. That deal, signed in late 2005, gives Astellas rights to develop and commercialize XP13512 in Japan, Korea, the Philippines, Indonesia, Thailand and Taiwan.

XenoPort is the only firm with a late-stage gabapentin drug in development for RLS. Most RLS drugs, including the marketed drugs Requip (GSK) and Mirapexin (Boehringer Ingelheim GmbH), are designed to act on the dopamine receptor, but XP13512's mechanism of action aims to take advantage of the voltage-dependent calcium channel to improve the absorption of gabapentin into the gastrointestinal tract. To date, the company has not conducted any head-to-head studies comparing XP13512 to a dopamine receptor agonist, but an approval of XP13512 would provide a treatment alternative for patients with RLS, a chronic condition characterized by burning, creeping, tugging or tingling sensations in the legs that forces movement to alleviate discomfort and, as a result, often disrupts sleep.

It would be "another treatment option," Barrett said, adding that there "will certainly be some patients who are not able to tolerate [the dopamine receptor agonist] drugs."

Prior the approval of the first RLS drugs - Requip gained the FDA's blessing in May 2005 - the condition frequently went undiagnosed. Even today, though the National Institutes of Health estimates that as many as 12 million people in the U.S. suffer from RLS, only a fraction of those with serious enough symptoms are receiving treatment. The advantage for XenoPort is that GSK and Boehringer already have been "getting the message out to physicians and patients," Barrett said, but there's still "plenty of room for this market to grow."

Safety data from the Phase III study showed no reported serious adverse events in XP13512-treated patients. The most commonly reported adverse events were somnolence, a common side effect of gabapentin, affecting 26.5 percent of patients in the treatment arm vs. 7.4 percent in the placebo arm, though Barrett said most reports came early in the treatment period. Patients on XP13512 also reported dizziness, 19.5 percent vs. 4.6 percent on placebo.

XP13512 is the lead drug candidate to emerge from XenoPort's Transported Prodrug technology, which spawned several other programs in its pipeline. So the positive Phase III data in RLS provided an "important validation of our underlying technology," Barrett said. It also gives a boost to ongoing development of XP13512 in neuropathic pain. As per the companies' February agreement, GSK is expected to take over development in that indication, leaving XenoPort the "financial resources to invest" in other products, analyst Megan Murphy, of Lazard Capital Markets, wrote in a research note.

Murphy, who maintained a "buy" rating, said the GSK deal also gives XenoPort "the luxury to focus" on what "we believe will prove to be an even more compelling asset," referring to XP19986, a prodrug of R-baclofen, which is in Phase II development for gastroesophageal reflux disease and also is being investigated for the treatment of spasticity.

The company also has in its pipeline XP21279, a prodrug of levodopa, for Parkinson's disease and XP20925, a prodrug of the aesthetic propofol.

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