Assistant Managing Editor

The last of three Phase III studies of the gabapentin drug, XP13512, met its endpoint in patients with restless legs syndrome (RLS), and partners XenoPort Inc. and GlaxoSmithKline plc are aiming for a new drug application in the third quarter.

XenoPort CEO Ronald Barrett called the outcome "obviously great news" for the company, which hopes its drug will become the first gabapentin agent available for 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.

While existing drugs, such as dopamine agonists from GSK, marketed as Requip, and Boehringer Ingelheim GmbH, sold as Mirapexin, have proved efficacious, XP13512 has shown impressive efficacy to date, with a better safety profile.

It has "consistently demonstrated efficacy over placebo in multiple Phase II and Phase III trials," Barrett said in a conference call. And the "excellent" safety data "bode well for '512 in today's safety-conscious regulatory and safety environment."

Data from the most recent study testing two doses 1,200 mg or 600 mg - vs. placebo in 325 patients diagnosed with moderate to severe primary RLS showed that treatment with the 1,200-mg dose resulted in statistically significant improvements in the co-primary endpoints, defined as a change from baseline for the International Restless Legs Syndrome rating scale and improvement on the Investigator Clinical Global Impression of Improvement scale at the end of 12 weeks of treatment. Significantly more patients treated with 1,200 mg (78 percent) were reported as "much improved" or "very much improved" on the CGI-I scale compared to placebo (45 percent).

The news was met with little reaction from Wall Street. After a small bump in morning trading, shares of XenoPort (NASDAQ:XNPT) closed at $53.43, down $1.55.

That was hardly surprising given that investors had been expecting further positive data since the first Phase III trial in April. After celebrating that first pivotal success - in which XP13512 demonstrated statically significantly improvements over placebo on both the IRLS and CGI-I scales at 12 weeks - by sending XenoPort shares soaring 44 percent, investors have nodded only in acknowledgment to further Phase III data. (See BioWorld Today, April 26, 2007.)

XenoPort and GSK reported results from the second Phase III trial last month. That 36-week study, designed specifically to assess relapse rates, showed that XP13512 resulted in a statistically significant lower proportion of relapse compared to placebo (9 percent vs. 23 percent). (See BioWorld Today, Jan. 16, 2008.)

In addition to testing the 1,200-mg dose, the final Phase III study evaluated a 600-mg dose, which also showed statistically significant improvements. Overall, however, that lower dose has generated "mixed results," Barrett said, adding that an earlier Phase II trial testing 600 mg of XP13512 over two weeks failed to meet its endpoint.

But the company remains confident that the FDA will accept the 1,200-mg dose, and in response to an analyst's questions, Barrett said he believes it's unlikely that the agency will ask for an additional trial testing 600 mg of drug vs. placebo.

While the need for a minimum effective dose is important for products with dubious safety profiles, Barrett said, "that's certainly not the case here."

During the 12-week treatment period, patients reported dizziness and somnolence as the most common adverse events, and those were defined as mild to moderate in intensity. Withdrawals due to adverse events were 7 percent in the 1,200-mg group, 6 percent in the 600-mg group and 6 percent in the placebo group.

There were three serious adverse events in the study, but the company said none of those was considered treatment-related.

Those promising safety data also supported "broad development of '512 in multiple indications," Barrett said.

Partner GSK has said it intends to explore the drug in other central nervous system disorders, including the start of Phase II trials this year in postherpetic neuralgia and painful diabetic neuropathy. The London-based pharma firm also said it plans to meet with the FDA about starting Phase II studies in migraine prophylaxis. In addition, plans are in the works to initiate two polysomnography studies of XP13512 in RLS patients that, pending positive results, could expand the product's label in that indication.

XenoPort partnered with GSK a year ago in a $640 million deal that gives GSK rights to development and market XP13512 worldwide, except for certain Asian territories, where the drug is partnered with Tokyo-based Astellas Pharma Inc. (See BioWorld Today, Feb. 9, 2007.)