Washington Editor

Investors were fired up Thursday after XenoPort Inc. reported top-line Phase IIb results showing that its gabapentin prodrug significantly reduced neuropathic pain associated with post-herpetic neuralgia (PHN) in adults, driving shares up 25.6 percent.

The Santa Clara, Calif.-based biotech's stock (NASDAQ: XNPT) closed at $24.75, a gain of $5.05.

XenoPort is developing gabapentin enacarbil, also known as XP13512 or GSK1838262, under a 2007 partnership with London-based GlaxoSmithKline plc, which holds certain co-development and commercialization rights.

The drug, which GSK plans to sell under the brand name Solzira, is under review at the FDA as a treatment for restless legs syndrome (RLS), with a decision due Nov. 9, the Prescription Drug User Fee Act (PDUFA) action date. (See BioWorld Today, April 14, 2009.)

The FDA has not yet called for an advisory panel meeting on Solzira, a new chemical entity designed to provide dose proportional and sustained exposure of gabapentin by taking advantage of high-capacity transport mechanisms in the gastrointestinal tract.

"The likelihood that we are going to have a panel before our PDUFA date is getting increasingly low," said XenoPort CEO Ronald Barrett.

If the FDA had informed GSK that no panel was required, as the agency has done recently for some other drugs, that would be a confidential communication that the firms would not discuss, he told investors and analysts Thursday during a conference call.

But, Barrett added, had the drugmakers been told that the PDUFA date for Solzira in RLS had been pushed back, "that would be material, and we would disclose it."

However, most analysts predicted that the drug's approval in RLS would be delayed.

Tokyo-based Astellas Pharma Inc. also holds rights to XP13512 in Japan and five Asian countries.

In addition to RLS and PHN pain, XenoPort and its partners also have been developing the drug as a treatment for migraine headaches.

The drug, however, failed in two midstage studies of diabetic neuropathic pain, with Astellas throwing in the towel early on one of those studies last year after an analysis showed it was unlikely the Phase II trial would reach statistical significance. (See BioWorld Today, Nov. 7, 2008, and April 28, 2009.)

While the market is relatively small for PHN pain, a condition that follows an outbreak of herpes zoster or shingles, and affects about 150,000 Americans each year, primarily people older than 50, analysts predicted that the Phase IIb positive results would give XP13512 a foothold in the overall pain market.

In comparison to PHN pain, the diabetic neuropathic pain market, which currently is dominated by Pfizer Inc.'s Lyrica (pregabalin), is 10 times greater, noted Leerink Swann analyst Steve Yoo.

Lyrica, which also is approved for PHN, fibromyalgia and partial onset seizures, posted $2.5 billion in worldwide sales last year, Yoo pointed out.

But Hapoalim Securities analyst Raghuram Selvaraju argued that the PHN pain space "still represents a solid market opportunity for XenoPort and GSK."

"In addition, the solid efficacy seen in this indication and the known efficacy of gabapentin across various forms of pain should, in our view, spur use of XP13512 in neuropathic pain disorders beyond PHN," Selvaraju said.

And regardless of XP13512's past trial failures in diabetic neuropathy, Selvaraju said he remained confident that the drug eventually would be used in that 15 million-patient market.

Meanwhile, he said, the PHN Phase IIb study could serve as one of the two registration quality trials for broadening XP13512's labeling.

In the Phase IIb study, conducted by GSK, 376 patients with PHN with pain for at least three months following healing of herpes zoster skin rash were randomized to receive placebo or 1,200 mg, 2,400 mg or 3,600 mg of XP13512 twice daily, explained David Stamler, XenoPort's chief medical officer.

All dosages of the drug demonstrated statistically significant improvements over placebo in the change from baseline to the end of maintenance treatment in the 24-hour average pain intensity score, the primary endpoint of the 14-week study, Stamler told investors and analysts.

The adjusted p-values for comparison of drug to placebo were 0.013 for the 1,200-mg dose, 0.029 for 2,400 mg and 0.002 for 3,600 mg, he said. The treatment effect for the 3,600-mg dosage group was numerically greater than the other two groups, Stamler said.

XP13512 was generally well tolerated at all dosages in the Phase IIb study, with dizziness and somnolence being the most common adverse events, he noted.

Most notable, Stamler said, were the results in the 1,200-mg dose group, with adverse events similar to that of the placebo group. Most of the adverse events were mild or moderate in intensity, he added.

The study withdrawal rate due to adverse events was no different than that in the placebo group, Stamler said.

However, he noted that one case of gastritis was attributed by a study investigator to the 3,600-mg dosage of XP13512.

While PHN is only a subset of the larger neuropathic pain market, approval in that indication is an "important driver to use in the wider pain setting," said Credit Suisse analyst Michael Aberman.

But, he said, some outstanding questions remain, which include the competitive profile of XP13512, given availability of both cheap generic and branded alternatives, and the implication of the Phase IIb data on the ability to address the larger pain market, including diabetic neuropathic pain.

Barrett said GSK plans to release the full results of the Phase IIb study at future medical conferences.

He noted that the pharma giant is conducting a PHN pain crossover study comparing 3,600 mg/day and 1,200 mg/day of XP13512 in patients who continue to have pain following a run-in period of treatment with 1,800 mg/day of gabapentin.

"We look forward to the results of this trial by year-end and to working with GSK to determine the next steps for the development of 512 in neuropathic pain," Barrett said.

Published  September 18, 2009