West Coast Editor
Depomed Inc. noted a strangely high and persistent placebo effect in the Phase III blowup of its postherpetic neuralgia (PHN) pain tablet Gabapentin GR, but the explanation failed to appease investors, and Wall Street shaved 59.4 percent off the value of the stock (NASDAQ:DEPO), which closed Tuesday at $2, down $2.93.
"It's only been 22 hours since we [learned of the results], and we're in the process of figuring out what we're going to do," said Mohamad Tabrizi, senior director of corporate communications for Menlo Park, Calif.-based Depomed. Institutional investors, he said, suggested another trial, differently designed, but the data must be sifted more.
"The difference between the placebo and the active arms was just outside of where we think it would be appropriate to submit to the agency for review, but it was close," Tabrizi told BioWorld Today.
Top-line numbers from the 10-week, 407-patient study showed Gabapentin GR, which targets GABA receptors in the brain, hit statistical significance in daily pain scores in the first six weeks in the once-daily treatment arm of the trial, and in first five weeks for the twice-daily treatment arm. In the end, though, the mean reductions in average scores from baseline were 1.83 (in the once-daily arm), 1.72 (twice daily) and 1.43 (placebo).
"In the last four weeks of the trial, patients on placebo started reporting improved pain scores," Tabrizi said, which had happened neither in earlier trials with Gabapentin GR nor with trials testing New York-based Pfizer Inc.'s Neurontin, of which Depomed's product is an extended-release version.
"That's a problem with pain trials in general," he said. "You've got patients reporting and physicians reporting, and it's subjective."
The results are especially puzzling insofar as the designated rescue medication in Depomed's study was Tylenol (acetaminophen, Johnson & Johnson), as guided by the FDA, compared to the Pfizer trials, which allowed Tylenol or Vicodin (acetaminophen with hydrocodone, Abbott). Given the milder rescue drug authorized in the Depomed trial, investigators reasonably might have expected a larger separation between the placebo and active arms, but that didn't happen.
Another issue with pain trials, has to do with keeping patients on placebo for as long as 10 weeks, Tabrizi acknowledged, and PHN is a particularly unpleasant condition. "If I were in the trial and my pain wasn't any better at week six or seven, I don't know how much I would stick with it," he said, noting that "if [trial participants] didn't have Vicodin available, they might run out and try something else that's even better," though patients were directed to report any medications used.
Depomed had better news in secondary endpoints. "Dizziness, sleepiness, somnolence - we hit all of those," Tabrizi said. Specifically, the secondary endpoints were sleep interference, Clinical Global Impression of Change (CGIC, a scale used by doctors) and Patient Global Impression of Change (PGIC, used by patients).
Sleep interference scores fell 2.01 points with Gabapentin GR compared to -1.39 with placebo (p=0.014). Physicians said 48 percent of patients taking the drug were "very much improved" or "much improved" compared to 27.1 percent of placebo patients (p<0.001), as measured by the CGIC. Similar results were observed for the PGIC in the once-daily and placebo arms (p=0.009).
PHN is caused by a shingles attack, and comes as a result of nerve damage in the aftermath. Bigger money with Gabapentin GR, though, might be in menopausal hot flashes. The rights to a patent covering the compound for that indication is sublicensed from PharmaNova Inc., of Rochester, N.Y.
Last month, Depomed started a 13-week trial in 108 patients at about 10 sites in the U.S. and Canada.
Could the results with PHN mean bad news for the trial with hot flashes? "We don't think so, not at all," Tabrizi said. "With hot flashes, you either have them or you don't. It's not like continuous pain that you can watch a movie or have a glass of wine and forget about for a while."
In the U.S., Depomed already markets Glumetza, the once-daily form of metformin, for adults with Type II diabetes, with Bristol, Tenn.-based King Pharmaceuticals Inc., which started knocking on Glumetza customers' doors weekly starting in March, and sales jumped 49 percent over February, after growing only 12 percent from January to February. King reported a 25 percent hike in prescribing physicians, and planned to persist in the sales push through August.
In the most recently reported week, Tabrizi said, prescriptions totaled more than 3,500, of which slightly less than 2,000 were new. "It's doing quite well," he said. "We're still in active launch promotion mode."
In April, a prior-approval supplement was filed with the FDA, asking clearance for the 1,000-mg tablet of Glumetza. The firm expects a decision before the end of the third quarter.
Biovail Corp., of Toronto, was formulating the tablet when Depomed acquired rights to Glumetza in late 2005, and the supplement is backed by data showing the 1,000-mg tablet works as well as two 500-mg tablets given under single-dose fed conditions.
Depomed also has ProQuin XR (ciprofloxacin), the once-daily therapy for urinary tract infections, once marketed by Esprit Pharma Inc., of East Brunswick, N.J., in the U.S., though the companies have had an uneasy relationship. Esprit paid Depomed a $10 million license fee late last year, and Depomed took back its notice of breach and demand for arbitration related to their deal.
The agreement also gave Depomed co-promotion rights. Earlier this month, though, Depomed terminated the pact. Esprit paid Depomed $17.5 million altogether - including a $5 million termination fee and $2.5 million in royalties from January to June - and will return ownership of the Proquin new drug application to Depomed. (See BioWorld Today, July 29, 2005.)
"Over two and a half years, they paid us $62.5 million, and we got the product back," Tabrizi said. "We can't complain." ProQuin XR "still has life in it," he added, and Depomed is "in very late stages of discussion" with a new partner.
Also this summer, Phase IIa data are expected with Depomed's compound for nocturnal acid breakthrough in gastroesophageal reflux disease.