West Coast Editor

Favorable top-line data with its 28-day, Phase II trial of APD356, an oral drug for obesity, boosted Arena Pharmaceuticals Inc.'s stock, and the company has plans in the works for a longer study.

"We have not yet completed all analyses, and of course some follow-up [echocardiograms] have not been conducted," said Jack Lief, president and CEO of San Diego-based Arena.

Still, Wall Street was pleased. Arena's shares (NASDAQ:ARNA) ended Wednesday at $6.49, up 52 cents, or 8.7 percent, after trading as high as $7.49.

"It's good to see positive data being rewarded again," said Jason Napodano, senior biotechnology analyst with Zack's Independent Research in Chicago, adding that Arena was "punished with the rest of small biotech the last two or three months on negative sentiment."

At the same time, he called the APD356 data too small and too early to provide solid evidence, and maintained a "hold" rating on the stock.

"We won't see an NDA filing on this thing for probably the next three and a half years," Napodano said, questioning whether Arena's good results will hold up in a longer trial.

Over the 28-day study period, patients taking the 15-mg dose of APD356, a selective agonist of 5-HT2C serotonin receptors, showed a highly statistically significant (p=0.0002) average weight loss of 2.9 pounds, as compared to 0.7 pounds for the placebo group. The drug was generally well tolerated at that dose, as well as 1 mg and 5 mg.

The trial enrolled 352 obese patients ranging in weight from 158 pounds to 468 pounds, and the primary endpoint was weight loss.

"We chose the dose that we felt was going to be well tolerated," Lief said in a conference call. "This is our first weight-loss study, and obviously we chose a dose that created a good weight loss. There are other doses that are possible and we're evaluating those."

In an earlier, 14-day safety trial, the dose went as high as 20 mg, and company officials said the "sweet spot" for dosing could be in the 10-mg to 15-mg range.

Arena is putting together a Phase IIb trial that will dose patients over a three-month period, to finish in the latter part of this year. If results are favorable, additional studies - including a 12-month pivotal Phase III trial - would begin next year, with a new drug application targeted for 2009.

Company officials acknowledged the headache and nausea side effects that developed in some patients. At the 15-mg dose, 20.7 percent reported headaches, compared to 14 percent on placebo. The numbers for nausea were 6.9 percent at that dose vs. 3.5 percent on placebo.

"There were a few severe headaches," said William Shanahan, Arena's chief medical officer, but most were moderate or mild, and the worst ones seemed to happen at the start of the trial without recurring.

"We're just getting into all of the data," he said.

Laboratory study by various groups with 5-HT2C agonists suggests the approach might be useful in various indications, but the obesity market has proved especially alluring. In the fall of 2002, Stockholm, Sweden-based Biovitrum AB inked a potential $150 million deal with GlaxoSmithKline plc, of London, to develop the former's 5-HT2C receptor agonists for that indication. (See BioWorld Today, Oct. 24, 2002.)

When last heard from, Biovitrum and GSK had decided to stop a Phase IIb trial with the appetite suppressor BVT933 in order to focus instead on more highly selective compounds of the same class. That was in May 2003, although in November of that year the firms offered data from work with the compound at the Society for Neuroscience's annual meeting in New Orleans.

"Biovitrum is no longer working on this, as we understand it [from the company]," Lief told BioWorld Today. "Glaxo doesn't tell us what they're doing." Lief added that there "might be some preclinical activity" by other firms, but nothing is known to be as far along as Arena's drug.

Napodano noted the Arena drug takes aim at "a similar target to Wyeth's fen-phen, at least the fen' part, so it's a pretty well studied receptor." Madison, N.J.-based Wyeth's fen-phen for obesity was pulled off the market in 1997 because of cardiovascular side effects, but Arena believes APD356 will not cause those.

"Everybody got scared away from obesity," but the market size is drawing them back, he said.

Probably the next major approval news in the indication will come from an overseas firm. Sanofi-Synthelabo SA, of Paris (now Sanofi-Aventis Group), developed the CB1 receptor antagonist Acomplia (rimonabant) for obesity, which awaits FDA approval.

Meanwhile, Arena needs to prove more with APD356, Napodano told BioWorld Today, citing the headaches and nausea in trial patients as his biggest concerns.

"We all have headaches and feel nauseated every now and then, and the last thing you're going to do is eat," he said. Trial subjects were allowed to continue their ordinary dietary habits, although they had to abstain from alcohol.

"Two pounds [of weight loss] is good over 28 days, but who knows how that will play out," Napodano said. "You need to demonstrate five to 10 pounds over an extended period for it to be considered worthwhile."