Arena is playing up the robust safety profile and approvability of its obesity drug lorcaserin after unveiling lackluster efficacy results from the Phase III BLOOM trial.

The 3,100-patient strong BLOOM study is one of two pivotal, double-blind trials for the new molecular entity from San Diego, Calif.-based Arena in the highly competitive obesity space. Results from the other trial - BLOSSOM - are due in the third quarter, and Phase III data from rival drugs will also be rolled out this year.

Arena reported March 30 that a 10 mg dose or lorcaserin proved safe and effective in the BLOOM study. The trial hit all co-primary endpoints in terms of the proportion of patients achieving 5 percent or greater weight loss, difference in mean weight loss compared to placebo, and the proportion of patients achieving 10 percent or greater weight loss.

According to FDA guidance, obesity products are deemed effective if they meet one of two standards: 1) the difference in mean weight loss between the active product and placebo treated groups is at least 5 percent and the difference is statistically significant; or 2) the proportion of subjects who lose at least 5 percent of baseline body weight in the active product group is at least 35 percent and also double the proportion crossing that weight loss threshold in the placebo treated group (¹ Also see "Obesity Guidance Should Be More Lenient On Indications, Firms Tell FDA" - Pink Sheet, 18 June, 2007. p. 5). The second path is referred to as "categorical" criteria.

Results stack up to FDA standard but still disappoint

In the BLOOM study, 47.5 percent of those taking lorcaserin lost 5 percent or more of their body weight, compared to just 20.3 percent in the placebo arm. Those who completed 52 weeks of treatment lost an average of 8.2 percent of body weight, or 17.9 pounds, compared to 3.4 percent, or 7.3 pounds, in the placebo group. Also, 22.6 percent of patients on lorcaserin lost at least 10 percent of body weight, compared to 7.7 percent on placebo.

"This satisfies the categorical criteria in the draft guidance. So we are very happy with the data," said Dominic Behan, chief scientific officer and co-founder, in an interview.

The drug proved to be well-tolerated and echocardiograms showed that it did not cause valvulopathy for the two-year treatment period.

But what really caught the eye of investors was the disappointing placebo-adjusted weight loss at one year of only 3.6 percent (5.8 percent for lorcaserin vs. 2.2 percent for placebo).

The company's CEO has been publicly predicting placebo-adjusted weight loss of from 7 percent to 10 percent, commented J.P. Morgan analyst Cory Kasimov in a March 30 note.

"While the results may technically satisfy the FDA requirements for approvability, we consider the weight loss benefits to be underwhelming," Kasimov wrote. "Moreover, management's highly bullish public stance ahead of the data may have also triggered additional disappointment in the actual results."

Reaching at least one of the criteria for FDA weight loss is a "small victory for Arena," wrote Lazard analyst Matthew Osborne in a March 30 note. But the 3.6 percent of placebo-subtracted weight loss for lorcaserin pales in comparison to combination regimens in development from other companies, he observed.

Earlier this year, Orexigen released results from one of four Phase III trials for the combination drug Contrave (32 mg naltrexone SR/360 mg bupropion SR) ("² Also see "Orexigen Starts Partnership Talks On Obesity Drug Contrave" - Pink Sheet, 13 January, 2009.). Obese patients treated with Contrave lost an average of 20.3 pounds to 25 pounds, or 9.3 percent to 11.5 percent of their baseline body weight, versus 11 pounds to 16 pounds, or 5.1 percent to 7.3 percent of baseline body weight, in the placebo group. Furthermore, 41.5 percent of patients on Contrave lost 10 percent or more of their body weight, versus 20 percent of those on placebo.

The trial met all of its endpoints and would satisfy the categorical criteria established by FDA. But the relative difference in absolute weight loss between the Contrave and placebo groups was only 4.2 percent and so the results would not satisfy FDA's first efficacy test. Orexigen noted at the time that it applied a very intense diet and exercise behavior modification program in this trial, which boosted placebo response rates, and signaled that the other trials in its Phase III program might show better results.

Vivus's combination drug Qnexa (phentermine and topiramate) performed well in the Phase III EQUATE study, achieving a 9.2 percent weight loss. However, that figure doesn't satisfy FDA guidance that combination drugs should offer double the benefits seen with the single agents (³ Also see "Vivus’ Qnexa Combo For Obesity Needs FDA ‘Persuasion’ To Take First-Line In Diabetes" - Pink Sheet, 15 December, 2008.). The Phase III Qnexa program also includes the EQUIP and CONQUER trials, with results due mid-year.

CNS profile proves clean

Meanwhile, Arena is standing by the results for its single agent, noting its novel mechanism of action and the unmet medical need.

"A very significant proportion of people - almost 50 percent - respond with a medically meaningful weight loss. That's a big number when you consider that two-thirds of the U.S. population [is] overweight or obese," Behan said. "So we think we have robust efficacy data applicable to a large proportion of the population suffering from obesity."

Arena argues that patients are more interested in weight loss results and a drug's side effect profile than a placebo-adjusted weight loss figure. Drop-out rates in BLOOM were similar for placebo and treatment groups, in the range of from 6 percent to 7 percent.

In the first year of the study, the most commonly reported adverse events were headache, upper respiratory tract infection, nasopharyngitis, sinusitis and nausea. The most common side effects reported in the second year, were upper respiratory tract infection, nasopharyngitis, sinusitis and arthalgia.

The drug's CNS effect profile also looked clean. Adverse events of depression, anxiety and suicidal ideation were uncommon and reported at a similar rate in the drug and placebo arms. No seizures were reported.

FDA has called upon Arena to rule out a 1.5-fold of greater risk of valvulopathy with 80 percent power. BLOOM showed no link to valve disease in patients taking lorcaserin continuously for two years.

Assuming similar results in BLOSSOM, "the integrated data set from the two trials will be more than sufficiently large to meet this requirement," Kasimov wrote.

Behan says the company expects BLOSSOM results will be consistent with BLOOM.

- Emily Hayes (e.hayes@elsevier.com)

Arena Defends Obesity Drug After Phase III BLOOM Wilts

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