Arena Airs More Mixed Data For Late-Stage Obesity Drug Lorcaserin

New Phase III data for Arena Pharmaceuticals' novel obesity compound lorcaserin have disappointed the market once again, even though the company is arguing that technically speaking, they will do the trick in satisfying guidelines for FDA approval.

On Sept. 18, the San Diego-based company said findings from the Behavioral modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial, part of a pivotal program that evaluated 7,000 patients for up to two years, will meet FDA standards - but only on one of two criteria, and only for one of two doses studied.

Arena plans to submit an NDA by year end, working with the FDA during the review process, and simultaneously preparing for the launch and commercialization of lorcaserin.

Lorcaserin is typically cast as a contender in a heated "three-way race" to release positive Phase III results in obesity and secure a partner. The two other commonly mentioned obesity drugs in late-stage development are Vivus's Qnexa and Orexigen's Contrave - both combination pills of generics (¹ 'The Pink Sheet,' April 6, 2009). Vivus and Orexigen have released Phase III results that cheered the market and allowed the companies to raise additional cash, if not reel in a partner just yet.

Stock Market Reacts To Results

At the open of the day of the BLOSSOM release, Arena's stock price was down to $4.39 from $4.90, but by the close, following an investors' call explaining the results, it was up to $5.18. On the next full day of trading, Sept. 21, the price edged up by 4.25 percent to $5.40.

Meanwhile, rival Orexigen apparently got a boost after investors had time to digest the results. From Sept. 18 to Sept. 21, Orexigen's stock price rose from $8.97 by an impressive 15 percent to $10.34.

Having already risen by 80 percent on the heels of its Sept. 8 Phase III release, Vivus' rise was more modest, up by 44 cents, or 3.4 percent to $11.48 on Sept. 21, with a market capitalization of about $800 million. On Sept. 17, Vivus announced plans for a public offering of 9 million shares at $10.50 apiece - equivalent to about $94.5 million.

Despite the market favoritism of the generic combos (because of their less equivocal results), Arena's drug stands out as a novel single agent, the first in a new class of agonists that work on the selective serotonin 2C receptor, which is expressed in the hypothalamus, the part of the brain that regulates control of appetite and metabolism.

President and CEO Jack Lief played up the novelty aspect (and the value of having strong patent protection, which will be a factor for the generic combinations) during a Sept. 18 investors' call detailing results: "Importantly, lorcaserin is protected with strong composition of matter patents that cover 95 percent of the global pharmaceutical market and continue until at least 2023," Lief said.

In the 52-week long BLOSSOM study, the company tested lorcaserin at 10 mg once daily and also 10 mg twice daily.

For FDA approval, the company plans to use an intent-to-treat analysis (rather than the per-protocol analysis), using last observation carried forward to account for dropouts - which the firm asserts is an appropriately rigorous statistical approach. Discontinuation rates in the study for the twice-daily, once-daily and placebo groups were 43 percent, 41 percent and 48 percent, respectively.

Trial Data May Meet One Of Two FDA Standards

The firm's ITT analysis shows 47.2 percent of patients on the 10 mg twice-daily dose lost 5 percent of their weight, compared to 25 percent for placebo. In terms of mean weight loss, patients who took lorcaserin 10 mg twice daily achieved an average weight loss of 5.9 percent of their body weight, compared to 2.8 percent for placebo.

In the ITT analysis, 40.2 percent of the once-daily lorcaserin patients met the 5 percent threshold (again compared to 25 percent for placebo). The mean weight loss for the once-daily group in that analysis was 4.8 percent of their body weight (vs. 2.8 percent for placebo).

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 (² (Also see "Obesity Guidance Should Be More Lenient On Indications, Firms Tell FDA" - Pink Sheet, 18 Jun, 2007.)). The second path's criteria are referred to as "categorical."

Arena argues that the data from the twice-daily group should meet FDA standards. For the categorical standard, the 47.2 percent achieving 5 percent or greater weight loss is "approximately double" the placebo figure, the company points out. However, the twice-daily data do not satisfy the first standard, because placebo-adjusted weight loss amounts to just 3.1 percent, falling short of 5 percent.

Data from the once-daily arm in the ITT analysis falls short on both measures.

BLOSSOM Falls Short Of BLOOM

In the previously released BLOOM study, lorcaserin met the categorical standard - but not the standard that measures results compared to placebo (³ (Also see "Arena Defends Obesity Drug After Phase III BLOOM Wilts" - Pink Sheet, 30 Mar, 2009.)).

J.P. Morgan's Cory Kasimov noted the BLOSSOM results were even worse than BLOOM, which showed 48 percent loss for the active drug group versus 20 percent for placebo in the categorical category. Furthermore, he noted, Qnexa and Contrave cleared the categorical hurdle with much more ease.

"Some may debate whether this even satisfies FDA requirements for approvability. Either way, we're concerned with any obesity drug having to argue semantics from an efficacy standpoint with the FDA," he wrote.

"While this may be viewed by FDA as meeting the guidance requirements, it still remains an open question whether the magnitude of weight loss benefit will be viewed as clinically and commercially significant," Kasimov concluded.

Arena could look to more positive and dramatic findings in certain subsets as a more attractive path forward, particularly given its appealing safety profile. During the Sept. 18 call, executives said they have not yet identified baseline characteristics that could help prospectively pick out the "super-responders."

The firm did point to analysis of patients who completed therapy (per-protocol, not ITT): those taking lorcaserin twice-daily lost an average of 17.0 pounds, or 7.9 percent of their body weight. The quartile of lorcaserin patients with the greatest weight loss shed an average of 35.1 pounds, or 16.3 percent of their body weight.

"We believe that this demonstrates lorcaserin's ability to help a significant number of patients achieve considerable weight loss," said Christy Anderson, vice president of clinical development, during the Sept. 18 investors' call.

Options for weight loss drugs are very limited today and prescribing doctors are looking for a variety of new options. With the National Institutes of Health reporting that more than half of U.S. adults are overweight or obese, there is room for several new treatments, wrote Oppenheimer & Co. analyst Bret Holley in a Sept. 18 note. Despite hurdles for acceptance and coverage, some analysts predict the U.S. market will triple in size from $1.7 billion in 2008 to nearly $6 billion by 2014 (⁴ (Also see "Market Snapshot: Obesity Space Is ‘Not For The Faint of Heart’" - Pink Sheet, 1 Jun, 2009.)).

A Safer "Fen-Phen" On Horizon?

During the call, the firm also noted that lorcaserin could be positioned as a replacement for the commonly used generic phentermine (Teva's Adipex-P ), but analysts see the situation differently.

Lorcaserin has a similar mechanism as fenfluramine, part of the notorious "fen-phen" cocktail, which was pulled from the market in 1997 due to cardiovascular risks. While the single-agent efficacy of lorcaserin is modest, the clean safety profile of the drug suggests it could be combined with other agents, in particular phentermine, Holley wrote.

"Our conversations with physicians have led us to believe that combo use of the drug will be the norm, upon approval," according to Holley. "Given lorcaserin's similar mechanism to fenfluramine, we believe there is the potential for synergy between the drugs, creating a fen-phen-like combination without the risk of valvulopathy."

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