Further Phase III Data May Not Help Approvability Of Arena’s Lorcaserin

The latest Phase III results for Arena Pharmaceuticals’ lorcaserin give little clarity to the regulatory path forward for the drug and add concerns about the safety of the obesity pill.

BLOOM-DM did show a decrease in blood sugar, but also valvulopathy.

Lorcaserin received a “complete response” letter from FDA on Oct. 22 requesting further analysis of the mammary tumor signals that appeared in rats, as well as the final results from the BLOOM-DM trial, a study of lorcaserin in obese patients with type 2 diabetes (Also see "FDA Issues Complete Response Letter for Arena's Lorcaserin" - Pink Sheet, 24 Oct, 2010.).

The San Diego-based biotech needed clearly positive results from the most recent late-stage trial to add to claims of efficacy for the drug, which FDA had said were too “marginal” to warrant approval at this time (Also see "Arena And Vivus Take Divergent Paths To Respond To Obesity Setbacks" - Pink Sheet, 1 Nov, 2010.).

Results of BLOOM-DM, which included about 600 patients randomized to a twice-daily dose of lorcaserin or placebo for 52 weeks, showed that those taking the 10 mg dose had a mean weight loss of 4.5%, compared to 1.5% for those on placebo. The 3% placebo-adjusted weight loss does not meet FDA’s requirements for efficacy and is slightly lower than reported in the previous Phase III studies, BLOOM and BLOSSOM.

“As stated previously, it is harder for patients with diabetes to lose weight,” VP-Clinical Development Christine Anderson said on a Nov. 9 conference call.

At the end of 52 weeks, 37.5% of lorcaserin patients lost 5% of their body weight, while only 16.1% of placebo patients reported 5% weight loss. This meets one of FDA’s criteria for obesity drug efficacy.

“The advisory panel noted that lorcaserin’s efficacy was marginal and these results may do little to alter that perception, especially given the small trial size,” said Leerink Swann analyst Steve Yoo.

While the efficacy data may do little to sway the agency toward an approvability decision, BLOOM-DM also revealed more data for FDA to consider.

Patients in the study had an average HbA1C level, a standard measure of blood sugar, of 8%. Lorcaserin patients experienced a decrease in blood sugar levels of 0.9%, compared to 0.4% for placebo-treated patients.

Yet, this slightly positive news was overshadowed by other issues that cropped up in the trial. Patients receiving lorcaserin were six times more likely to develop heart valve problems, or valvulopathy, at the end of the 52 weeks – 2.9% of lorcaserin-treated patients reported new cases of valvulopathy, compared to 0.5% of placebo patients.

While heart problems have always been a concern with lorcaserin because it targets the same receptors as fenfluramine – a component of the withdrawn diet drug regimen Fen-Phen – FDA did not cite this as one of the problems in the “complete response” letter.

The valvulopathy data reported in the BLOOM-DM study are not considered statistically significant and Arena management made sure to point out on the conference call that the study was not powered to measure the significance of these events.

Signals of valvulopathy were not seen in the BLOOM and BLOSSOM studies, which had many more patients, but were not completely ruled out either. The new signals of valvulopathy are unclear at best, but they do raise concerns that FDA will be unlikely to overlook. Arena did not expound on why the rates of valvulopathy were higher in the BLOOM-DM study.

Beyond these issues, patients on lorcaserin in the most recent study showed higher levels of hypoglycemia, 29.3%, compared to 21.0% for placebo patients. While there were no severe hypoglycemic events, this also raised questions from analysts.

“In light of lorcaserin’s limited efficacy, the concerns over rodent mammary tumors and the new numerical increase in valvulopathy seen in the BLOOM DM trial, we are removing lorcaserin from our valuation of Arena as we now assume the drug is unapprovable,” said Hapoalim Securities analyst Jon LeCroy.

Analysts from BMO Capital were not as pessimistic, but still expressed concerns, saying, “We think a larger study will be needed to evaluate the benefit-risk ratio, particularly in light of additional safety signals including new valvulopathy and hypoglycemia.”

Arena execs said they firmly believe in the approvability of the drug and intend to meet with FDA before the end of the year. The company intends to file an application for approval in Europe next year.

By Lisa LaMotta