FDA issues complete response letter for lorcaserin

FDA has issued a complete response letter (CRL) for lorcaserin’s (Arena and Eisai) New Drug Application. Lorcaserin is intended for weight management, including weight loss and maintenance of weight loss, in some patients who are obese (≥30) or patients who are overweight (BMI≥27) and have at least 1 weight-related co-morbid condition.

The CRL included the following requests related to the nonclinical issues:

• Provide a detailed accounting of all slides prepared from female rats that contributed to mammary-tumor incidence data in each update to FDA and to the final study report;

• In consultation with FDA, identify an independent pathologist or group of pathologists to readjudicate all mammary and lung tissues (neoplastic and nonneoplastic lesions) from all female rats;
• Demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is reasonably irrelevant to human risk assessment;

• Provide additional data/information regarding the distribution of lorcaserin to the central nervous system in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.

With respect to the clinical reasons, FDA stated in the CRL that the weight-loss efficacy of lorcaserin in overweight and obese individuals without type 2 diabetes is marginal and recommended that Arena submit the final study report of the BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) trial. FDA also stated in the letter that in the event that evidence cannot be provided to alleviate concern regarding clinical relevance of the tumor findings in rats, additional clinical studies may be required to obtain a more robust assessment of lorcaserin’s benefit-risk profile.

The BLOOM-DM trial evaluated lorcaserin versus placebo over a 1-year treatment period in obese and overweight patients with type 2 diabetes mellitus. The trial is complete, and Arena expects to announce top-line results in the next few weeks and to have a completed study report by the end of the year.

Additionally, FDA stated in the CRL that based on its review of the materials submitted in the NDA, it would recommend placement of lorcaserin in Schedule IV of the Controlled Substance Act. The CRL provided the opportunity to complete preclinical studies that may lead to a different recommendation.

“Given the epidemic of obesity and the limited array of treatment options available to providers and patients, this decision regarding lorcaserin is obviously disappointing,” said David Calabrese, clinical editor of Formulary and chief clinical officer, MedMetrics Health Partners, Worcester, Mass.

“At the same time however, FDA’s job is to carefully synthesize and appraise all aspects of safety and efficacy in its deliberations, and in this case the risk-benefit profile of lorcaserin was deemed unacceptable by FDA standards,” added Calabrese. “Following on the heels of FDA’s rejection of Qnexa in July, this decision clearly sends a strong message to manufacturers and the healthcare community that its tolerance for safety risk in a market the size of the US obesity population is fairly limited.”