As many expected, FDA followed its advisory panel’s suggestions and has asked for additional clinical and nonclinical data before approving Arena Pharmaceuticals and Eisai’s weight-management therapy, lorcaserin. The NDA covered use of the drug for weight loss and maintenance of weight loss in patients who are obese or overweight and have at least one weight-related co-morbid condition.
While the agency does not seem to require more clinical studies, it is asking for data to clarify concerns over studies in rats showing that the drug, at higher doses than would be used in humans, was linked to cancer. FDA also pointed to efficacy issues in patients other than those with type 2 diabetes.
The nonclinical issues identified in the complete response letter (CRL) included diagnostic uncertainty in the classification of mammary masses in female rats, unresolved exposure-response relationship for lorcaserin-emergent mammary adenocarcinoma, as well as unidentified mode of action and unclear safety margin for lorcaserin-emergent brain astrocytoma.
The companies were asked to do the following: provide a detailed account of all slides prepared from female rats that contributed to mammary tumor incidence data in each update to the FDA and to the final study report; in consultation with the FDA, identify an independent pathologist or group of pathologists to re-adjudicate 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; and provide additional data/information regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.
With respect to the clinical reasons, the 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 trial. The FDA also stated that in the event 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-to-risk profile.
The BLOOM-DM trial evaluated lorcaserin versus placebo over a one-year treatment period in obese and overweight patients with type 2 diabetes mellitus. The trial is complete, and Arena expects to announce results in the next few weeks and to have a completed study report by the end of the year.
Lorcaserin’s NDA included 18 clinical trials covering 8,576 patients. The pivotal Phase III trial program, BLOOM and BLOSSOM, evaluated nearly 7,200 patients treated for up to two years. The trials showed an average weight loss among those taking the drug of 5.8% compared with 2.5% among those taking a placebo.
Additionally in the CRL, FDA stated that it would recommend placement of lorcaserin in Schedule IV of the Controlled Substance Act based on its review of the materials submitted in the NDA. The CRL provided the opportunity to complete preclinical studies that may lead to a different recommendation.
The decision comes as no surprise as about a month ago FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9 to 5 against approval of lorcaserin. In fact, it marks the agency’s overall trepidation with sanctioning obesity therapies. Earlier this month the agency requested that Abbott remove its obesity medication Meridia from the market after a clinical trial raised concerns about cardiovascular risk.
Also, in July the Endocrinologic and Metabolic Drugs Advisory Committee recommended against approval of Vivus Pharmaceuticals’ Qnexa because of the possibility of psychiatric side effects and other potential safety concerns.
That leaves Orexigen’s Contrave, and the advisory committee will vote on its approval in December. In the meantime, Arena shareholders have been lobbying Congress to urge FDA to give lorcaserin the go-ahead.