The Food and Drug Administration issued a complete response letter to Arena Pharmaceuticals for its obesity drug Lorqess (lorcaserin) on Oct. 22, a move most analysts thought was inevitable after an advisory committee voted 9-5 against approval in September.
In a press release, Arena said that the FDA rejected the new drug application for lorcaserin for both clinical and nonclinical reasons. Complete response letters are not made public by the agency and only the company can reveal contents at its discretion.
According to Arena, the FDA is asking the company to provide “a detailed accounting 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” and to identify an independent pathologist to reassess the data concerning the tumors in female rats and provide “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.”
The letter stated that the “weight loss efficacy of lorcaserin in overweight and obese individuals without type 2 diabetes is marginal” and requested that the company submit the data from the Behavioral Modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus (BLOOM-DM) trial, a study of the effects of lorcaserin on about 600 patients with type 2 diabetes.
The FDA has indicated in the past and did so again in the complete response letter that positive data from this trial would help support claims of efficacy for lorcaserin, but it added in the letter that additional studies may be needed to provide a “more robust assessment of lorcaserin’s benefit-risk profile.” Arena said that the BLOOM-DM study is complete and that data are expected within the next few weeks.
In addition to the agency’s notes about safety and efficacy, the FDA said that lorcaserin would be considered a Schedule IV substance under the Controlled Substance Act.
“While the complete response letter provides us with recommendations from the agency, we intend to meet with the FDA to obtain further clarity on the approval path and timeline. We will work with the agency to address the issues with our NDA as quickly as possible,” Jack Lief, Arena’s president and chief executive officer, said in a statement.
While the letter from the FDA provides Arena with a clearer road map to approval, it still presents many challenges for the company. At the very soonest, the company may be able to resubmit its application for the drug before the end of the year – placing the next approval decision in summer 2011.
Advisory Committee’s Chief Concerns: Marginal Efficacy, Neoplasms in Rats
The complete response letter reflects the Endocrinologic and Metabolics Advisory Committee’ negative recommendation on Sept. 16. The panel expressed concerns not only about safety, but also efficacy. Despite lorcaserin’s targeting the same appetite-suppressing serotonin receptor as Wyeth’s Fen-Phen – which was plagued by heart issues before it was pulled off the market – Arena took special care to make sure lorcaserin targeted a more selective subtype of the receptor, thus avoiding heart concerns with the drug.
Even though Arena took care to try to develop a drug with a clean safety profile, neoplasms found in rats during animal studies of the drug became a major sticking point when the committee considered how the drug’s use would translate in humans. The issue had come up prior to the committee meeting, but the company and others seemed to disregard it as an insignificant concern.
Beyond the safety concerns, several panel members expressed their unease about the “slim margin” of efficacy. The FDA’s demand for further examination of lorcaserin isn’t surprising, given the advisory committee was also worried that the population represented in the clinical trials studying lorcaserin was not indicative of real-world circumstances – patients with comorbidities such as heart disease and diabetes were not included in the trials.
Noting that one phase III study had 42 exclusionary criteria and a second had 35, Sanjay Kaul, a cardiologist at Cedar Sinai Medical Center in Los Angeles, contended that “we have no idea what the benefit/risk is” in the population that will use Lorqess.
“If you use such a selective patient population where you filter out patients that are less likely to respond in terms of weight loss, and are less likely to experience an adverse outcome, you overestimate efficacy and you underestimate risk,” he concluded.
Since the committee meeting, Arena has been hit with investor lawsuits for failing to fully disclose all information about animal trials related to the drug.