FDA requests withdrawal of lorcaserin (Belviq) over a cancer signal

The U.S. Food and Drug Administration announced on February 13, 2020 that it had asked Eisai Inc. to voluntarily withdraw the weight-loss drug Belviq and Belviq XR (lorcaserin) from the U.S. market because a required safety trial showed an increased occurrence of cancer ^[1]. Eisai said the same day that it would withdraw the products and discontinue sales, while stating that its own reading of the data differs from the agency's ^[2].

What the trial found

When FDA approved lorcaserin in 2012, it required the manufacturer to run a randomized, double-blind, placebo-controlled trial to evaluate cardiovascular risk ^[1]. That trial, CAMELLIA-TIMI 61, enrolled about 12,000 overweight or obese men and women and ran from January 2014 to June 2018 across the U.S., Canada, Mexico, the Bahamas, Europe, South America, Australia and New Zealand ^[1]. Participants had to have established cardiovascular disease, or be men at least 50 or women at least 55 with type 2 diabetes plus another cardiovascular risk factor ^[1]. They were assigned to lorcaserin 10 mg twice daily or placebo, and median follow-up was 3 years and 3 months ^[1].

The drug passed its main cardiovascular test. There was no meaningful difference between lorcaserin and placebo in major adverse cardiovascular events, with a hazard ratio of 1.005 (95% CI 0.842 to 1.198), meeting the noninferiority margin of 1.4 ^[1]. Eisai called it the largest cardiovascular outcome trial conducted to date for a weight-loss medication, run at more than 400 sites in eight countries, and said lorcaserin produced sustained weight loss without a higher rate of major cardiovascular events than placebo ^[2].

The problem showed up elsewhere. During the trial, 462 patients on lorcaserin (7.7 percent) were diagnosed with 520 primary cancers, compared with 423 patients on placebo (7.1 percent) diagnosed with 470 cancers ^[1]. FDA described that as roughly one additional cancer per 470 patients treated for one year ^[1]. Imbalances in pancreatic, colorectal and lung cancers contributed to the overall difference, and while there was no apparent difference in the first months of treatment, the gap widened with longer time on the drug ^[1].

FDA said it acted because it believes the risks of lorcaserin outweigh its benefits ^[1]. Eisai said its assessment is that Belviq and Belviq XR continue to have a positive benefit-risk profile in the population they were approved for, but that it agreed to withdraw at the agency's request and respects the decision ^[2]. The company noted the drug had been evaluated in more than 30 clinical trials involving over 22,000 patients over 15 years ^[2].

Why it matters for patients

Belviq was one of a small number of prescription drugs approved for chronic weight management in adults with a BMI of 30 or higher, or 27 or higher with a weight-related condition such as high blood pressure, high cholesterol or type 2 diabetes ^[2][3]. Its removal narrows that list, and FDA advised patients to stop taking lorcaserin and to talk with their health care professionals about alternative weight-loss medicines and weight management programs ^[1].

FDA said it is not recommending special cancer screening for people who took lorcaserin, and that standard screening recommendations apply the same way they would for anyone else ^[1]. The agency also gave instructions for disposing of unused pills, either at a drug take-back location or in household trash after mixing them with an unappealing substance such as dirt, cat litter or used coffee grounds ^[1]. Patients and providers with questions were directed to Eisai Medical Information at 1-888-274-2378 ^[2].

The episode also shows why FDA requires long-term outcome trials after approval for obesity drugs. The study was designed to answer a heart-safety question, and it did, but the cancer imbalance it turned up was enough to end the drug's time on the market ^[1][2].

What happens next

FDA first alerted the public to a possible cancer risk with lorcaserin on January 14, 2020, based on a preliminary analysis, then completed its review and requested withdrawal on February 13, 2020 ^[1][3].

In a notice published March 4, 2021, FDA formally determined that Belviq 10 mg tablets and Belviq XR 20 mg extended-release tablets were withdrawn from sale for reasons of safety or effectiveness, meaning the agency will not accept or approve generic applications for lorcaserin ^[3]. FDA said the cancer imbalance persisted across multiple analyses, was corroborated by animal data, could not be addressed adequately through labeling, and that the needed safety questions are unlikely to be studied ethically in a new trial ^[3]. The exact effective date of the approval withdrawal is not stated in these sources.