First weight loss drug to be approved by the FDA in thirteen years….
It did not make the first go around with the US Food and Drug Administration, but the second trip appears to have done the trick.
This week, the agency approved lorcaserin (to be called Belviq, Arena Pharmaceuticals, San Diego, CA) for the treatment of obesity. The approval follows an overwhelming vote by the Endocrinologic and Metabolic Drugs Advisory Committee in favor of lorcaserin as an adjunct to diet and exercise in patients with a body-mass index (BMI) >30. For patients with weight-related comorbidities, the drug is indicated for individuals with a BMI >27.
In October 2010, the FDA rejected lorcaserin because of concerns about a cancer signal detected in preclinical animal studies and asked for more data, including results from the BLOOM-DM trial, a study testing the weight-loss drug in overweight and obese subjects with diabetes. In addition, the 2010 advisory panel considered the weight loss in nondiabetic overweight and obese subjects “marginal.” In the phase 3 clinical trials, known as BLOOM and BLOSSOM, the average weight loss in the lorcaserin-treated patients was 5 to 6 kg.
In May, the FDA advisory committee was presented with the new data, and the panel appeared satisfied that there was no increased risk of cancer with lorcaserin. The FDA, in its own review, also agreed that the risk of tumors in treated patients was “negligible.” That said, it still expressed some concern about a possible increased risk of valvulopathy and adverse cardiovascular events associated with lorcaserin.
In February, the FDA advisory committee also voted in favor of approving the obesity drug Qnexa (Vivus, Mountain View, CA), a combination of phentermine and controlled-release topiramate, but the FDA has still not approved the drug. A decision on Qnexa is expected in July, after the FDA requested additional time in April to review material from the company.
Lorcaserin is the first approved drug for treating obesity since the approval of orlistat (Xenical, Roche; Alli, GlaxoSmithKline) in 1999.
Lorcaserin’s approval by the FDA marks the end of a long era without any new treatments for obesity, a condition that desperately needs more treatment options. This medication is an agonist of the 5-hydroxytryptamine (5-HT, or serotonin) receptor 5-HT2C. It works selectively on the central 5-HT2C receptors, with a functional selectivity of about 15 and 100 times that for 5-HT2A and 5-HT2B, respectively. This is important, because previously available nonselective serotonergic agents for obesity management, such as fenfluramine, caused valvulopathy and pulmonary arterial hypertension via an effect on the 5-HT2B receptors, which is expressed on cardiac valvular interstitial cells and pulmonary artery smooth muscle cells.
The suppression of appetite, however, is predominantly mediated by the 5-HT1B and 5-HT2C receptors. Receptor pharmacology studies strongly suggest that lorcaserin will not activate the 5-HT2B receptor at therapeutic doses; appropriately powered risk-ratio analyses ruled out a 1.5-fold or greater incidence of valvulopathy with lorcaserin treatment for up to 2 years.
The mechanism by which lorcaserin results in weight loss appears to be by influencing appetite, which in turn reduces total energy intake, as opposed to altering energy expenditure or substrate oxidation. Clinical trials have shown that lorcaserin produces about 4 kg of weight loss over a 1-year period compared with placebo, with some sustained weight loss benefit after 2 years of treatment. Thus, the weight loss seen with lorcaserin is slightly greater than that seen with orlistat, which provides 2-3 kg of placebo-subtracted weight loss.
Lorcaserin has been shown to improve glycemic control in addition to facilitating weight loss in persons with type 2 diabetes, and it has modestly beneficial effects on lipids and blood pressure as well. In a recent trial in type 2 diabetes patients, weight loss was 4.5% of total body weight with lorcaserin twice daily and 5% with lorcaserin once daily, vs 1.5% with placebo. A1c decreased by 0.9% with lorcaserin twice daily, 1.0% with lorcaserin once daily, and 0.4% ± 0.06% with placebo. Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin twice daily, 10.5% on lorcaserin once daily, and 6.3% on placebo. As in the nondiabetic obese population, the most common adverse events were headache, back pain, nasopharyngitis, and nausea.
Particularly noteworthy is the fact that lorcaserin does not have an adverse effect on blood pressure or heart rate, which has been a concern with other previously considered (and subsequently rejected or withdrawn) agents. This also justifies the proposed indications for use of lorcaserin as an adjunct to diet and exercise for weight management, including weight loss and maintenance of weight loss in obese patients (BMI ≥ 30 kg/m2) and overweight patients (BMI ≥ 27 kg/m2) with at least 1 weight-related comorbidity (e.g., hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, sleep apnea, type 2 diabetes).
In regard to side-effect profile, lorcaserin is generally well tolerated. As noted earlier, the most common side effects observed in studies were upper respiratory tract infection, headache, and nausea; discontinuation rates in clinical trials were similar to those for placebo.
As 5-HT2A agonism has been associated with perceptual disturbances, and because lorcaserin has the potential to bind 5-HT2A receptors, it has been evaluated and found to have low abuse potential.
Thus, lorcaserin is now an option for facilitating moderate weight loss in a patient with obesity and is a welcome addition to an area where therapeutic agents are sparse. That said, the weight loss seen with lorcaserin is not as great as that seen with other agents that are still being evaluated and which may come to market soon. But as the first new viable option for treatment of obesity in many years, lorcaserin may help pave the way for other new medications in this therapeutic area.
Astrup A. Is cardiometabolic risk improved by weight-loss drugs? Lancet. 2010;376:567-568. Astrup A. Drug management of obesity–efficacy versus safety. N Engl J Med. 2010;363:288-290. Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067-3077. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity. 2012. doi: 10.1038/oby.2012.66.