On June 27, 2012, Arena Pharmaceuticals and its commercialization pattern Eisai, Inc. (Woodcliff Lake, NJ) announced that the U.S. FDA had approved its antiobesity drug lorcaserin–the first drug for long-term weight loss to be approved in the U.S. in 13 years. Lorcaserin will be marketed under the trade name Belviq.
The FDA approved lorcaserin as an adjunct to diet and exercise for chronic weight management in adult patients who are obese [initial body mass index (BMI) of 30 kg/m2 or greater], as well as for overweight patients with a BMI of 27 kg/m2 or greater who also have at least one weight-related comorbidity, such as hypertension, dyslipidemia, or type 2 diabetes. The approved indication includes a statement that the safety and efficacy of coadministration of lorcaserin with other products intended for weight loss and the effect of lorcaserin on cardiovascular morbidity and mortality have not been established.
According to the Arena/Eisai announcement, three double-blind, randomized, placebo-controlled trials showed that lorcaserin plus diet and exercise was more effective than diet and exercise alone in helping patients lose 5% or more of their body weight after one year and managing the weight loss for up to two years.
The most common adverse effects seen in nondiabetics treated with lorcaserin were headache, dizziness, fatigue, nausea, dry mouth, and constipation. In patients with type 2 diabetes, the most common adverse effects were hypoglycemia, headache, back pain, cough, and fatigue.
The FDA has recommended that lorcaserin be classified as a scheduled drug. The U.S. Drug Enforcement Administration (DEA) will review this recommendation and determine the final scheduling designation. Once this has been done, Eisai will announce when and under what terms lorcaserin will be available to U.S. physicians and patients.
The approval of lorcaserin includes a commitment by Arena and Eisai to conduct post-marketing studies to assess the safety and efficacy of lorcaserin for weight management in obese pediatric patients, as well as to evaluate the effect of long-term treatment with lorcaserin on the incidence of major adverse cardiovascular events in overweight and obese subjects with cardiovascular disease or multiple cardiovascular risk factors. The cardiovascular outcomes trial will include echocardiographic assessments.
The implications of the approval of lorcaserin for the obesity drug market
Arena is to be congratulated for its persistence in getting lorcaserin approved. As of February 1, 2011, all three of the obesity drug candidates that came up for FDA review in 2010-–Vivus’ Qnexa, Arena’s lorcaserin, and Orexigen’s Contrave–were rejected for approval by the FDA, and sent back for further studies. Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. All of these agents target the central nervous system (CNS).
Concern about long-term safety was the major consideration in the rejection of the NDAs for Qnexa, lorcaserin, and Contrave, and safety issues were also the reason for the withdrawal of sibutramine. That left only one anti-obesity drug approved by the FDA for long term use– orlistat (Roche’s Xenical), with no new drugs In sight. The outlook for obesity drugs was gloomy indeed, and many commentators pronounced the obesity drug field “dead”.
However, as of May 2012, after the further studies prescribed by the FDA in 2010, two of the obesity drug Class of 2010–Qnexa and lorcaserin–had received positive votes by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, and had been awaiting final FDA action later this year. Now lorcaserin has been approved. Qnexa is scheduled for an FDA decision by July 17, 2012.
The approval of lorcaserin–especially if Qnexa is also approved–is expected to lift what we have called “the pall of gloom” from the antiobesity drug market. Development of early-stage antiobesity drugs at larger companies that had been put on hold may proceed again, young companies in the field may find it easier to raise capital, and Big Pharma dealmakers may have renewed interest in anitobesity drugs. According to a Jun 28, 2012 article on Bloomberg.com, Big Pharma dealmaking interest has already been aroused.
Limitations of lorcaserin
Despite the excitement over the approval of lorcaserin, the drug has severe limitations.
As we outlined in our September 23, 2010 article on this blog, lorcaserin is a selective serotonin receptor agonist, which is specific for the 5-HT2C serotonin receptor. This contrasts with the nonselective serotonin reuptake inhibitor and serotonin-releasing agents, fenfluramine and dexfenfluramine, which are notorious for their association with heart valve abnormalities.
Lorcaserin was designed to be a more selective agent that works by a similar mechanism to dexfenfluramine or fenfluramine. The anorectic effect of fenfluramine/dexfenfluramine is due to their activity on 5-HT2C, but the adverse effects of these agents appears to be due to their activity on 5-HT2B. Therefore, lorcaserin is expected to be a safer agent that fenfluramine/dexfenfluramine.
However, like fenfluramine and dexfenfluramine, the efficacy of lorcaserin appears to be minimal. Pivotal Phase 3 clinical trials showed an average weight loss of 5.8% among subjects taking lorcaserin, as compared to 2.5% for the placebo group.
A Phase 3 clinical trial published in the New England Journal of Medicine (NEJM) in July 2010 showed that the drug caused significant weight loss and improved maintenance of weight loss as compared to placebo, in a generally healthy obese population. Lorcaserin also improved values for such biomarkers as lipid levels, insulin resistance, inflammatory markers and blood pressure.
In its July 15, 2010, meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee noted that lorcaserin, although its efficacy was not great, met FDA efficacy criteria for approvable antiobesity drugs. However, some panelists thought that in populations containing more patients with comorbidities (e.g., diabetes, cardiovascular disease) there might be a lesser degree of efficacy and/or additional safety issues than in populations of generally healthy obese individuals.
However, since that time the results of additional Phase 3 clinical studies in obese individuals with comorbidities, especially type 2 diabetes, have been published. Efficacy results in type 2 diabetics were similar to those seen in obese, nondiabetic individuals. Nevertheless, the efficacy of locaserin remains minimal.
According to the Bloomberg article, analysts believe that insurers will probably not cover lorcaserin due to its low efficacy. However, at a cost of $4 a day for twice-daily therapy with lorcaserin, sales may still reach $2 billion by 2020.
Qnexa, as we discussed in our August 4, 2010 blog article, appears to have a higher efficacy than loracaserin. In the more recent 56-week EQUIP Study of Qnexa in severely obesity individuals (published in February 2012), average weight loss for patients on Qnexa who completed the study was 14.4% and 6.7% with top dose Qnexa and low dose Qnexa, respectively, compared to 2.1% in the placebo group. However, whether Qnexa will be approved awaits the FDA decision by July 12, 2012.
The approval of lorcaserin signals new life for antiobesity drug discovery and development, and the marketing of antiobesity agents. This includes approaches that work by increasing energy expenditure, rather than the usual approaches of decreasing appetite by targeting the CNS. We discussed some of these approaches in our May 23, 2012 article on this blog.
The need for antiobesity agents is great, and with the fast accelerating incidence of obesity and its complications, the need is also accelerating. Moreover, our understanding of the pathogenesis of obesity is limited. Thus both continuing basic research and development of agents with novel mechanisms are sorely needed.
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