Lorcaserin hydrochloride, indicated for weight management in patients who are obese or overweight, in addition to a reduced-calorie diet and exercise, was approved today by the FDA in a landmark decision after 2 years of scrutiny.
The drug, Belviq (Arena Pharmaceuticals, Inc.), is a 5HT2c receptor agonist indicated for use in adults with a BMI ≥30, or those with a BMI ≥27 and at least one weight-related condition like hypertension, type 2 diabetes or dyslipidemia.
The drug works by suppressing appetite and induces a feeling of satiety, and is thought to avoid the precipitation of cardiac valvular disease associated with activation of 5-HT2B receptors (as seen with fenfluramine use).
“Obesity threatens the overall well being of patients and is a major public health concern,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research said in a press release. “The approval of this drug, used responsibly in combination with a healthy diet and lifestyle, provides a treatment option for Americans who are obese or are overweight and have at least one weight-related comorbid condition.”
In 1997, fenfluramine and dexfenfluramine were taken off the market following evidence that the weight loss drugs caused heart valve damage. This effect is thought to be related to activation of the serotonin 2B receptor on heart tissue.
This was an item of concern when it came time for the FDA’s Endocrinologic and Metabolic Drug Advisory Committee to review the drug application on October 1, 2010.
The first sets of studies of lorcaserin were conducted in 2002-2004 in support of early clinical trials, and the second was conducted in 2009 in the course of characterizing metabolites of lorcaserin. A 5% weight loss in 47.5% of patients assigned lorcaserin vs. 20.3% of patients assigned placebo was reported in a phase 3 trial, as indicated by researchers in a previous FDA committee meeting.
According to data, approximately one-third of patients lost approximately 11% or 25 lbs after 52 weeks. Additionally, 50% of patients assigned to lorcaserin reached HbA1c ≤7% at week 52.
Allison B. Goldfine, MD, associate professor at Harvard Medical School, who voted for approval of the drug in 2010 said, “This is a small magnitude of weight loss, but it can be clinically important.”
In its 9-5 rejection vote, the committee cited questions about the data regarding the effect of lorcaserin on valvular heart disease. According to FDA Briefing Documents, the relative risk (RR) for valvular heart disease in patients who were assigned lorcaserin was 1.07 (95% CI, 0.74-1.55). Other adverse events associated with use of the drug were a higher incidence of depression and suicidal ideation, as well as cognitive adverse events, such as forgetfulness.
Along with recommendations for additional animal studies of neoplasms, the panel also suggested conducting clinical trials in patients with comorbid conditions, such as diabetes and CVD. These patients had been excluded from the phase 3 studies submitted to the FDA for review.
Proving safety, efficacy
In their second application to the FDA’s Endocrinologic and Metabolic Drug Advisory Committee, in May of this year, Arena Pharmaceuticals, Inc. provided clinical study designs and patient baseline characteristics, efficacy results and clinical perspective, clinical safety results, preclinical studies and preclinical safety as it relates to human risk.
Lorcaserin’s safety and efficacy was evaluated in three randomized, placebo-controlled trials that included approximately 8,000 overweight and obese adult patients, with and without type 2 diabetes.
Evidence was brought to the committee about patients treated with lorcaserin hydrochloride for 52 to 104 weeks as an add-on to lifestyle modifications like reduced calorie diet and exercise counseling.
Based on these results, the committee approved the application. Edward W. Gregg, PhD, chief of epidemiology and statistics branch at the Division of Diabetes Translation at the CDC, who voted for the approval of the drug, said, “the difference here as opposed to a year and a half ago, when we reviewed this, I think that their work basically did a lot to allay the risks that we were concerned about.”
However, the committee suggested a post-marketing study to evaluate cited concerns on uncertainty of risk for mammary tumor and valvular heart disease associated with the drug.
Because lorcaserin has not been studied in patients with serious valvular heart disease, the FDA suggests that the drug be used with caution in patients with the condition.
Arena Pharmaceuticals, Inc. will be required to complete six post marketing studies, per recommendations by the committee, upon approval. The studies are required to include one long-term cardiovascular outcome trial to determine the potential risk for major cardiac events such as MI and stroke.
According to an FDA press release, the most common side effects of lorcaserin in patients without diabetes are: headache, dizziness, fatigue, nausea, dry mouth and constipation. In patients with diabetes, side effects include: hypoglycemia, headache, back pain, cough and fatigue.
For more information:
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