On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes.
On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who "have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol".
Lorcaserin is a selective 5-HT2C receptoragonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets. 5-HT2C receptors are located almost exclusively in the brain, and can be found in the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. The activation of 5-HT2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety. This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT2C versus the closely related 5-HT2B receptor, and 17x selectivity over the 5-HT2A receptor.
Phase IIb and other early clinical trial results
Arena states that "[d]ata from Phase 2 clinical trials of lorcaserin demonstrated that patients who received the drug experienced significantly greater weight loss than patients who received placebo." At the end of 12 weeks, the groups which were administered lorcaserin lost an average of 4.0 pounds (10 mg/day), 5.7 pounds (15 mg/day), and 7.9 pounds (20 mg/day). The placebo group lost an average of 0.7 pounds, despite the fact that all groups received no diet or exercise instruction.
Upon discontinuation of lorcaserin treatment, lost weight is regained. In Phase 2 clinical trials, patients were tracked for 2 weeks post trial completion, and all groups regained weight more rapidly than they had lost. In pre-clinical trial studies, the weight of rats returned to control levels.
Phase III clinical trials
The Lorcaserin Phase III program consists of three different Phase III trials, BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), BLOSSOM (Behavioral modification and LOrcaserin Second Study for Obesity Management), and BLOOM-DM (Diabetes Management).
BLOOM top line results were released on 30 March 2009. Measurements of efficacy using an intention to treat – last observation carried forward (ITT-LOCF), analysis showed that 47.5% of lorcaserin patients lost at least 5% of their body weight, compared to 20.3% for placebo. This result satisfies one of two alternate efficacy benchmarks in the most recent FDA draft guidance, which provides that a weight-management product can be considered effective if after one year of treatment the proportion of subjects who lose greater than or equal to 5% of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant.
Additionally, 22.6% of lorcaserin patients lost at least 10% of their body weight, compared to 7.7% for placebo. Lorcaserin patients achieved an average weight loss of 5.8% of their body weight, or 12.7 pounds, compared to 2.2%, or 4.7 pounds, for placebo. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea.
BLOSSOM results were released on September 18, 2009. Measurements of efficacy using an intent-to-treat last observation carried forward, or ITT-LOCF, analysis showed that 47.2% of lorcaserin patients lost at least 5% of their body weight, compared to 25.0% for placebo. Lorcaserin patients achieved an average weight loss of 5.9%, or 12.7 pounds (5.7 kg), compared to 2.8%, or 6.3 pounds (2.86 kg), for placebo.
This trial examined the effect of lorcaserin in patients with diabetes mellitus. 16.1% lost 5% or more weight under placebo, whereas 37.5% lost 5% or more under lorcaserin.
Lorcaserin had a Prescription Drug User Fee Act (PDUFA) date of 22 October 2010. On 16 September 2010, a federal advisory committee voted against recommending approval for lorcaserin. In their 9-5 vote, the committee had raised concerns about the safety of the drug, particularly the findings of tumors in rats.
On 23 October 2010, the FDA decided not to approve the drug based on the available data. This was not only because of cancer promoting properties could not be ruled out, but also because the weight loss efficacy was "marginal".
After additional studies were completed and additional information submitted to the FDA, an advisory panel was convened on 10 May 2012. The advisory panel voted 19-4-1 to recommend lorcaserin to the FDA. The FDA stated the weight loss passed FDA standards for efficacy and the drug did not have cancer risks based on clarifications in the data. The FDA panelist recommended that post marketing studies regarding potential heart valve issues be completed. The FDA has not stated one way or the other if they believe this is necessary at this time although no safety markers related have been indicated during clinical studies. On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for some adults.
In clinical trials, the most common side effect was headache, experienced by about 18% of drug arm participants compared to 11% of placebo participants. Headache was the only reported side effect to occur at a frequency greater than 5 percentage points above placebo. Other reported side effects and their rates for lorcaserin and placebo patients, respectively, were as follows: upper respiratory tract infection (14.8% vs. 11.9%), nasopharyngitis (13.4% vs. 12.0%), sinusitis (7.2% vs. 8.2%) and nausea (7.5% vs. 5.4%). Adverse events of depression, anxiety and suicidal ideation were infrequent and were reported at a similar rate in each treatment group.
On 15 September 2010 it was reported by national news-media that lorcaserin was associated with the development of cancer in laboratory rats.
Rates of new FDA-defined valvulopathy in BLOOM were as follows: lorcaserin 10 mg twice daily (2.7%) and placebo (2.3%) at Week 52 and lorcaserin 10 mg twice daily (2.6%) and placebo (2.7%) at Week 104. For BLOSSOM, rates of new FDA-defined valvulopathy in BLOSSOM at Week 52 were as follows: lorcaserin 10 mg twice daily (2.0%), 10 mg once daily (1.4%) and placebo (2.0%).
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