Lorcaserin 846589-98-8

Mechanism of action

Lorcaserin is a selective 5-HT_2C receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT_2C over other related targets. 5-HT_2C 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-HT_2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety. the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100:1 affinity for 5-HT_2C versus other receptors.

Clinical trials

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. " Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea.

BLOSSOM

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, compared to 2. 8%, or 6. 3 pounds, for placebo.

BLOOM-DM

This trial examined the effect of lorcaserin in patients with diabetes mellitus. It was scheduled to end in May 2010. , no results are available.

Time schedule

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".

Echocardiograms for valvulopathy

Regarding the risk of cardiac fibrosis, Arena Pharmaceuticals sought to rule out an increase in the rate of valvulopathy of 20% or more because a number of anorectic drugs have been withdrawn for cardiovascular side-effects. In agreement with the FDA, Arena conducted regular and multiple echocardiograms of the phase III participants. At the 3, 6, and 12-month interval, the echocardiograms of participants of the BLOOM trial did not show any significant increase in valvulopathy over baseline, so the independent Echocardiographic Data Safety Monitoring Board (EDSMB) hired to monitor the trial allowed the trial to continue to the end. On 15 September 2010 shares of Arena fell nearly 40%, from $6. 85 to $4. 13, on news that the lorcaserin has been linked to formation of malignant tumors in rats. On 16 September, an FDA advisory panel voted 9 to 5 to recommend against approval of the drug based on concerns over both safety and efficacy, trading on Arena's stock was stopped on that date, but after hours, the stock price fell about 40 percent.