Lorcaserin

Drugbox
IUPAC_name = (1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine


width= 180
CAS_number= 846589-98-8
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PubChem= 11673085
DrugBank=
C=11 | H=14 | Cl=1 | N=1
molecular_weight = 195.688 g/mol
smiles = C [C@H] 1CNCCC2=C1C=C(C=C2)Cl
bioavailability=
metabolism =
elimination_half-life=
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legal_status =
routes_of_administration= oral

Lorcaserin (APD-356) is a serotonergic weight-loss drug developed by Arena Pharmaceuticals. It is currently undergoing the final phase of clinical trials in preparation for submission for FDA approval.

Overview

According to their published statements, Arena believes ["Lorcaserin Hydrochloride for Obesity" http://www.arenapharm.com/wt/page/lho.html] that lorcaserin is a selective 5-HT_2C receptor agonist. 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. Arena believes that the activation of 5-HT_2C receptors in the hypothalamus promotes weight loss through appetite suppression. However, the science remains imprecise. While it is generally thought that 5-HT_2C receptors help to regulate appetite as well as mood, motor behavior, and endocrine secretion ["Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies" Therapie. 2005 Sep-Oct;60(5):441-60. http://biopsychiatry.com/5ht2c-antidep.htm] , the exact mechanism of appetite regulation is not yet known. 5-HT_2C agonists have been shown to elicit hyperactivity and oral dyskinesia (involuntary movements, "tics") in lab animals, leading one group of researchers to conclude that such results " [raise] questions about the use of the 5-HT_2C receptor as a target for novel therapeutic agents for obesity". ["A 5-HT2C agonist elicits hyperactivity and oral dyskinesia with hypophagia in rabbits." Physiol Behav. 2004 Aug;82(1):97-107. http://www.ncbi.nlm.nih.gov/pubmed/15234597] Hypolocomotion, hyperthermia, and penile erection are other reactions that have been observed as a result of 5-HT_2C agonists. ["5-HT_2C receptors mediate penile erections in rats: actions of novel and selective agonists and antagonists." Eur J Pharmacol. 1997 Apr 23;325(1):9-12. http://www.ncbi.nlm.nih.gov/pubmed/9151932] 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) ["Arena Pharmaceuticals Announces Positive Phase 2b Clinical Trial Results of Novel Anti-Obesity Compound" http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=320421] , all less than one pound per week. The placebo group lost an average of .7 pounds, despite the fact that all groups received no diet or exercise instruction.

Arena admits that upon discontinuation of lorcaserin treatment, the lost weight is regained.

Arena is taking care to demonstrate -- and announce to investors and potential consumers [Arena Pharmaceuticals Research & Development Day, November 9 2006 http://files.shareholder.com/downloads/ARNA/423624742x0x212571/1e6d752f-570c-4102-b9c5-3347b784e649/#page=97] -- that lorcaserin does not cause heart valve damage as fenfluramine, a presumed 5-HT2B agonist, did. Arena stated that the Phase 2 clinical trials, the participants of which had been pre-screened to exclude valvulopathy, show that Lorcaserin "has no effect on heart valve regurgitation at 12 weeks."

On March 18, 2008, Arena announced that 12-month echocardiograms of the participants of the first of three Phase 3 clinical trials ("BLOOM") did not meet the trial-stopping criteria developed by an independent Echocardiographic Data Safety Monitoring Board (EDSMB), and so the trial continues. BLOOM participants will receive 18- and 24-month follow-up echocardiograms, but these results will not be reviewed by an EDSMB. Two other Phase 3 trials ("BLOSSOM", and "BLOOM-DM") provide echocardiograms but they will not be reviewed by an EDSMB. BLOOM participants were pre-screened to exclude valvulopathy, but BLOSSOM and BLOOM-DM participants were not.

Arena's projected release date for Lorcaserin is 2010. Arena has developed a sophisticated marketing plan to target the massive base of overweight and obese consumers [Arena Pharmaceuticals Research & Development Day, November 9 2006 http://files.shareholder.com/downloads/ARNA/423624742x0x212571/1e6d752f-570c-4102-b9c5-3347b784e649/#page=164] , including pre-launch marketing and brand positioning beginning in 2007, packaging, support, and internet development beginning in 2008, and a "Speaker's Program" beginning in 2009 during their New Drug Application process with the FDA ["New Drug Application (NDA) Process" http://www.fda.gov/CDER/REGULATORY/APPLICATIONS/nda.htm] . This plan predicts an initial number of prescriptions of 10 million for revenue potential of $1 billion. [Arena Pharmaceuticals Research & Development Day, November 9 2006 http://files.shareholder.com/downloads/ARNA/423624742x0x212571/1e6d752f-570c-4102-b9c5-3347b784e649/#page=171]

References