Lorcaserin

Lorcaserin
Systematic (IUPAC) name
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Identifiers
CAS number	846589-98-8
ATC code	none
PubChem	11673085
Chemical data
Formula	C11H14ClN
Mol. mass	195.688 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	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.^[1]

Overview

According to their published statements, Arena believes that lorcaserin is a selective 5-HT_2C receptor agonist,^[2] and in vitro testing of the drug showed reasonable selectivity for 5-HT_2C over other related targets.^[3] 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, and this is supported by animal studies, but it is unclear whether the dose range used in human trials will be sufficient to demonstrate the same level of weight loss. While it is generally thought that 5-HT_2C receptors help to regulate appetite as well as mood, motor behavior, and endocrine secretion^[4], the exact mechanism of appetite regulation is not yet known.

Side effects

Lorcaserin produced a variety of side effects in human clinical trials, although less than 10% of patients dropped out because of side effects. By far the most common side effect was headache, experienced by slightly under 1/3rd of trial participants. Other common side effects include dizziness and nausea.^[5] These side effects are typical of better studied 5-HT_2C agonists such as mCPP, and may be dose limiting factors in clinical use. Significantly, no evidence of dangerous effects on heart valves was seen with these initial trials of lorcaserin, although a 12 week study is too short to adequately assess side effects such as inappropriate proliferation of cardiac fibroblasts.

Other 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".^[6] Hypolocomotion, hyperthermia, and penile erection are other reactions that have been observed in animals as a result of 5-HT_2C agonists.^[7] The relevance of these side effects to therapeutic human use of 5-HT_2C agonists is unclear as the doses used in animal research are generally significantly higher.

Lorcaserin could possibly cause depressive and anxiogenic symptoms in some patients, via its activation of the 5ht2c receptor in the brain. 5ht2c activation prevents the release of dopamine and norepinephrine in the brain. Care should be taken when prescribing Lorcaserin to individuals with a history of depressive, anxiety, of other psychiatric disorders. However, after long term treatment, Lorcaserin could begin to cause antidepressant effects due to the downregulation of 5ht2c receptors in the brian.

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." ^[8] 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)^[9]. 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.^[10] In pre-clinical trial studies, lab rat weights returned to control levels.^[11]

Arena is taking care to demonstrate ^[12] that lorcaserin does not cause heart valve damage in the same way as previously withdrawn serotonergic weight loss drugs such as fenfluramine and chlorphentermine. 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."^[13]

On March 17, 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.^[14] 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.

Future prospects

Arena's projected release date for Lorcaserin is 2010. Arena has developed a marketing plan to target the massive base of overweight and obese consumers^[15], 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^[16]. This plan predicts an initial number of prescriptions of 10 million for revenue potential of $1 billion.^[17] 2009-09-17 update: http://www.reuters.com/article/hotStocksNews/idUSTRE58H2BT20090918

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References