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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
Therapeutic considerations
Pregnancy cat.  ?
Legal status Uncontrolled
Routes Oral

Lorcaserin (APD-356) is a serotonergic weight-loss drug developed by Arena Pharmaceuticals. As of December 22, 2009 an NDA has been submitted to the FDA in the United States and lorcaserin is pending approval.[1]

Contents

Overview

According to their published statements, Arena believes that lorcaserin is a selective 5-HT2C receptor agonist,[2] and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets.[3] 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. Arena believes that the activation of 5-HT2C 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-HT2C 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, but at rates not meaningfully different than placebo - 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-HT2C 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-HT2C 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-HT2C 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-HT2C agonists.[7] The relevance of these side effects to therapeutic human use of 5-HT2C agonists is unclear as the doses used in animal research are generally significantly higher.

Lorcaserin could potentially cause or increase depressive and anxiogenic symptoms in susceptible individuals, via activation of 5-HT2C receptors in the brain. 5-HT2C receptor activation inhibits release of the neurotransmitter dopamine in the brain, whereas various psychostimulant and antidepressant medications (Amphetamine, Methylphenidate, Bupropion) and psychoactive substances (Caffeine, Nicotine, Ethanol) function by enhancing dopamine release and neurotransmission. Selective 5-HT2C agonists have been shown to worsen depression, anxiety, and OCD symptoms in susceptible individuals. Care should be taken when prescribing Lorcaserin to patients with a predisposition to, or history of depressive, anxiety, or other psychiatric disorders.

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

See also

References

  1. ^ "lorcaserin New Drug Application". http://www.drugs.com/nda/lorcaserin_091222.html. 
  2. ^ Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics. 2008 May;325(2):577-87. PMID 18252809
  3. ^ Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ. Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. Journal of Medicinal Chemistry. 2008 Jan 24;51(2):305-13. PMID 18095642
  4. ^ 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
  5. ^ Steven R. Smith, Warren Prosser, David Donahue, Christen Anderson, William Shanahan, and the APD356-004 Study Group. Lorcaserin (APD356), a Selective 5-HT2C Agonist, Safely Induces Weight Loss in a 12-week Study of Healthy Obese Patients. Arena Pharmaceuticals shareholder information release.
  6. ^ A 5-HT2C agonist elicits hyperactivity and oral dyskinesia with hypophagia in rabbits. Physiology and Behavior. 2004 Aug;82(1):97-107. PMID 15234597
  7. ^ 5-HT2C receptors mediate penile erections in rats: actions of novel and selective agonists and antagonists. European Journal of Pharmacology. 1997 Apr 23;325(1):9-12. PMID 9151932
  8. ^ Lorcaserin Hydrochloride for Obesity http://www.arenapharm.com/wt/page/lho.html
  9. ^ "Arena Pharmaceuticals Announces Positive Phase 2b Clinical Trial Results of Novel Anti-Obesity Compound" http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=320421
  10. ^ http://files.shareholder.com/downloads/ARNA/0x0x212573/1ced2b2b-c63d-4e27-ac98-015b5621911a/#page=6
  11. ^ Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. http://www.ncbi.nlm.nih.gov/pubmed/18252809
  12. ^ Arena Pharmaceuticals Research & Development Day, November 9 2006 http://files.shareholder.com/downloads/ARNA/423624742x0x212571/1e6d752f-570c-4102-b9c5-3347b784e649/#page=97
  13. ^ http://files.shareholder.com/downloads/ARNA/0x0x212573/1ced2b2b-c63d-4e27-ac98-015b5621911a/#page=14
  14. ^ Arena Pharmaceuticals' Lorcaserin for Obesity Passes Major Safety Milestone http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=320197
  15. ^ Arena Pharmaceuticals Research & Development Day, November 9 2006 http://files.shareholder.com/downloads/ARNA/423624742x0x212571/1e6d752f-570c-4102-b9c5-3347b784e649/#page=164
  16. ^ "New Drug Application (NDA) Process" http://www.fda.gov/CDER/REGULATORY/APPLICATIONS/nda.htm
  17. ^ Arena Pharmaceuticals Research & Development Day, November 9 2006 http://files.shareholder.com/downloads/ARNA/423624742x0x212571/1e6d752f-570c-4102-b9c5-3347b784e649/#page=171







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