Chemistry:Lorcaserin

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Short description: Antiobesity drug
Lorcaserin
Lorcaserin.svg
Lorcaserin ball-and-stick model.png
Clinical data
Trade namesBelviq
Other namesAPD-356
AHFS/Drugs.comMonograph
MedlinePlusa613014
License data
Pregnancy
category
  • US: X (Contraindicated)[1]
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding70%[3]
MetabolismHepatic (extensive)[3]
Elimination half-life11 hours[3]
ExcretionRenal (92.3%), Faecal (2.2%)[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC11H14ClN
Molar mass195.69 g·mol−1
3D model (JSmol)
  (verify)

Lorcaserin, marketed under the brand name Belviq,[4][5] was a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating a type of serotonin receptor known as the 5-HT2C receptor in a region of the brain called the hypothalamus, which is known to control appetite.[6] It was approved in 2012, and in 2020, it was removed from the market in the United States due to an increased risk of cancer detected in users of Belviq.[7][2]

Medical uses

Lorcaserin was used long term for weight loss in those who are obese.[8]

The safety and efficacy of Belviq were evaluated in three randomized, placebo-controlled trials that included nearly 8,000 obese and overweight patients, with and without type 2 diabetes, treated for 52 to 104 weeks.[4] All participants received lifestyle modification that consisted of a reduced calorie diet and exercise counseling.[4] Compared with placebo, treatment with Belviq for up to one year was associated with average weight loss ranging from 3 percent to 3.7 percent.[4]

About 47 percent of patients without type 2 diabetes lost at least 5 percent of their body weight compared with about 23 percent of patients treated with placebo.[4] In people with type 2 diabetes, about 38 percent of patients treated with Belviq and 16 percent treated with placebo lost at least 5 percent of their body weight.[4] Belviq treatment was associated with favorable changes in glycemic control in those with type 2 diabetes.[4] The approved labeling for Belviq recommends that the drug be discontinued in patients who fail to lose 5 percent of their body weight after 12 weeks of treatment, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment.[4]

The drug's manufacturer was required to conduct six postmarketing studies, including a long-term cardiovascular outcomes trial to assess the effect of Belviq on the risk for major adverse cardiac events such as heart attack and stroke.[4]

Side effects

In December 2012, the US Drug Enforcement Administration proposed classifying lorcaserin as a Schedule IV drug because it has hallucinogenic properties at higher than approved doses and users could develop psychiatric dependencies on the drug.[9][10] On 7 May 2013, the US Drug Enforcement Administration classified lorcaserin as a Schedule IV drug[11] under the Controlled Substances Act.[9]

There had been concern that lorcaserin could cause cardiac valvulopathy based upon the reports of subjects taking the drug in Phase 2 trials. However, a 2016 Phase 3 clinical trial found no statistically significant differences in valvulopathy rates compared to control, being 2.4% for the drug subjects and 2.0% for controls, and concluded that the drug was safe for the target population[12][13] although more long-term data was needed.[14]

FDA required a post-marketing cardiovascular safety trial as a condition of lorcaserin's approval (a requirement for all weight management drugs since the withdrawal of sibutramine in 2010 due to cardiovascular harm).[15] The CAMELLIA-TIMI 61 trial was conducted for this purpose, and it showed no difference in rates of major adverse cardiovascular events ("MACE+", a composite of "cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization") between lorcaserin and placebo.[16] However secondary analysis of CAMELLIA-TIMI 61 by FDA showed a likely higher cancer risk in those taking lorcaserin.[17][15] The trial was conducted in approximately 12,000 participants over five years and more patients taking lorcaserin were diagnosed with cancer compared to patients taking placebo.[15] CAMELLIA-TIMI 61 was powered to detect differences in MACE, but was not adequately powered to detect differences in cancer rates over the five-year study period.[18]

In February 2020, the FDA requested that the manufacturer of lorcaserin voluntarily withdraw the drug from the US market because a safety clinical trial showed an increased occurrence of cancer. The drug manufacturer, Eisai, voluntarily withdrew the drug.[19]

Mechanism of action

Lorcaserin is a selective 5-HT2C receptor agonist,[20][21] and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets.[22][23][24] 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.[25] 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,[26] the exact mechanism of appetite regulation was not known as of 2005. Lorcaserin has shown 100x selectivity for 5-HT2C versus the closely related 5-HT2B receptor, and 17x selectivity over the 5-HT2A receptor.[27][28]

Receptor[3] EC50 [nM] Ki[nM]
5-HT2C 39 13
5-HT2B 2380 147
5-HT2A 553 92

Approval history

On 22 December 2009, a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States.[29]

On 16 September 2010, an FDA advisory panel voted 9–5 against approval of the drug based on concerns over both efficacy and safety, particularly the findings of mammary gland tumors of female rats.[30][31] On 23 October 2010, the FDA decided not to approve the drug based on the available data. This was not only because cancer promoting properties could not be ruled out, but also because the weight loss efficacy was considered "marginal".[32]

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 such as high blood pressure or type 2 diabetes.[33]

On 27 June 2012, the FDA approved lorcaserin for use in adults with a body mass index (BMI) of 30 or greater (obese), or adults with a BMI of 27 or greater (overweight) and who had at least one weight-related condition such as high blood pressure (hypertension), type 2 diabetes, or high cholesterol (dyslipidemia).[4][34]

On 15 July 2016, FDA approved the extended release version of lorcaserin for weight management with once-daily dosing instead of twice daily dosing.[35]

On 17 September 2020, FDA withdrew approval for lorcaserin and for extended-release lorcaserin tablets.[36]

References

  1. ↑ "Lorcaserin Use During Pregnancy". 4 November 2019. https://www.drugs.com/pregnancy/lorcaserin.html. 
  2. ↑ 2.0 2.1 "FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market". 14 January 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-withdrawal-weight-loss-drug-belviq-belviq-xr-lorcaserin-market. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Belviq (lorcaserin hydrochloride) tablet [Eisai, Inc"]. DailyMed. Eisai, Inc. August 2012. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 "FDA approves Belviq to treat some overweight or obese adults". U.S. Food and Drug Administration (FDA) (Press release). 27 June 2012. Archived from the original on 1 October 2012. Retrieved 14 January 2020. This article incorporates text from this source, which is in the public domain.
  5. ↑ "Belviq". Trademarkia. 23 Jun 2011. http://www.trademarkia.com/belviq-85354490.html. 
  6. ↑ "Lorcaserin Hcl for the treatment of obesity". Expert Opinion on Pharmacotherapy 16 (16): 2531–8. 2015. doi:10.1517/14656566.2015.1096345. PMID 26472579. 
  7. ↑ "Belviq, Belviq XR (lorcaserin) by Eisai: Drug Safety Communication - FDA Requests Withdrawal of Weight-Loss Drug". 13 February 2020. https://www.fda.gov/safety/medical-product-safety-information/belviq-belviq-xr-lorcaserin-eisai-drug-safety-communication-fda-requests-withdrawal-weight-loss-drug. 
  8. ↑ "Management of obesity". Lancet 387 (10031): 1947–56. May 2016. doi:10.1016/S0140-6736(16)00271-3. PMID 26868660. 
  9. ↑ 9.0 9.1 "Reg Watch". The Hill. December 19, 2012. https://thehill.com/business-a-lobbying/273901-reg-watch. 
  10. ↑ "Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV". 2012-12-19. https://federalregister.gov/a/2012-30531. 
  11. ↑ "Department Of Justice Drug Enforcement Administration 21 CFR Part 1308, Placement of Lorcaserin into Schedule IV". 2013-05-08. https://federalregister.gov/a/2013-10895. 
  12. ↑ "Safety and tolerability review of lorcaserin in clinical trials". Clinical Obesity 6 (5): 285–95. October 2016. doi:10.1111/cob.12159. PMID 27627785. 
  13. ↑ "BELVIQ and BELVIQ XR HCP Home Page". http://www.belviqhcp.com/resources/. 
  14. ↑ "Safety and tolerability of new-generation anti-obesity medications: a narrative review". Postgraduate Medicine 130 (2): 173–182. March 2018. doi:10.1080/00325481.2018.1435129. PMID 29388462. 
  15. ↑ 15.0 15.1 15.2 "Safety clinical trial shows possible increased risk of cancer with weight-loss medicine Belviq, Belviq XR (lorcaserin)". 14 January 2020. https://www.fda.gov/drugs/drug-safety-and-availability/safety-clinical-trial-shows-possible-increased-risk-cancer-weight-loss-medicine-belviq-belviq-xr.  This article incorporates text from this source, which is in the public domain.
  16. ↑ "Cancer Risk Associated with Lorcaserin - The FDA's Review of the CAMELLIA-TIMI 61 Trial". The New England Journal of Medicine 383 (11): 1000–1002. September 2020. doi:10.1056/NEJMp2003873. PMID 32905671. 
  17. ↑ "Cancer Risk Associated with Lorcaserin - The FDA's Review of the CAMELLIA-TIMI 61 Trial". The New England Journal of Medicine 383 (11): 1000–1002. September 2020. doi:10.1056/NEJMp2003873. PMID 32905671. 
  18. ↑ "Design and rationale for the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial". American Heart Journal 202: 39–48. August 2018. doi:10.1016/j.ahj.2018.03.012. PMID 29803985. 
  19. ↑ "FDA In Brief: FDA Requests Voluntary Withdrawal of Weight-Loss Medication After Clinical Trial Shows an Increased Occurrence of Cancer". FDA. 2020-02-13. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-requests-voluntary-withdrawal-weight-loss-medication-after-clinical-trial-shows. 
  20. ↑ "Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization". The Journal of Pharmacology and Experimental Therapeutics 325 (2): 577–87. May 2008. doi:10.1124/jpet.107.133348. PMID 18252809. 
  21. ↑ "Novel synthesis of antiobesity drug lorcaserin hydrochloride.". Organic Process Research & Development 19 (9): 1263–1267. September 2015. doi:10.1021/acs.oprd.5b00144. 
  22. ↑ Smith B, Smith J, "5HT2c receptor modulators", US patent 6953787, published 2003-10-04, issued 2005-11-10
  23. ↑ Smith B, Gilson III CA, Schultz J, Smith J, "Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases", US patent 7704993, published 2004-16-06, issued 2010-27-04
  24. ↑ Smith B, Smith J, "5HT2c receptor modulators", US patent 8207158, published 2011-27-05, issued 2012-26-06
  25. ↑ "Lorcaserin" (in de). Österreichische Apothekerzeitung 64 (19): 1083. 13 September 2010. 
  26. ↑ "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie 60 (5): 441–60. 2005. doi:10.2515/therapie:2005065. PMID 16433010. http://biopsychiatry.com/5ht2c-antidep.htm. 
  27. ↑ "Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity". Bioorganic & Medicinal Chemistry Letters 15 (5): 1467–70. March 2005. doi:10.1016/j.bmcl.2004.12.080. PMID 15713408. 
  28. ↑ "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 51 (2): 305–13. January 2008. doi:10.1021/jm0709034. PMID 18095642. 
  29. ↑ "Lorcaserin New Drug Application". Drugs.com. 22 December 2009. https://www.drugs.com/nda/lorcaserin_091222.html. 
  30. ↑ "F.D.A. Panel Rejects Diet Pill". The New York Times. 16 September 2010. https://prescriptions.blogs.nytimes.com/2010/09/16/f-d-a-panel-rejects-diet-pill-2/?pagewanted=all. 
  31. ↑ "F.D.A. Panel Urges Denial of Diet Drug". The New York Times. 16 September 2010. https://www.nytimes.com/2010/09/17/health/17drug.html. 
  32. ↑ "FDA Issues Complete Response Letter for Lorcaserin New Drug Application". 23 October 2010. http://www.prnewswire.com/news-releases/fda-issues-complete-response-letter-for-lorcaserin-new-drug-application-105586113.html. 
  33. ↑ "New Diet Drug Lorcaserin Wins Vote From FDA Panel". webmd. 10 May 2012. http://www.webmd.com/diet/news/20120510/new-diet-drug-lorcaserin-wins-vote-from-fda-panel. 
  34. ↑ "Drug Approval Package: Belviq (lorcaserin hydrochloride) Tablets NDA #022529". August 7, 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022529Orig1s000TOC.cfm. 
  35. ↑ "Belviq XR (lorcaserin hydrochloride) extended-release tablets". 26 October 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208524Orig1s000TOC.cfm. 
  36. ↑ FDA (2020-09-17), Eisai, Inc.; Withdrawal of Approval of Two New Drug Application for BELVIQ (lorcaserin hydrochloride) and BELVIQ XR (lorcaserin hydrocholoride), pp. 58063–58064, https://www.federalregister.gov/documents/2020/09/17/2020-20458/eisai-inc-withdrawal-of-approval-of-two-new-drug-application-for-belviq-lorcaserin-hydrochloride-and, retrieved 2023-05-12 

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