Lorcaserin

Last updated

Lorcaserin
Lorcaserin.svg
Lorcaserin ball-and-stick model.png
Clinical data
Trade names Belviq
Other namesAPD-356
AHFS/Drugs.com Monograph
MedlinePlus a613014
License data
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 70% [2]
Metabolism Hepatic (extensive) [2]
Elimination half-life 11 hours [2]
Excretion Renal (92.3%), Faecal (2.2%) [2]
Identifiers
  • (1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.237.138 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H14ClN
Molar mass 195.69 g·mol−1
3D model (JSmol)
  • CC1CNCCC2=C1C=C(C=C2)Cl
  • InChI=1S/C11H14ClN/c1-8-7-13-5-4-9-2-3-10(12)6-11(8)9/h2-3,6,8,13H,4-5,7H2,1H3/t8-/m0/s1 Yes check.svgY
  • Key:XTTZERNUQAFMOF-QMMMGPOBSA-N Yes check.svgY
   (verify)

Lorcaserin, marketed under the brand name Belviq, [3] [4] was a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating serotonin receptor the 5-HT2C receptor in the hypothalamus, a region of the brain which is known to control appetite. [5] 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. [6] [1]

Contents

Medical uses

Lorcaserin was used long term for weight loss in those who are obese. [7]

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. [3] All participants received lifestyle modification that consisted of a reduced calorie diet and exercise counseling. [3] 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. [3]

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. [3] 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. [3] Belviq treatment was associated with favorable changes in glycemic control in those with type 2 diabetes. [3] 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. [3]

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. [3]

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. [8] [9] On 7 May 2013, the US Drug Enforcement Administration classified lorcaserin as a Schedule IV drug [10] under the Controlled Substances Act. [8]

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 [11] [12] although more long-term data was needed. [13]

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). [14] 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. [15] However secondary analysis of CAMELLIA-TIMI 61 by FDA showed a likely higher cancer risk in those taking lorcaserin. [16] [14] 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. [14] 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. [17]

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. [18]

Mechanism of action

Lorcaserin is a selective 5-HT2C receptor agonist, [19] [20] and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets. [21] [22] [23] 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. [24] 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, [25] 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. [26] [27]

Receptor [2] EC50 [nM]Ki[nM]
5-HT2C 3913
5-HT2B 2380147
5-HT2A 55392

Approval history

On 22 December 2009, a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States. [28]

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. [29] [30] 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". [31]

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. [32]

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). [3] [33]

On 15 July 2016, FDA approved the extended release version of lorcaserin for weight management with once-daily dosing instead of twice daily dosing. [34]

On 17 September 2020, FDA withdrew approval for lorcaserin and for extended-release lorcaserin tablets. [35]

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References

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  10. ↑ "Department Of Justice Drug Enforcement Administration 21 CFR Part 1308, Placement of Lorcaserin into Schedule IV". 8 May 2013.
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  14. 1 2 3 "Safety clinical trial shows possible increased risk of cancer with weight-loss medicine Belviq, Belviq XR (lorcaserin)". U.S. Food and Drug Administration (FDA). 14 January 2020. Retrieved 14 January 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  15. ↑ Sharretts J, Galescu O, Gomatam S, Andraca-Carrera E, Hampp C, Yanoff L (September 2020). "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. doi:10.1056/NEJMp2003873. PMID   32905671. S2CID   221625777.
  16. ↑ Sharretts J, Galescu O, Gomatam S, Andraca-Carrera E, Hampp C, Yanoff L (September 2020). "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. doi:10.1056/NEJMp2003873. PMID   32905671. S2CID   221625777.
  17. ↑ Bohula EA, Scirica BM, Fanola C, Inzucchi SE, Keech A, McGuire DK, et al. (August 2018). "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. doi:10.1016/j.ahj.2018.03.012. PMID   29803985. S2CID   44070009.
  18. ↑ "FDA In Brief: FDA Requests Voluntary Withdrawal of Weight-Loss Medication After Clinical Trial Shows an Increased Occurrence of Cancer". FDA. 13 February 2020.
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  20. ↑ Zhu Q, Wang J, Bian X, Zhang L, Wei P, Xu Y (September 2015). "Novel synthesis of antiobesity drug lorcaserin hydrochloride". Organic Process Research & Development. 19 (9): 1263–1267. doi:10.1021/acs.oprd.5b00144.
  21. ↑ USpatent 6953787,Smith B, Smith J,"5HT2c receptor modulators",published 2003-10-04,issued 2005-11-10
  22. ↑ USpatent 7704993,Smith B, Gilson III CA, Schultz J, Smith J,"Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases",published 2004-16-06,issued 2010-27-04
  23. ↑ USpatent 8207158,Smith B, Smith J,"5HT2c receptor modulators",published 2011-27-05,issued 2012-26-06
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  25. ↑ Millan MJ (2005). "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. doi:10.2515/therapie:2005065. PMID   16433010. Archived from the original on 28 August 2015.
  26. ↑ Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, et al. (March 2005). "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. doi:10.1016/j.bmcl.2004.12.080. PMID   15713408.
  27. ↑ Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, et al. (January 2008). "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. doi:10.1021/jm0709034. PMID   18095642.
  28. ↑ "Lorcaserin New Drug Application". Drugs.com. 22 December 2009. Archived from the original on 3 March 2016.
  29. ↑ Pollack A (16 September 2010). "F.D.A. Panel Rejects Diet Pill". The New York Times . Archived from the original on 17 July 2011.
  30. ↑ Pollack A (16 September 2010). "F.D.A. Panel Urges Denial of Diet Drug". The New York Times . Archived from the original on 22 August 2017.
  31. ↑ "FDA Issues Complete Response Letter for Lorcaserin New Drug Application". 23 October 2010. Archived from the original on 24 October 2010.
  32. ↑ "New Diet Drug Lorcaserin Wins Vote From FDA Panel". webmd. 10 May 2012. Archived from the original on 12 May 2012.
  33. ↑ "Drug Approval Package: Belviq (lorcaserin hydrochloride) Tablets NDA #022529". U.S. Food and Drug Administration (FDA). 7 August 2012. Retrieved 14 January 2020.
  34. ↑ "Belviq XR (lorcaserin hydrochloride) extended-release tablets". U.S. Food and Drug Administration (FDA). 26 October 2016. Retrieved 14 January 2020.
  35. ↑ FDA (17 September 2020), Eisai, Inc.; Withdrawal of Approval of Two New Drug Application for BELVIQ (lorcaserin hydrochloride) and BELVIQ XR (lorcaserin hydrocholoride), pp. 58063–58064, retrieved 12 May 2023
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