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 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. [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]

Related Research Articles

<span class="mw-page-title-main">Metformin</span> Medication used to treat diabetes by reducing glucose levels

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. Metformin is not associated with weight gain and is taken by mouth.

An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

<span class="mw-page-title-main">Dapagliflozin</span> Diabetes medication

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand names Victoza and Saxenda among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

<span class="mw-page-title-main">Vorapaxar</span> Chemical compound

Vorapaxar is a thrombin receptor antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co.

<span class="mw-page-title-main">Enobosarm</span> Investigational selective androgen receptor modulator

Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of breast cancer. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy, and stress incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved, and development for this use was terminated. Enobosarm is taken by mouth.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

Arena Pharmaceuticals, Inc. is an American biopharmaceutical company founded in 1997 and headquartered in San Diego, California. The company has small molecule drugs in development for possible clinical utility in multiple therapeutic areas. The company's most advanced investigational clinical programs are ralinepag in testing for pulmonary arterial hypertension (PAH), etrasimod in evaluation for inflammatory indications and APD371 for the treatment of pain associated with Crohn's disease. In 2016, the company downsized and shifted its focus to developing new drugs currently being tested in clinical trials. In December 2021, Pfizer announced that it had agreed to acquire Arena for $6.7 billion in cash. In March 2022, it was announced the acquisition by Pfizer had been concluded.

<span class="mw-page-title-main">Naltrexone/bupropion</span> Medication for treatment of obesity

Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant. It is taken by mouth. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight.

<span class="mw-page-title-main">Lenvatinib</span> Chemical compound

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

5-HT2C receptor agonists are a class of drugs that activate 5-HT2C receptors. They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

<span class="mw-page-title-main">Setmelanotide</span> Chemical compound

Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.

<span class="mw-page-title-main">Ozanimod</span> Medication

Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It was developed by Novo Nordisk in 2012 and approved for use in the US in 2017. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic (injectable) and Rybelsus (pill) for diabetes, and under the brand name Wegovy for weight loss.

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic medication

Tirzepatide, sold under the brand name Mounjaro among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered through subcutaneous injection.

References

  1. 1 2 "FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market". U.S. Food and Drug Administration (FDA). 14 January 2020. Retrieved 1 April 2020.
  2. 1 2 3 4 5 "Belviq (lorcaserin hydrochloride) tablet [Eisai, Inc]". DailyMed. Eisai, Inc. August 2012. Archived from the original on 21 October 2013. Retrieved 21 October 2013.
  3. 1 2 3 4 5 6 7 8 9 10 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. ↑ "Belviq". Trademarkia. 23 June 2011. Archived from the original on 30 June 2012. Retrieved 27 June 2012.
  5. ↑ Shukla AP, Kumar RB, Aronne LJ (2015). "Lorcaserin Hcl for the treatment of obesity". Expert Opinion on Pharmacotherapy. 16 (16): 2531–8. doi:10.1517/14656566.2015.1096345. PMID   26472579. S2CID   44520532.
  6. ↑ "Belviq, Belviq XR (lorcaserin) by Eisai: Drug Safety Communication - FDA Requests Withdrawal of Weight-Loss Drug". U.S. Food and Drug Administration (FDA). 13 February 2020. Retrieved 18 February 2020.
  7. ↑ Bray GA, Frühbeck G, Ryan DH, Wilding JP (May 2016). "Management of obesity". Lancet. 387 (10031): 1947–56. doi:10.1016/S0140-6736(16)00271-3. PMID   26868660. S2CID   21805769.
  8. 1 2 Wilson MR (19 December 2012). "Reg Watch". The Hill. Archived from the original on 20 March 2013.
  9. ↑ "Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV". 19 December 2012.
  10. ↑ "Department Of Justice Drug Enforcement Administration 21 CFR Part 1308, Placement of Lorcaserin into Schedule IV". 8 May 2013.
  11. ↑ Greenway FL, Shanahan W, Fain R, Ma T, Rubino D (October 2016). "Safety and tolerability review of lorcaserin in clinical trials". Clinical Obesity (Review). 6 (5): 285–95. doi:10.1111/cob.12159. PMID   27627785. S2CID   38418965.
  12. ↑ "BELVIQ and BELVIQ XR HCP Home Page". www.belviqhcp.com. Archived from the original on 16 June 2016.
  13. ↑ Patel DK, Stanford FC (March 2018). "Safety and tolerability of new-generation anti-obesity medications: a narrative review". Postgraduate Medicine (Narrative review). 130 (2): 173–182. doi:10.1080/00325481.2018.1435129. PMC   6261426 . PMID   29388462.
  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.
  19. ↑ Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, et al. (May 2008). "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. doi:10.1124/jpet.107.133348. PMID   18252809. S2CID   20924745.
  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
  24. ↑ Spreitzer H (13 September 2010). "Lorcaserin". Österreichische Apothekerzeitung (in German). 64 (19): 1083.
  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
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.