Lorcaserin

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Lorcaserin
Systematic (IUPAC) name
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Clinical data
Trade namesBelviq
Licence dataUS FDA:link
Pregnancy cat.X (US)
Legal statusSchedule IV (US)
RoutesOral
Pharmacokinetic data
Protein binding70%[1]
MetabolismHepatic (extensive)[1]
Half-life11 hours[1]
ExcretionRenal (92.3%), Faecal (2.2%)[1]
Identifiers
CAS number616202-92-7 N
ATC codeNone
PubChemCID 11658860
ChemSpider9833595 YesY
UNII637E494O0Z YesY
ChEMBLCHEMBL360328 YesY
Chemical data
FormulaC11H14ClN 
Mol. mass195.688 g/mol
 N (what is this?)  (verify)
 
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Lorcaserin
Systematic (IUPAC) name
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Clinical data
Trade namesBelviq
Licence dataUS FDA:link
Pregnancy cat.X (US)
Legal statusSchedule IV (US)
RoutesOral
Pharmacokinetic data
Protein binding70%[1]
MetabolismHepatic (extensive)[1]
Half-life11 hours[1]
ExcretionRenal (92.3%), Faecal (2.2%)[1]
Identifiers
CAS number616202-92-7 N
ATC codeNone
PubChemCID 11658860
ChemSpider9833595 YesY
UNII637E494O0Z YesY
ChEMBLCHEMBL360328 YesY
Chemical data
FormulaC11H14ClN 
Mol. mass195.688 g/mol
 N (what is this?)  (verify)

Lorcaserin (APD-356, trade name upon approval Belviq,[2][3] expected trade name during development, Lorqess[4][5]) is a weight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. On 22 December 2009 a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States.[6] On 16 September 2010, an FDA advisory panel voted to recommend against approval of the drug based on concerns over both safety and efficacy.[7] In October 2010, the FDA stated that it could not approve the application for lorcaserin in its present form.[8]

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 like high blood pressure or type 2 diabetes.[9]

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who "have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol".[2][10]

On 7 May 2013, the US Drug Enforcement Administration has classified lorcaserin as a Schedule IV drug[11] under the Controlled Substances Act.[12]

Mechanism of action[edit]

Lorcaserin is a selective 5-HT2C receptor agonist,[13] and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets.[14][15][16] 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.[17] 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,[18] the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT2C versus the closely related 5-HT2B receptor, and 17x selectivity over the 5-HT2A receptor.[19][20]

Receptor[1]EC50 [nM]Ki[nM]
5-HT2C3913
5-HT2B2380147
5-HT2A55392

Clinical trials[edit]

Phase IIb and other early clinical trial results[edit]

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."[21] 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).[22] 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.[23] In pre-clinical trial studies, the weight of rats returned to control levels.[13]

Phase III clinical trials[edit]

The Lorcaserin Phase III program consists of three different Phase III trials, BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), BLOSSOM (Behavioral modification and LOrcaserin Second Study for Obesity Management), and BLOOM-DM (Diabetes Management).

BLOOM[edit]

BLOOM top line results were released on 30 March 2009. Measurements of efficacy using an intention to treatlast observation carried forward (ITT-LOCF), analysis showed that 47.5% of lorcaserin patients lost at least 5% of their body weight, compared to 20.3% for placebo. This result satisfies one of two alternate efficacy benchmarks in the most recent FDA draft guidance, which provides that a weight-management product can be considered effective if after one year of treatment the proportion of subjects who lose greater than or equal to 5% of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant.

Additionally, 22.6% of lorcaserin patients lost at least 10% of their body weight, compared to 7.7% for placebo. Lorcaserin patients achieved an average weight loss of 5.8% of their body weight, or 12.7 pounds, compared to 2.2%, or 4.7 pounds, for placebo.[24] Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea.[25]

BLOSSOM[edit]

BLOSSOM results were released on September 18, 2009. Measurements of efficacy using an intent-to-treat last observation carried forward, or ITT-LOCF, analysis showed that 47.2% of lorcaserin patients lost at least 5% of their body weight, compared to 25.0% for placebo. Lorcaserin patients achieved an average weight loss of 5.9%, or 12.7 pounds (5.7 kg), compared to 2.8%, or 6.3 pounds (2.86 kg), for placebo.[26]

BLOOM-DM[edit]

This trial examined the effect of lorcaserin in patients with diabetes mellitus. 16.1% lost 5% or more weight under placebo, whereas 37.5% lost 5% or more under lorecaserin.[27]

Time schedule[edit]

Lorcaserin had a Prescription Drug User Fee Act (PDUFA) date of 22 October 2010.[28] On 16 September 2010, a federal advisory committee voted against recommending approval for lorcaserin. In their 9-5 vote, the committee had raised concerns about the safety of the drug, particularly the findings of tumors in rats.[29]

On 23 October 2010, the FDA decided not to approve the drug based on the available data. This was not only because of cancer promoting properties could not be ruled out, but also because the weight loss efficacy was "marginal".[8]

After additional studies were completed and additional information submitted to the FDA, an advisory panel was convened on 10 May 2012. The advisory panel voted 19-4-1 to recommend lorcaserin to the FDA. The FDA stated the weight loss passed FDA standards for efficacy and the drug did not have cancer risks based on clarifications in the data. The FDA panelist recommended that post marketing studies regarding potential heart valve issues be completed. The FDA has not stated one way or the other if they believe this is necessary at this time although no safety markers related have been indicated during clinical studies.[citation needed] On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for some adults.[10][30]

Side effects[edit]

Generally, lorcaserin was shown in phase III testing to be a mild and tolerable agent. Trial participants found lorcaserin about as tolerable as placebo, with 7% of participants in both the lorcaserin drug and placebo arms dropping out due to side effects. Lorcaserin had the lowest discontinuation rates due to adverse events of any obesity drug in a phase III trial, as compared to discontinuation rates due to adverse events for bupropion/naltrexone (26% vs 13% for placebo), phentermine/topiramate (18% vs 9% for placebo), orlistat (7% vs 4% for placebo), sibutramine (9% vs 9%) and rimonabant (15% vs 7%).

Lorcaserin produced side effects in human clinical trials, but at rates not significantly different than placebo and mostly with mild and transient severity. The most common side effect was headache, experienced by about 18% of drug arm participants compared to 11% of placebo participants. Headache was the only reported side effect to occur at a frequency greater than 5 percentage points above placebo. Other reported side effects and their rates for lorcaserin and placebo patients, respectively, were as follows: upper respiratory tract infection (14.8% vs. 11.9%), nasopharyngitis (13.4% vs. 12.0%), sinusitis (7.2% vs. 8.2%) and nausea (7.5% vs. 5.4%). Adverse events of depression, anxiety and suicidal ideation were infrequent and were reported at a similar rate in each treatment group.

On 15 September 2010 it was reported by national news-media that lorcaserin was associated with the development of cancer in laboratory rats.[31]

In December 2012, the US Drug Enforcement Administration proposed classifying lorcaserin as a Schedule IV drug because it has hallucinogenic properties and users could develop psychiatric dependencies on the drug.[12][32]

Echocardiograms for valvulopathy[edit]

Regarding the risk of cardiac fibrosis, Arena Pharmaceuticals sought to rule out an increase in the rate of valvulopathy of 20% or more because a number of anorectic drugs have been withdrawn for cardiovascular side-effects. In agreement with the FDA, Arena conducted regular and multiple echocardiograms of the phase III participants. At the 3, 6, and 12-month interval, the echocardiograms of participants of the BLOOM trial did not show any significant increase in valvulopathy over baseline, so the independent Echocardiographic Data Safety Monitoring Board (EDSMB) hired to monitor the trial allowed the trial to continue to the end.[33] BLOOM participants received 18- and 24-month follow-up echocardiograms, but these results will not be reviewed by an EDSMB. The two other Phase 3 trials provide multiple and regular echocardiograms but they were not be reviewed by an EDSMB. BLOOM participants were pre-screened to exclude valvulopathy, but BLOSSOM and BLOOM-DM participants were not. Like BLOOM, BLOSSOM showed no significant increase in valvulopathy.

Rates of new FDA-defined valvulopathy in BLOOM were as follows: lorcaserin 10 mg twice daily (2.7%) and placebo (2.3%) at Week 52 and lorcaserin 10 mg twice daily (2.6%) and placebo (2.7%) at Week 104. For BLOSSOM, rates of new FDA-defined valvulopathy in BLOSSOM at Week 52 were as follows: lorcaserin 10 mg twice daily (2.0%), 10 mg once daily (1.4%) and placebo (2.0%).

Financial aspects[edit]

In 2010, Arena Pharmaceuticals attended multiple biotechnology and pharmaceutical conferences and hosted several conference calls to discuss the Phase III results released so far. Market reaction to these results had been confused, driving Arena's stock (NASDAQ: ARNA) price to a high of over $7.00 in early 2009, and to a low of $2.61 in mid-2010. While management had stated its desire to partner lorcaserin with a large pharmaceutical company, in 2010 it raised money from private investors two separate times, raising a total of nearly $60 million. On 3 June 2010, management began to discuss the possibility of a go-it-alone strategy.[34] Piper Jaffray has forecast lorcaserin sales of $3 billion in 2015.[35] Arena has a very close financial relationship with a group of private funds under the Deerfield umbrella name (Deerfield Private Design Fund, L.P., Deerfield Private Design International, L.P., Deerfield Partners, L.P., Deerfield International Limited, Deerfield Special Situations Fund, L.P., and Deerfield Special Situations Fund International Limited) under which Deerfield has lent Arena $100 million, purchased 11 million shares, and holds 28 million warrants to purchase additional shares at prices ranging from $3.23 to $5.48.[36] On 15 September 2010 shares of Arena fell nearly 40%, from $6.85 to $4.13, on news that the lorcaserin has been linked to formation of malignant tumors in rats.[31] On 16 September, an FDA advisory panel voted 9 to 5 to recommend against approval of the drug based on concerns over both safety and efficacy, trading on Arena's stock was stopped on that date, but after hours, the stock price fell about 40 percent.[7] The stock price bottomed at $1.22 in 2011, and remained mostly under $2 per share until March 2012. Since there were no cancer experts on the FDA advisory panel, and there was no indications of tumors in studies involving Locaserin in mice, chimpanzees and humans, Arena was asked to follow up with numerous studies to clarify the rat tumor issue. Completed studies showed the tumors in rats were mostly benign, and the FDA concluded that the mammary tumors are attributable to increased prolactin, a mechanism peculiar to the rat. In May, 2012, the FDA advisory committee voted 19-4-1 to recommend Locaserin be approved by the FDA, and the stock price jumped to $5.50. The stock price rose over the next two months to about $12 per share when approved by the FDA and renamed Belviq. Since then, the stock has drifted lower, to as low as $6.65 on July 5, 2013. Early prescription data are now driving the price of the stock. Arena has partnered with Eisai Pharmaceuticals for sales of Belviq in the Americas, and with Ildong Pharmaceuticals in South Korea.

See also[edit]

References[edit]

  1. ^ a b c d e "BELVIQ (lorcaserin hydrochloride) tablet [Eisai, Inc]". DailyMed. Eisai, Inc. August 2012. Retrieved 21 October 2013. 
  2. ^ a b "FDA approves Arena obesity drug; first in 13 years". Reuters. 27 June 2012. 
  3. ^ "Belviq". Trademarkia. 23 Jun 2011. Retrieved 27 June 2012. 
  4. ^ "Lorqess". EvaluatePharma. 7 September 2010. Retrieved 13 September 2010. 
  5. ^ "Lorqess". Trademarkia. 25 March 2010. Retrieved 13 September 2010. 
  6. ^ "Lorcaserin New Drug Application". Drugs.com. 22 December 2009. 
  7. ^ a b Andrew Pollack (16 September 2010). "F.D.A. Panel Urges Denial of Diet Drug". New York Times. 
  8. ^ a b "FDA Issues Complete Response Letter for Lorcaserin New Drug Application". 23 October 2010. 
  9. ^ "New Diet Drug Lorcaserin Wins Vote From FDA Panel". webmd. 10 May 2012. 
  10. ^ a b "FDA approves lorcaserin, first weight-loss drug OK'd since 1999". Los Angeles Times. June 27, 2012. 
  11. ^ "DEPARTMENT OF JUSTICE Drug Enforcement Administration 21 CFR Part 1308, Placement of Lorcaserin into Schedule IV". 
  12. ^ a b Wilson, Megan R. (December 19, 2012). "Reg Watch". The Hill. 
  13. ^ a b Thomsen, W. J.; Grottick, A. J.; 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. (2008). "Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization". Journal of Pharmacology and Experimental Therapeutics 325 (2): 577–587. doi:10.1124/jpet.107.133348. PMID 18252809.  edit
  14. ^ US patent 6953787, Brian Smith, Jeffrey Smith, "5HT2c receptor modulators", published 2003-10-04, issued 2005-11-10 
  15. ^ US patent 7704993, Brian Smith, Charles A. Gilson, III, Jeffrey Schultz, Jeffrey Smith, "Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases", published 2004-16-06, issued 2010-27-04 
  16. ^ US patent 8207158, Brian Smith, Jeffrey Smith, "5HT2c receptor modulators", published 2011-27-05, issued 2012-26-06 
  17. ^ Spreitzer, Helmut (13 September 2010). "Lorcaserin". Österreichische Apothekerzeitung (in German) 64 (19): 1083. 
  18. ^ Millan, M. J. (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie 60 (5): 441–460. doi:10.2515/therapie:2005065. PMID 16433010.  edit
  19. ^ Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Thomsen, W. J.; Saldana, H. R.; Whelan, K. T.; Menzaghi, F.; Webb, R. R.; Beeley, N. R. A. (2005). "Discovery and SAR of new benzazepines as potent and selective 5-HT2C receptor agonists for the treatment of obesity". Bioorganic & Medicinal Chemistry Letters 15 (5): 1467–1470. doi:10.1016/j.bmcl.2004.12.080. PMID 15713408.  edit
  20. ^ Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Dosa, P. I.; Covel, J. A.; Ren, A.; Webb, R. R.; Beeley, N. R. A.; Martin, M.; Morgan, M.; Espitia, S.; Saldana, H. R.; Bjenning, C.; Whelan, K. T.; Grottick, A. J.; Menzaghi, F.; Thomsen, W. J. (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-HT2CReceptor Agonist for the Treatment of Obesity". Journal of Medicinal Chemistry 51 (2): 305–313. doi:10.1021/jm0709034. PMID 18095642.  edit
  21. ^ "Lorcaserin Hydrochloride for Obesity". [dead link]
  22. ^ "Arena Pharmaceuticals Announces Positive Phase 2b Clinical Trial Results of Novel Anti-Obesity Compound". Arena Pharmaceuticals. 13 December 2009. 
  23. ^ "Lorcaserin (APD356), a Selective 5-HT2C Agonist, Safely Induces Weight Loss in a 12-week Study of Healthy Obese Patients". Shareholder.com. 
  24. ^ http://www.arenapharm.com/wt/page/bloom.html[dead link]
  25. ^ Smith, Steven R.; Neil J. Weissman, M.D., Christen M. Anderson, M.D., Ph.D., Matilde Sanchez, Ph.D., Emil Chuang, M.D., Scott Stubbe, M.B.A., Harold Bays, M.D., William R. Shanahan, M.D. (July 15, 2010). "Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management". N Engl J Med (363): 245–256. doi:10.1056/NEJMoa0909809. PMID 20647200. Retrieved 4 April 2011. 
  26. ^ http://www.arenapharm.com/wt/page/blossom.html[dead link]
  27. ^ O'Neil, P. M.; Smith, S. R.; Weissman, N. J.; Fidler, M. C.; Sanchez, M.; Zhang, J.; Raether, B.; Anderson, C. M.; Shanahan, W. R. (2012). "Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study". Obesity 20 (7): 1426–1436. doi:10.1038/oby.2012.66. PMID 22421927.  edit
  28. ^ Arena Pharmaceuticals Announces Notification of Tentative September 16th FDA Advisory Committee Meeting to Review Lorcaserin for Weight Management, 2 June 2010
  29. ^ Pollack, Andrew (16 September 2010). "F.D.A. Panel Rejects Diet Pill". The New York Times. 
  30. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm
  31. ^ a b Larkin, Catherine (15 September 2010). "FDA staff says Arena diet pill linked to cancer". SFGate. 
  32. ^ "Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV". 
  33. ^ "Arena Pharmaceuticals' Lorcaserin for Obesity Passes Major Safety Milestone". Arena Pharmaceuticals. 17 March 2008. 
  34. ^ Arena Pharmaceuticals to Receive $35.5 Million from Deerfield Management, 3 June 2010
  35. ^ "Arena weight-loss data expected to underwhelm". Reuters. 13 September 2009. 
  36. ^ U.S. Securities and Exchange Commission: Purchase and Exchange Agreement

External links[edit]