Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A review of late-stage CNS drug candidates for the treatment of obesity

International Journal of Obesity volume 37, pages 107–117 (2013)Cite this article

Subjects

Abstract

Obesity is an important causative factor in morbidity, disability and premature death. Increasing levels of obesity will impose enormous health, financial and social burdens on worldwide society unless effective interventions are implemented. For many obese individuals, diet and behavioural modification need to be supplemented by pharmacotherapy. Preclinical research has revealed a greater understanding of the complex nature of the hypothalamic regulation of food intake and has generated a wide range of new molecular targets for the development of drug candidates for obesity treatment. As shown by the clinical results that have been obtained with this next generation of therapies, some approaches, for example, fixed-dose drug combinations, have already demonstrated an ability to deliver levels of efficacy that are not achievable with the current antiobesity drug therapies. The regulatory and marketing landscape for development, registration and commercialisation of novel centrally acting drugs for treatment of obesity and related metabolic disorders has changed substantially in recent years. Now a much greater emphasis is placed on tolerability and safety, as well as efficacy. In this review we briefly describe the therapeutic approaches to tackle obesity that are in late-stage clinical development. We then discuss drugs in late-stage development for the treatment of obesity and also future directions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. International Association for the Study of Obesity [IASO] 2011, http://www.iaso.org.

  2. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP . The continuing epidemics of obesity and diabetes in the United States. J Am Med Ass 2001; 286: 1195–1200.

    Article  CAS  Google Scholar 

  3. Pi-Sunyer X . The obesity epidemic: pathophysiology and consequences of obesity. Obesity Res 2002; 10: 97S–104S.

    Article  Google Scholar 

  4. National Cholesterol Education Program. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) Final report. Circulation 2002; 106: 3143–3420.

    Article  Google Scholar 

  5. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317: 703–713.

    Article  Google Scholar 

  6. Montani J-P, Antic V, Yang Z, Dulloo A . Pathways from obesity to hypertension: from the perspective of a vicious triangle. Int J Obes 2002; 26: S28–S38.

    Article  CAS  Google Scholar 

  7. Beckman JA, Creager MA, Libby P . Diabetes and atherosclerosis. Epidemiology, pathophysiology, and management. J Am Med Ass 2002; 287: 2570–2581.

    Article  CAS  Google Scholar 

  8. Diabetes UK 2010, http://www.diabetes.org.uk.

  9. International Obesity Task Force [IOTF] 2010, http://www.iotf.org.

  10. Wolk R, Shamsuzzaman AS, Somers VK . Obesity, sleep apnoea and hypertension. Hypertension 2003; 42: 1067–1074.

    Article  CAS  Google Scholar 

  11. Felson DT . Weight and osteoarthritis. Am J Clin Nutr 1996; 63: 430S–432S.

    Article  CAS  Google Scholar 

  12. Bhole V, deVera M, Rahman MM, Krisnan E, Choi H . Epidemiology of gout in women: 52-year follow up of a prospective cohort. Arthritis Rheum 2010; 62: 1069–1076.

    Article  Google Scholar 

  13. Heshka S, Heymsfield S . Obesity and gallstones. In: Bjorntorp P (ed). International Textbook of Obesity. Wiley: Chichester, 2001, pp 399–409.

    Chapter  Google Scholar 

  14. James WPT, Chunming C, Inoue S . Appropriate Asian body mass indices? Obesity Rev 2002; 3: 137–232.

    Article  Google Scholar 

  15. Deutenberg P, Deurenberg-Yap M, Guricci S . Asians are different from Caucasians and from each other in their body mass index/body fat percent relationship. Obesity Rev 2002; 3: 141–146.

    Article  Google Scholar 

  16. Moon OR, Kim NS, Jang SM, Yoon TH, Kim O . The relationship between body mass index and the prevalence of obesity-related diseases based on the 1995 National Health Interview Survey in Korea. Obes Rev 2002; 3: 191–196.

    Article  CAS  Google Scholar 

  17. Centers for Disease Control and Prevention (CDC). Differences in prevalence of obesity among black, white, and Hispanic adults - United States, 2006-2008. MMWR Morb Mortal Wkly Rep 2009; 58: 740–744.

    Google Scholar 

  18. McNeely W, Benfield P . Orlistat. Drugs 1998; 56: 241–249.

    Article  CAS  Google Scholar 

  19. Déspres JP, Golay A, Sjostrom L, Rimonabant in Obesity Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121–2134.

    Article  Google Scholar 

  20. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S . Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389–1397.

    Article  CAS  Google Scholar 

  21. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF . Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660–1672.

    Article  CAS  Google Scholar 

  22. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J . Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006; 295: 761–775.

    Article  CAS  Google Scholar 

  23. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup AV . A meta-analysis of the efficacy and safety of the anti-obesity agent Rimonabant]. Ugeskr Laeger 2007; 169: 4360–4363.

    PubMed  Google Scholar 

  24. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al., SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363: 905–917.

    Article  CAS  Google Scholar 

  25. Meridia US Product Label 2010, http://www.rxabbott.com/pdf/meridia.pdf.

  26. Brenot F, Herve P, Petitpretz P, Parent F, Duroux P, Simonneau G . Primary pulmonary hypertension and fenfluramine use. Br Heart J 1993; 70: 537–541.

    Article  CAS  Google Scholar 

  27. Abenheim L, Moride Y, Bremost F, Rich S, Benichou J, Kurz X . Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–616.

    Article  Google Scholar 

  28. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581–588.

    Article  CAS  Google Scholar 

  29. Gardin JM, Schumacher D, Constantine G, Davis KD, Leung C, Reid CL . Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. J Am Med Ass 2000; 283: 1703–1709.

    Article  CAS  Google Scholar 

  30. VIVUS Inc. Press release 2011, http://ir.vivus.com/releases.cfm.

  31. VIVUS Inc. Press release 2010, http://ir.vivus.com/releases.cfm.

  32. Arena Pharmaceuticals Press release. 2012, http://invest.arenapharm.com/releases.cfm.

  33. Food and Drug Administration (FDA). Center for Drug Evaluation and Research (CDER). Draft. Guidance for Industry. Developing Products for Weight Management. 2007, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071612.pdf.

  34. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guidance on Clinical Evaluation of Medicinal Products Used in Weight Control 2007, http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003264.pdf.

  35. Heal DJ, Gosden J, Smith SL . Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders. Br J Clin Pharmacol 2009; 68: 861–874.

    Article  CAS  Google Scholar 

  36. Haddock CK, Poston WSC, Dill PL, Foreyt JP, Ericsson M . Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomised clinical trials. Int J Obes Relat Metab Disor 2002; 26: 262–273.

    Article  CAS  Google Scholar 

  37. Lee MD, Somerville EM, Kennett GA, Dourish CT, Clifton PG . Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice. Psychopharmacology 2004; 176: 39–49.

    Article  CAS  Google Scholar 

  38. Linné Y, Hemmingsson E, Adolfsson B, Ramsten J, Rössner S . Patient expectations of obesity treatment-the experience from a day-care unit. Int J Obes Relat Metab Disord 2002; 26: 739–741.

    Article  Google Scholar 

  39. Kaly P, Orellana S, Torrella T, Takagishi C, Saff-Koche L, Murr MM . Unrealistic weight loss expectations in candidates for bariatric surgery. Surg Obes Relat Dis 2008; 4: 6–10.

    Article  Google Scholar 

  40. Dutton GR, Perri MG, Stine CC, Goble M, Van Vessem N . Comparison of physician weight loss goals for obese male and female patients. Prev Med 2010; 50: 186–188.

    Article  Google Scholar 

  41. Rabner JG, Greenstein RJ . Obesity surgery: expectation and reality. Int J Obes 1991; 15: 841–845.

    CAS  PubMed  Google Scholar 

  42. Wee CC, Jones DB, Davis RB, Bourland AC, Hamel MB . Understanding patients' value of weight loss and expectations for bariatric surgery. Obesity Surg 2006; 16: 496–500.

    Article  Google Scholar 

  43. Walfish S, Brown TA . Patient expectations of weight loss from bariatric surgery. Bariatric Nurs Surg Patient Care 2006; 1: 205–210.

    Article  Google Scholar 

  44. Smiertka JK, MacPherson BH . Bariatric surgery postoperative behavioural change: the importance of ongoing assessment and teaching. Obesity Surg 1995; 5: 337–340.

    Article  CAS  Google Scholar 

  45. Bolen SD, Clark JM, Richards TM, Shore AD, Goodwin SM, Weiner JP . Trends in and patterns of obesity reduction medication use in an insured cohort. Obesity 2010; 18: 206–209.

    Article  Google Scholar 

  46. Vickers SP, Dourish CT, Kennett GA . Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 2001; 41: 200–209.

    Article  CAS  Google Scholar 

  47. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000; 102: 2836–2841.

    Article  CAS  Google Scholar 

  48. Rothman RB, Baumann MH . Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther 2002; 95: 73–88.

    Article  CAS  Google Scholar 

  49. Setola V, Roth BL . Why mice are neither miniature humans nor small rats: a cautionary tale involving 5-hydroxytryptamine-6 serotonin receptor species variants. Mol Pharmacol 2003; 64: 1277–1278.

    Article  CAS  Google Scholar 

  50. Fiorella D, Rabin RA, Winter JC . The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis. Psychopharmacology 1995; 121: 347–356.

    Article  CAS  Google Scholar 

  51. Chojnacka-Wójcik E, Kłodziñska A . Involvement of 5-hydroxytryptamine 2A (5-HT2A) receptors in the mediation of the discriminative stimulus properties of (+/−)DOI in rats. Pol J Pharmacol 1997; 49: 299–304.

    PubMed  Google Scholar 

  52. Griffith JD, Nutt JG, Jasinski DR . A comparison of fenfluramine and amphetamine in man. Clin Pharmacol Ther 1975; 18: 563–570.

    Article  CAS  Google Scholar 

  53. Vickers SP, Benwell KR, Porter RH, Bickerdale MJ, Kennett GA, Dourish CT . Comparative effects of continuous infusion of mCPP, Ro 60-0175 and d-amphetamine on food intake, water intake, body weight and locomotor activity in rats. Br J Pharmacol 2000; 130: 1305–1314.

    Article  CAS  Google Scholar 

  54. Vickers SP, Easton N, Webster LJ, Wyatt A, Bickerdale MJ, Dourish CT et al. Oral administration of the 5-HT2C receptor agonist, mCPP, reduces body weight gain in rats over 28 days as a result of maintained hypophagia. Psychopharmacology 2003; 167: 274–280.

    Article  CAS  Google Scholar 

  55. Kennett G, Adams D, Bentley J, Benwell K, Bickerdike M et al. VER-8775, a novel selective orally active 5-HT2C receptor agonist, reverses weight gain in mice with dietary-induced obesity. British Pharmacological Society - PA2 Online 2004, Poster 018P.

  56. Dourish CT, Adams DR, Bentley J, Benwell K, Bickerdike MJ, Harrison K et al. Discovery and development of selective 5-HT2C receptor agonists for obesity. Fundam Clin Pharmacol 2004; 18, SAT S1.4, 127–134.

    Article  Google Scholar 

  57. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D . Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 2008; 325: 577–587.

    Article  CAS  Google Scholar 

  58. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S et al. Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010; 363: 245–256.

    Article  CAS  Google Scholar 

  59. Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P, Turner P . International trial of long-term dexfenfluramine in obesity. Lancet 1989; 2: 1142–1145.

    Article  CAS  Google Scholar 

  60. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al., for the BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM Trial. J Clin Endocrinol Metab 2011; 96: 3067–3077.

    Article  CAS  Google Scholar 

  61. Arena Pharmaceuticals Press release. 2010 http://invest.arenapharm.com/releases.cfm.

  62. Shram MJ, Schoedel KA, Bartlett C, Shazer RL, Anderson CM, Sellers EM . Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT(2C)) receptor agonist, in recreational polydrug users. Clin Pharmacol Ther 2011; 89: 683–692.

    Article  CAS  Google Scholar 

  63. Shram MJ, Schoedel KA, Bartlett C, Shazer RL, Anderson CM, Sellers EM . Abuse potential assessment of lorcaserin, a selective and potent agonist at the serotonin 2C (5-HT2C) receptor, in healthy male and female recreational polydrug users. Clin Pharmacol Ther 2010; 87 (Suppl 1): S10.

    Google Scholar 

  64. Kang JG, Park CY, Kang JH, Park YW, Park SW . Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity. Diabetes Obes Metab 2010; 12: 876–882.

    Article  CAS  Google Scholar 

  65. Hendricks EJ, Greenway FL, Westman EC, Gupta AK . Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring) 2011; 19: 2351–2360.

    Article  CAS  Google Scholar 

  66. Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998; 352: 167–172.

    Article  Google Scholar 

  67. Finer N, Bloom SR, Frost GS, Banks LM, Griffiths J . Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study. Diabetes Obes Metab 2000; 2: 105–112.

    Article  CAS  Google Scholar 

  68. Weintraub M, Sundaresan PR, Madan M, Schuster B, Balder A, Lasagna L et al. The enhancement of behaviour modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Long-term weight control study I (weeks 0–34). Clin Pharmacol Ther 1992; 51: 586–594.

    Article  CAS  Google Scholar 

  69. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005; 142: 532–546.

    Article  CAS  Google Scholar 

  70. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC . Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes 1998; 22: S18–S28.

    CAS  Google Scholar 

  71. Prow MR, Lancashire B, Aspley S, Heal DJ, Kilpatrick IC . Additive effects on rat brain 5-HT release of combining phentermine with dexfenfluramine. Int J Obes 2001; 25: 1450–1453.

    Article  CAS  Google Scholar 

  72. Tao R, Fray A, Aspley S, Brammer R, Heal D, Auerbach S . Effects on serotonin in rat hypothalamus if d-fenfluramine, aminorex, phentermine and fluoxetine. Eur J Pharmacol 2002; 445: 69–81.

    Article  CAS  Google Scholar 

  73. Gardin JM, Weissman NJ, Leung C, Panza JA, Fernicola D, Davis KD et al. Clinical and echocardiographic follow-up of patients previously treated with dexfenfluramine or phentermine/fenfluramine. J Am Med Ass 2001; 286: 2011–2014.

    Article  CAS  Google Scholar 

  74. Richelson E, Pfenning M . Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol 1984; 104: 277–286.

    Article  CAS  Google Scholar 

  75. Aubin HJ, Lebargy F, Berlin I, Bidaut-Mazel C, Chemali-Hudry J, Lagrue G . Efficacy of bupropion and predictors of successful outcome in an sample of French smokers: a randomized placebo-controlled trial. Addiction 2004; 99: 1206–1218.

    Article  CAS  Google Scholar 

  76. Gadde KM, Zhang W, Foust MS . Bupropion treatment of olanzapine-associated weight gain: an open-label, prospective trial. J Clin Psychopharmacol 2006; 26: 409–413.

    Article  CAS  Google Scholar 

  77. Contrave NDA. 2010 http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm235671.pdf.

  78. Orexigen Therapeutics Inc. Press release 2011, http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-news&nyo=0.

  79. Rowley H, Butler SA, Prow MR, Dykes SG, Aspley S, Kilpatrick IC et al. Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats. Synapse 2000; 38: 167–176.

    Article  CAS  Google Scholar 

  80. Astrup A, Toubro S . Topiramate: a new potential pharmacological treatment for obesity. Obesity Res 2004; 12 (Suppl): 167S–173S.

    Article  CAS  Google Scholar 

  81. Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obesity Res 2003; 11: 722–733.

    Article  CAS  Google Scholar 

  82. Rosenstock J, Hollander P, Gadde KM, Sun X, Strauss R, Leung A, OBD-202 Study Group. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care 2007; 30: 1480–1486.

    Article  CAS  Google Scholar 

  83. Vullo D, Franchi M, Gallori E, Antel J, Scozzafava A, Supuran CT . Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. J Med Chem 2004; 47: 1272–1279.

    Article  CAS  Google Scholar 

  84. Vivus Press Release. 2010, http://ir.vivus.com/releasedetail.cfm?ReleaseID=537928.

  85. Qnexa NDA 2010, http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm218824.pdf.

  86. Orexigen website. http://www.orexigen.com/.

  87. Lorcaserin NDA. 2010, http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm225631.pdf.

  88. Hanotin C, Thomas F, Jones SP, Leutenegger E, Drouin P . A comparison of sibutramine and dexfenfluramine in the treatment of obesity. Obesity Res 1998; 6: 285–291.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. RenaSci Consultancy Limited, Biocity, Nottingham, UK

    D J Heal, J Gosden & S L Smith

Authors
  1. D J Heal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Gosden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S L Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D J Heal.

Ethics declarations

Competing interests

S Smith, J Gosden and D Heal are full-time employees of RenaSci Ltd, which is a commercial provider of consultancy and experimental services. D Heal is a shareholder in RenaSci Ltd.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Heal, D., Gosden, J. & Smith, S. A review of late-stage CNS drug candidates for the treatment of obesity. Int J Obes 37, 107–117 (2013). https://doi.org/10.1038/ijo.2012.26

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2012.26

Keywords

  • CNS drugs
  • Lorcaserin
  • Qnexa
  • Contrave
  • regulatory environment

Search

Advanced search

Quick links