The Uphill Battle Facing Antiobesity Drugs

COMMENTARY The uphill battle facing antiobesity drugs

M Daubresse1,2 and GC Alexander1,2,3

International Journal of Obesity (2015) 39, 377–378; doi:10.1038/ Evaluation Study of Cardiovascular Endpoints and Outcomes trial ijo.2014.169 was terminated and rimonabant was removed from the European market in January 2009. Three years later, the FDA voted against the approval of lorcaserin (Belviq), an anorectic with serotonergic Almost 70% of adults in the United States are overweight, and of properties, owing to safety and efficacy concerns, and despite these, one-third are clinically obese.1 Obesity is associated with obtaining approval in June 2012, lorcaserin has been sparsely mortality and morbidity from a host of conditions ranging from prescribed. cardiovascular diseases and diabetes to osteoarthritis and cancer.1 Most recently, the fixed-dose combination of phentermine and The estimated direct cost of obesity totals nearly $200 billion dollars topiramate was brought to market as Qsymia. Both phentermine, annually.1 Federal, state and local governments have implemented which acts as an appetite suppressant and topiramate, an numerous policy strategies to mitigate the impact of the obesogenic anticonvulsant with weight loss side effects, were previously on environment on individuals.2 However, despite these efforts and the market as individual agents with FDA-approved indications for decades of research and development, the role of medicines in the weight loss and seizures, respectively. As the first fixed-dose routine management of obesity is anything but clear. combination of its kind, with a novel mechanism of action, Amphetamines and related sympathomimetic drugs, such as investors had high expectations for Qsymia’s potential. However, diethylproprion (Tenuate), benzphetamine (Didrex), phentermine its approval in July 2012 was not without difficulty and despite (Adipex) and phendimetrazine (Bontril), were some of the earliest enthusiasm about its potential value, it has been sparsely adopted, 5 antiobesity therapies approved by the FDA (Food and Drug surprising those who bet heavily on its success. From November Administration). Although use of these drugs is associated with 2010 to October 2013, Qsymia made up fewer than 2% of the short-term weight loss, their adoption in clinical practice has been volume of antiobesity medicines prescribed. A variety of reasons limited. Although use of these drugs is associated with short-term account for Qsymia’s troubles, including: a lack of long-term weight loss and some physicians may commonly prescribe them, efficacy data; safety concerns such as fetal toxicity, increased heart their adoption in clinical practice has been limited. These agents rate, and suicidal ideation; tolerability issues such as dizziness; and currently capture a trivial amount of the total market for an FDA requirement that the product be dispensed through prescription drugs, and of the obesity drugs approved for use in special mail-order programs. the United States phentermine (Adipex) remains the most The barriers faced by individual anorectic products belie larger frequently prescribed (Table 1). In the 1970’s, these drugs were regulatory and clinical challenges to their mainstream adoption, followed by the approval of a serotoninergic anorectic, fenflur- and contribute to the irony that despite American’s penchant for amine, whose adoption was also limited by risks of valvular heart high rates of pharmaceutical use, obesity drugs have fared disease and pulmonary hypertension. After a 1992 clinical trial of a remarkably poorly in the market. Similar to other chronic diseases, fenfluramine and phentermine combination yielded significantly obesity requires long-term management, yet the FDA indication greater weight loss results compared with either drug used alone for most antiobesity agents are for short-term use, rates of and fewer fenfluramine-related side effects, the popularity of the discontinuation are extremely high, and most patients regain combination skyrocketed. However, increasing evidence of the weight lost after cessation of therapy.6 Pharmacologic agents are association between serotoninergic anorectics such as ‘fen–phen’ not front line therapies for the management of obesity, nor do and dexfenfluramine, and valvular heart disease and pulmonary they represent the standard of care. For example, recently hypertension, led to their market withdrawal several years later. developed guidelines for the management of obesity from the Several other products have also stumbled during either late American Heart Association and other professional societies phase development or upon their market debut. Sibutramine contain no questions specific to pharmacotherapies; instead, the (Meridia), a serotonin–norepinephrine reuptake inhibitor guidelines focus on the association between weight loss and approved in 1997, was associated with only modest reductions cardiovascular morbidity and mortality, and the comparative in weight loss and was later withdrawn from the market in effectiveness of dietary weight loss strategies.7 Also hindering the October 2010, owing to the occurrence of adverse events among adoption of obesity agents is the presence of effective surgical FDA-mandated study participants for whom sibutramine was alternatives that are not only unavailable for conditions such as likely contraindicated.3 The adoption of orlistat (Xenical), which hypertension, hyperlipidemia and diabetes, but also contribute to prevents the absorption of fat through the inhibition of lipase, has the management of these cardiovascular risk factors. Furthermore, been limited by its gastrointestinal side effects. Rimonabant pivotal clinical trials used for market access, in addition to (Acomplia), a cannabinoid receptor agonist, was approved for use consistently high dropout rates approaching 40–50%,8 use a in Europe in 2006. Rimonabant later failed to receive approval combination of both drug and behavioral therapies, and base from the FDA in 2007, owing to concerns related to adverse primary endpoints on FDA guidance establishing a benchmark of psychiatric effects. Following a controversial decision by the a mean drug-associated weight loss that exceeds the mean European Medicines Agency,4 the Comprehensive Rimonabant placebo weight loss by 5%. Although there are numerous social,

1Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 2Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MD, USA and 3Division of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA E-mail: [email protected] Accepted article preview online 12 September 2014; advance online publication, 7 October 2014 Commentary 378

Table 1. Leading antiobesity medications by treatment class, 2011–2013

Active compounds Mechanism of Date of FDA Available as Prescription volume (in Percent of action approval generic thousands) prescriptions

Phentermine (adipex) Anorexigenic May-59 Yes 19 844 87 Phendimetrazine (bontril) Anorexigenic Jul-76 Yes 1493 6.6 Diethylproprion (tenuate) Anorexigenic Aug-59 Yes 705 3 Phentermine/topiramate (qsymia) Anorexigenic Jul-12 No 345 1.5 Benzphetamine (didrex) Anorexigenic Oct-60 Yes 158 0.7 Orlistat (xenical) Lipase inhibitor Apr-99 Yes 157 0.7 Lorcaserin (belviq) Anorexigenic Jun-12 No 107 0.5 Sibutramine (meridia) Anorexigenic Nov-97 Discontinued 0.2 0 Total —— — 22 809 100 Sources: Food and Drug Administration; IMS Health National Prescription Audit, 2011–2013.

physiological and metabolic benefits that may coincide with such funding sources had no role in the design and conduct of the study, analysis or changes, it remains unclear how temporary periods of drug- interpretation of the data and preparation or final approval of the manuscript before assisted weight loss affect longevity.9 As with statins, large, well- publication. The statements, findings, conclusions, views and opinions contained and controlled clinical trials demonstrating the cardiovascular benefits expressed in this article are based in part on data obtained under license from the of antiobesity agents will be vital in demonstrating their ultimate following IMS Health Incorporated information service(s): National Prescription Audit value, rather than solely their impact on patients’ body (2011–2013). The statements, findings, conclusions, views and opinions contained mass index. and expressed herein are not necessarily those of IMS Health Incorporated or any of For the near-term, most research and development of its affiliated or subsidiary entities. pharmacotherapies for weight loss is focusing on combining existing molecules into fixed-dose combination therapies. Despite Qsymia’s fate, early results from Phase III clinical trials report favorably on the performance of a fixed-dose combination of REFERENCES buproprion, a nontricyclic antidepressant approved for depression 1 IOM (Institute of Medicine). Accelerating Progress in Obesity Prevention: Solving the and smoking cessation, and naltrexone, an opioid receptor Weight of the Nation. The National Academies Press: Washington, DC, USA, 2012. antagonist approved for alcohol and opioid dependence. Other 2 Dietz WH, Benken DE, Hunter AS. Public health law and the prevention and fixed-dose combinations in Phase III trials include bupropion and control of obesity. Milbank Q. 2009; 87:215–227. zonisamide, an anticonvulsant, and metreleptin/pramlintide, 3 Haslam D. Sibutramine: gone, but not forgotten. Pract Diab Int 2010; 27:96–97. which combines analogs of the human hormone leptin and 4 Topol EJ, Bousser M-G, Fox KAA, Montelescot G. Termination of the CRESCENDO amylin.10 Based on the experience of their historical counterparts, trial—Authors' reply. Lancet 2010; 376: 1984–1985. the success of future therapies will largely rely on the amount and 5 Staton T. ‘With Qsymia still flailing, Vivus to cut 20 jobs, replace CFO’. Available at fi fl quality of research efforts devoted to achieving a deeper http://www. ercepharma.com/story/qsymia-still- ailing-vivus-cut-20-jobs-replace-cfo/ 2013-11-06?utm_medium= nl&utm_source = internal (accessed 14 January 2014). understanding of the body’s caloric regulatory mechanisms.11,12 fi 6 Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obe- Although the past ve decades may dampen the hopes of success sity. Ann Intern Med. 1993; 119:707–713. for therapies entering the market in the near future, there remains 7 Jensen MD, Ryan DH. New obesity guidelines: promise and potential. JAMA 2014; an undeniably large need for the development of safe and 311:23–24. effective antiobesity drugs. 8 Ware JH. Interpreting incomplete data in studies of diet and weight loss. NEnglJ Med. 2003; 348: 2136–2137. 9 Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial CONFLICT OF INTEREST —a prospective controlled intervention study of bariatric surgery. J Intern Med. Dr Alexander is Chair of the FDA’s Peripheral and Central Nervous System Advisory 2013; 273:219–234. Committee, serves as a paid consultant to IMS Health, and serves on an IMS Health 10 ClinicalTrials.gov (metreleptin pramlintide). Available at www.clinicaltrials. scientific advisory board. This arrangement has been reviewed and approved by gov/ct2/results?term = metreleptin+pramlintide&Search = Search.clinic (accessed Johns Hopkins University in accordance with its conflict of interest policies. 14 January 2014). 11 Blomain ES, Dirhan DA, Valentino MA, Kim GW, Waldman SA. Mechanisms of weight regain following weight loss. ISRN Obes 2013; 16: 210524. ACKNOWLEDGEMENTS 12 Ochner CN, Barrios DM, Lee CD, Pi-Sunyer FX. Biological mechanisms that GCA is supported by the Agency for Healthcare Research and Quality (RO1 promote weight regain following weight loss in obese humans. Physiol Behav HS0189960) and the National Heart, Lung and Blood Institute (R01HL107345). The 2013; 120:106–113.