Rarely a day goes by without mention in the media of obesity and its comorbidities, including type 2 diabetes mellitus and hypertension. There are constant reports on the significant impact of the obesity epidemic on patients, healthcare resources, and society. Patients, physicians and politicians have long been highlighting the need for safe, effective, and simple treatments.
Dietary and behavioral modifications have a limited impact, and can be difficult to sustain in the long term. Bariatric surgery is the most effective option, but it is expensive, comparatively risky, and only available to a small fraction of the millions who are overweight and obese. Taking a tablet seemed to provide a treatment approach that might balance safety and efficacy, but the available drugs had limited efficacy, were often poorly tolerated, and no new agent had established itself in years.
Then, in 2012, lorcaserin (Arena Pharmaceuticals and Eisai's Belviq) and a phentermine/topiramate extended-release combination product (Vivus's Qsymia) were both approved for chronic weight control in the United States, and later that year, Qsymia was launched. The launch of Belviq in the U.S. market is imminent, and it is currently under review with the regulatory authorities Europe.
It would seem that, at first glance, these novel obesity treatments would fulfill a number of the criteria required for becoming great commercial successes: widespread public and professional awareness of the problem check; chronic disease check; increasing numbers of drug-treatable patients check; high patient and physician demand for novel treatments check; and limited competition check. Moreover, Qsymia is twice as efficacious as any other available agent, and Belviq has demonstrated benefits across a range of the comorbidities associated with obesity. So with these factors in their favor, surely these agents are a safe bet to be blockbusters. Sorry. No.
Why? Because for patients, physicians, and regulatory authorities, once bitten, twice shy.' In fact, the critical stakeholders in the obesity field have been bitten more than once. Safety concerns have plagued obesity drugs, ranging from the cardiac valvulopathy associated with the fen-phen combination of fenfluramine (Wyeth's Pondimin) or dexfenfluramine (Wyeth's Redux), and phentermine (UCB's Ionamin, Teva's branded generic Adipex-P, generics), through to the depression and suicidality associated with rimonabant (Sanofi's Acomplia), and the heart rate and blood pressure changes associated with sibutramine (Abbott's Meridia/Reductil). Even the glucagon-like peptide -1 (GLP-1) analogues, such as liraglutide (Novo Nordisk's Victoza), which is widely used in diabetes and is under investigation for obesity, have been linked with pancreatitis and cancer.
Regulatory authorities are forced to walk a tightrope between the opposing need for new therapies for obesity and the need to ensure that history does not repeat. To do this, approved antiobesity agents are now subject to various checks and balances, including Risk Evaluation and Mitigation Strategies (REMSs) and/or postmarketing cardiovascular outcomes trials (CVOTs). Such measures may highlight a safety signal and reduce the risks to patients, but they also limit the therapeutic potential of these agents, and they can create uncertainty in the minds of prescribers and providers.
Primum non nocere, or first, do no harm, is one of the principal concepts of medical ethics, and it would appear that physicians have not forgotten this important tenet. Recently published data from a Decision Resources primary market research survey shows that more U.S. physicians are primarily influenced by the safety of novel antiobesity agents than efficacy (see graphic below). This is reflected in the initial sales of Qsymia. Since its launch in September 2012, the uptake of Qsymia has been slow. Although it is the most efficacious agent available, the risks of birth defects and adverse central nervous system effects are making prescribers wary, and it was twice rejected by the European regulatory authorities. Safety concerns are also likely to limit uptake of Belviq. Belviq is a centrally acting agent with documented adverse CNS effects, and its serotonergic mechanism of action has addictive potential. Consequently, it is undergoing DEA review, and has been for some time. Moreover, having a similar mechanism of action to dexfenfluramine and fenfluramine raises the fear of a new fen-phen controversy, as Belviq's modest efficacy may encourage some physicians to boost weight reduction by the addition of generic phentermine. Other investigational agents, such as a sustained-release bupropion/naltrexone combination (Orexigen Therapeutics and Takeda's Contrave) will also be subject to the same scrutiny.
Despite the growing obesity epidemic, and the seemingly huge commercial possibilities, the chances of a blockbuster drug are not as great as they were once thought to be. It is perhaps better to remember that when considering the potential for antiobesity agents the only safe bet is that physicians, providers and regulators will take a safety first approach.
Tim Blackstock, M.B. Ch.B., is a business insights analyst in the Cardiovascular, Metabolic, and Renal Disorders team at Decision Resources.
An in-depth analysis of the obesity therapeutic area and an epidemiology driven sales forecast model are presented in Decision Resources. Obesity Pharmacor.