Lorcaserin Data Fails to Convince FDA Advisors

After presenting to the FDA Advisory Committee on Sibutramine on Wednesday, I had to hurry off to join the faculty of the 2nd SCOPE Summer School on the Management of the Obese Patient, in Cambridge, UK.

Fortunately, I was able to follow most of yesterday’s FDA advisory meeting on the 5-HT2c antagonist lorcaserin (Lorqess), another obesity drug (thank you Lisa LaMotta for your play-by-play live blogging on Minyanville), at the end of which the advisors voted 9 to 5 against its approval.

Clearly, the committee appeared unswayed by the weight-loss efficacy of lorcaserin (which only narrowly made the categorical criterium of the FDA but failed the placebo-substracted 5% weight loss margin) and harboured continuing concerns regarding potential risks of neoplasms and valvular heart disease. Other adverse events, which the advisors considered minor, were a higher incidence for depression as well as cognitive adverse events, such as forgetfulness.

Along with recommendations for additional animal studies of neoplasms, the panel suggested conducting clinical trials in patients with comorbid conditions, such as diabetes and CVD.

With this vote, if accepted by the FDA (which is not bound by the Committee decision), the future of obesity drugs may appear bleak for the foreseeable future.

For one, it appears that advisors are not convinced that an average weight loss of 5% is in itself enough to have a meaningful beneficial effect – even if a notable subset of subjects go on to lose 10 or even 15% of their weight.

The onus on companies will be to show that this degree of weight loss is indeed associated with significant health benefits – something that is impossible to show in otherwise “healthy” obese subjects (i.e. Edmonton Obesity Staging System (EOSS) Stage 0 patients).

While the advisors are not necessarily looking for weight-independent effects of weight loss agents, they certainly want to see at least a hint of improvement in health-related measures of obesity.

Thus, as one advisor noted in the context of sibutramine, “this drug appears to deliver weight loss without any of the health benefits that should be expected with losing weight”.

This means that future obesity-drug development programs must essentially exclude “healthy” obese individuals (EOSS Stage 0) patients from their studies, rather than continuing to exclude patient with CVD or diabetes from their trial programs.

I am sure that had Abbott been able to present data from the SCOUT study, showing an improvement in quality of life or in any of the many obesity related comorbidities, the 8 to 8 vote may well have turned out differently.

Similarly, had Arena been able to present convincing data on the improvement of diabetes, dyslipidemia, sleep apnea, back pain or any other obesity related health problem, even if only in the subset of patients losing 10% or 15% of their weight, the advisors may have been swayed to look at the risk/benefit ratio more favourably.

Personally, as blogged before, I continue to feel strongly that the current “all-comers” approach to obesity drugs is doomed to failure as there is really no biological rationale to expect that any single drug will “on average” prove effective in all patients with a condition as heterogeneous and complex as obesity. Thus, while it may well be possible to find drugs that are highly effective (and hopefully safe) in a subset of obese patients, it is highly unlikely that we will ever find a drug that works for everyone.

Hopefully, we will not have to look back at the past two days as essentially the end of pharmacological treatments for obesity.

Rather, I believe that drug companies must hear the clear message delivered by the advisors that they will need to refocus their attention to demonstrating that their drugs do in fact deliver on the expected health benefits of weight loss rather than just weight loss alone.

Cambridge, UK

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Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR, & Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group (2010). Multicenter, placebo-controlled trial of lorcaserin for weight management. The New England journal of medicine, 363 (3), 245-56 PMID: 20647200