FDA obesity drug guidance may need to be taken to heart

If there are any clues to be found about how the FDA plans to test the safety of obesity drugs from now on, it probably comes from its guidance on diabetes therapies. That is the likely scenario following two days of advisory committee hearings this week on the issue, with expert advisers recommending that companies need to run cardiovascular risk trials even on those treatments that do not show a safety signal.

Given where they stand in the approval queue and the analysis that has already been done, the current crop of very late stage obesity drugs probably will not be affected much by any policy emerging from the regulator. However, the path forward for such earlier stage products as Orexigen’s Empatic may be more complicated by new clinical requirements.

Big risk

The long history of safety issues arising from weight-loss drugs and a huge and diverse population that might take them – more than one-third of Americans are estimated to be obese – has the FDA understandably worried about the potential for widespread harm. Of the three of the current wave of obesity drugs that are engaged in their second tries at US approval, news could come in less than three weeks from Vivus’ Qnexa (Event - Safety worries still overshadow Qnexa, February 14, 2012).

Orexigen’s Contrave is in the midst of launching a cardiovascular outcomes trial in 10,000 patients that the FDA has agreed will provide sufficient safety data on an interim analysis triggered by 87 events, which analysts from Leerink Swann believe will allow for approval in 2014 (FDA breathes life into Orexigen with new clinical plan, September 21, 2011). The third candidate, Arena’s Lorqess, has been forced to deal with worries over cancer in rats, another sign of just how sensitive the FDA and its expert advisers have been to safety issues with these agents (Event - Cancer signal still a question for Arena obesity pill, March 26, 2012).

This extreme regulatory caution has, despite the huge sales potential for an effective drug, caused most drug developers to steer well clear of the area. The phase III drug with the biggest potential in obestiy, according to EvaluatePharma sales by indication data, is Novo Nordisk’s GLP-1 Victoza, although the Danish company is aiming this more at patients with diabetes and metabolic disorders, not obesity broadly.

The only other phase III product that has any analyst forecasts attached to it is Takeda and Norgine’s cetilistat, which works on a similar mechanism of action as Xenical. And phase II is not without its diabetes drugs being repurposed for obesity - such as Amylin’s blood-glucose treatment Symlin and Johnson & Johnson’s SGLT2 inhibitor canagliflozin – or drugs targeting a specialised population, such as Corcept Therapeutics’ Cushing disease drug Korlym and Eli Lilly-partnered CORT 108297, both targeting weight loss in patients taking antipsychotics. Drugs targeting narrow populations raise fewer safety alarm bells with the regulator because fewer people will be exposed to the risk and the current pipeline suggests some researchers may be attempting to exploit this.

However the fall out from the withdrawal of Meridia/Reductil and the fenfluramine/phentermine affair of the 1990s will leave their mark on this space for some time (Meridia adcom leaves obesity space clear as mud, September 16, 2010).

Innovation wanted

One impact has been to crimp real innovation in obesity medicine. Of the current cohort of drugs nearing approval only Lorqess contains a compound that is not already on the market in other indications. Repurposed drugs with a known side effect profile might have seemed to be the way to go, but the struggles of Vivus, Arena and Orexigen suggest otherwise.

The FDA since 2007 has had explicit guidance on the efficacy thresholds necessary to file for approval, but has not necessarily sent a clear signal on safety other than that it is very sensitive because of the potential population exposure. Compared with the clear safety guidance that now exists for diabetes drugs – including a requirement that phase II and III trials be designed such that a cardiovascular meta-analysis can be performed and inclusion of patients at increased risk of heart-related events – directives for obesity drugs are still wanting.

With the feedback from this week's panel, FDA guidance should now emerge. But it seems likely that getting an obesity drug to market in the future will likely require bigger trials and more detailed analysis of cardiovascular risk. The cost no doubt will discourage many from entering the space; for others, knowing how to allay the regulator’s understandable safety worries will give them greater certainty, and with the potential payoff, could spur innovation.

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