This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
--------------------------------------------------------------------------------------------------------
Obesity compounds in late-stage development by Amylin Pharmaceuticals, Arena, Orexigen Therapeutics and Vivus, will likely face a challenging regulatory environment this year, physicians told Pharmawire.
As weight loss is only a surrogate measure of a patient’s quality of life, companies developing these compounds will face a high burden of proof to show that these drugs cause no psychological harm.
The FDA has long held a position that the actual way a patient loses the weight is important, since the means to an end may be adverse, said Dr David Orloff, ex-director of the division of the metabolism and endocrinology products at the FDA from 2000-2006, and executive director of regulatory affairs at Medpace.
There has been no demonstration in clinical trials on how weight loss treatment affects how a patient functions, feels or survives, as weight-loss is only a surrogate marker of benefit, Orloff explained. There is definitely a requirement from the FDA for a high assurance of safety, he added. The adverse psychological effects the failed CB-1 class had on mood, behavior and cognition provide a clear example of the level of tolerance that the regulatory agencies have for adverse events with obesity drugs, he added.
The problem with the CB-1 class was that everyone looked at the peripheral effects of the drugs, but the class mainly worked on the brain, according to Justin Halford, an expert in appetite and obesity at the University of Liverpool. The companies involved in the development were led by the regulatory agencies but if these drugs had been checked for specificity, the failure of the entire class could have been prevented, he speculated.
Regulatory agencies are not asking sufficient questions about the exact mechanism of action for drugs that act on behavior, said Halford. Ignoring the idea of how weight-loss is achieved, is storing up problems, he said. We still don’t know the effects of these drugs on behavior, mood and cognition, he said.
Timothy Morris, CFO of Vivus Pharmaceuticals, a firm developing a proprietary obesity therapeutic called Qnexa, said he agreed that safety will be very important. ”We will probably collect a variety of information, but [information on patient behavior] is not required for approval. The FDA will probably look at safety, efficacy and the drug’s mechanism of action,” he said.
Amylin, Arena and Orexigen declined to comment for this article.
The safety bar for approval is very high, said Dr Daniel Bessesen, an endocrinologist and professor at the UC Denver School of Medicine. While the market potential for obesity drugs is enormous, the hurdles are phenomenal, added Dr Nick Finer, an obesity clinician at the Wellcome Trust Clinical Research Facility, Addenbrooke’s Hospital.
It still remains unclear what a company needs to do to convince the regulatory agencies of the safety and efficacy of an obesity drug, Finer added. There is a high burden of evidence to show that patients on these drugs report no psychological harm, he said. This is of particular concern, as these drugs will be taken over the long term, which makes them subject to misuse, he said.
Dr Steven Smith, co-primary investigator on Arena Pharmaceutical’s obesity drug lorcaserin drug trials, said there are still concerns that the insistence on a perfectly clean drug profile does not address the real risk-benefit ratio for patients with a higher body mass index.
In terms of efficacy, the FDA looks for a minimum of one to two years of data that demonstrates at least a 5% placebo subtracted weight-loss, said Finer. In Europe, the regulatory board looks for at least a 10% weight-loss from baseline that is statistically greater than the loss with placebo. There is a definite need for direct measurements of health improvement like a decrease in cardiovascular risk, or improvements in glycemic control, but measuring these hard outcomes is difficult, Finer said.
If an obesity drug eventually reaches the market, it will need to clear a commercial viability bar, since a number of drugs that only showed a 5% weight-loss are not market blockbusters, Bessesen said.
This is the rationale behind Vivus’s Qnexa and Orexigen’s Contrave, two obesity therapies in development that combine two generic drugs, as patients want more weight-loss than the individual drugs can provide, Smith said. “The truth is, products live or die based on total weight-loss,” said Bessesen.
To receive approval for a combination drug, the FDA requires that the safety and efficacy of the fixed dose agent is more efficacious than either individual component, said Finer. “While there are theoretical reasons for combination, I wouldn’t want to use any of these agents alone,” Finer said, citing their side-effect profiles.
A fixed-dose combination that is associated with at least twice the weight-loss of either component will be viewed more favourably, but this is a tough thing to achieve, said Finer. ”We’re already struggling with evaluating single agents.”
The FDA does not have a clear approach to approval of combination drugs, but if the components are already marketed, there is more data on their safety profiles, said Finer. A fixed dose combination drug is still bound to the same standards of safety and efficacy as a novel agent. While it is reasonable to look at these combinations, it is interesting that only the smaller, newer pharmaceutical companies are developing them, he said. “There is a high risk, but it may pay off,” said Finer.
--------------------------------------------------------------------------------------------------------
For more information or to inquire about a trial please email sales@pharmawire.com or call Americas: +1 212-500-1384 or Europe: + 44 (0)20 7059 6251
