On November 16, 2010, the FDA Arthritis Advisory Committee will review the BLA for BENLYSTA, the first new drug for lupus in decades. There’s been a lot of hype about this drug from Human Genome Sciences and Glaxo Smith Kline. The BLA was submitted on June 10, 2010 and the FDA gave it a Priority Review Status. All seemed to be going well and in September 2010, Glaxo reported that it was preparing for launch.
Now the FDA has called for an Advisory Committee meeting to review the application and address some significant questions, questions that regardless of the answer, raise some serious questions about an overwhelming endorsement of the drug by the Advisory Committee and indeed may result in a Complete Response Letter on December 9, 2010 rather than an approval.
Here are the issues as laid out by the FDA Briefing Document that are raising the caution flag for us:
- Efficacy of a lupus drug is determined by scores contributed from a number of organ systems. The overall positive BENLYSTA data are driven by high response rates in musculoskeletal and mucocutaneous system scores while having little effect on organ systems associated with poor outcome and mortality.
- The FDA states there is a lack of efficacy in African Americans.
- The efficacy of BENLYSTA appears to be less in patients in North American trials (US and Canada) than other regions.
- There appears to be an increased risk of some adverse expereinces including malignancy, suicide and suicidal tendencies and death on patients taking BENLYSTA.
It is important to note that BENLYSTA is given on top of current standard therapy for lupus, so there is little increased benefit (even less for US patients and none for African Americans) over standard therapy and an increased risk over standard therapy. Looks like overall benefit risk for US patient population is decreased.
While a package insert could be written to work around most of the shortcomings that have been cited by the FDA, such as “relief of musculoskeletal and mucocutaneous symptoms associated with lupus”, “patients of African American heritage are not likely to benefit”, “patients with a history of suicide or suicidal tendencies etc are contraindicated”, it is difficult for us to reconcile a package insert that provides the proper benefit risk description of the reduced efficacy in North Americans patients. That being said, we think the Advisory Committee is going to have a difficult time not requiring an additional study in US patients when the FDA asks them what further data should be collected. It follows then that the FDA will not be able to issue an approval letter when the PDUFA Date rolls around on December 9, 2010.
Arena Pharmaceuticals has submitted information on their one year study of LORQESS (lorcaserin) to the FDA to support their NDA application for the drug in treating obesity. We, as well as others have provided opinions on the likelihood of Arena being successful, the Advisory Committee did not recommend approval and the FDA has not approved LORQESS. Yet, Arena keeps trying.
The new one year data provide some additional information on the efficacy that still isn’t enough to convince me that the drug is at least meeting the minimum requirements of the FDA Guidelines for Obesity Drugs. I can’t even say that the results are marginal. At the end of a year, LORQESS patients showed a 4.5% weight loss from baseline compared to a 1.5% weight loss for placebo patients.
By far, the most alarming data in the one year study are the reports of study patients who showed heart valve problems. The LORQESS patient group reported 2.9% of patients with heart valve problems vs. only 0.5% reported for the placebo group.
Doesn’t anyone at Arena remember all the heart valve problems with diet drugs 10 years ago? C’mon, somebody take the shovel away from them – the hole is deep enough already!
It seems that there are lots of opinions floating around about the future of diet drugs in the wake of the recent FDA actions against QNEXA (Vivus) and LORQESS (Arena). I’d like to add my opinion but I think the only opinion that really counts is that of the FDA and they have stated their opinion very clearly – it’s all about the benefit risk.
Consider if you will the Guidance that the FDA has on the proof of efficacy for drugs to treat weight loss. There are 2 ways to prove efficacy and it must be proven in clinical trials of at least one years duration. At one year, the FDA requires that there be a 5% difference between the drug and the placebo and the difference must be statistically significant OR at least 35% of those treated with the test drug lose 5% of their base line weight, this weight loss be at least double that achieved by the placebo group and be statistically significant.
This is not the Mount Everest of clinical endpoints. Do the arithmetic, yes, arithmetic, not statistics on this example. Take a group of 200 pound people, put them on a diet. If the placebo group doesn’t lose any weight, the drug group only has to lose 10 pounds to prove efficacy. That’s probably the equivalent of one cupcake a week for the duration of the trial.
Now look at the regulatory decision the FDA has to make on benefit risk. Against the benefit of just achieving efficacy per the Guidance, any increase in risk becomes unacceptable.
What does this mean for CONTRAVE which gets served up to the Advisory Committee on December 7, 2010 and the other diet drugs that are in development? It means the benefit has got to be a lot bigger than a cupcake a week and the risk has got to be weigh weigh low. The alternative treatment is diet and exercise – safe and effective, high benefit and low risk.