Sarepta got approval yesterday for their Duchenne muscular dystrophy therapy, Exondys (eteplirsen), after many, many twists and turns at the FDA. (When you consider that the advisory committee meeting on this was back in April, you get the idea). I can recommend this summary at Endpoints for what’s gone on with this decision, which has to be regarded as extraordinary.
How so? Well, here’s the 126-page summary review document (and the fact that this can be accurately called a summary tells you something right there). Take a look at the first few pages, which are from FDFA Commissioner Robert Califf. He stipulates that the company had an adequate chance to present all its data, and goes on to say that the underlying science of DMD (and Sarepta’s therapeutic rationale for treating it) are not in dispute. The problem is that the company’s development program was “unusual” in the way that it had a very small number of patients and was “characterized by major flaws in the clinical study design”.
The review goes on to note that everyone agrees that Sarepta increases the amount of dystrophin protein, but after that, the trouble begins. The increase was much smaller than anyone had expected or hoped for, and is well into the range of arguing whether it can possibly be clinically significant. The FDA’s own standards for clinical endpoints call for them to be “reasonably likely” to be meaningful, and this is (necessarily) a judgment call. The FDA’s own review team concluded that eteplirsen was not likely to show any real benefit, while Janet Woodcock, head of the whole Center for Drug Evaluation and Research, disagreed. And in the end, Califf declined to overrule her call, and the drug was approved. Overruling the CDER director, he says, would only be appropriate when the director’s reasoning was clearly flawed, and in this case, both her view and that of the review committee members are tenable (even though they disagree).
I can see why Califf did this, then, but what does that leave us with? Sarepta’s drug does seem rather unlikely to provide much benefit, and is reasonably likely to provide none at all. It is priced in line with other rare-disease drugs, at around $300,000 per year, and that may well be 300 grand worth of placebo. Luciana Borio, acting chief scientist at the agency, was against the idea, saying that approval would open the door to other clinical development programs that were run just as poorly (and she went on to accuse the company of “serious irresponsibility” by selectively publishing data during the whole process). Ellis Unger, director of the Office of Drug Evaluation, was also opposed, saying that the drug was a “scientifically elegant placebo”, and that patients and their families were taking on unknown risks for likely nonexistent benefits. (The small number of patients – twelve – also makes evaluation of side effects difficult).
I find myself agreeing more with Borio and Unger on this one. I think that Sarepta should have run a better trial, and should have gathered more data when the FDA told them that more information was needed. Instead, the company stood pat, called up Duchenne-affected boys and their families to plead with the FDA, and won over Janet Woodcock, and that appears to be enough. Is this going to be the new way to get a drug approved? Run a trial in a dozen people, generate unconvincing data, and then lobby Janet Woodcock? I share the worries that this might open the floodgates, because after all, Sarepta got their drug through.
It’s true that the agency is asking for more data after the drug goes onto the market, and it’s possible that approval could be withdrawn if no benefit becomes apparent (as was the case with Avastin and breast cancer). But that was an awfully difficult process, and any attempt to withdraw Exondys from the market will be met by the same tactics of parading diseased children in front of the cameras. No, in the end, I think that the FDA’s job is to approve drugs that work, and no one knows if this one works or not. The people that want the agency’s approval rules loosened should watch closely, because this is the world that they’ve wanted to live in. Let’s see how it is there.