Disclaimer: I don’t have to imagine what’s it like to see the life of one’s own child hang on the edge — or the swift, relentless destruction of their vitality and liberty by a rare disease. But that’s another story, or two. Here the subject is an advocate mother’s view of Duchenne Muscular Dystrophy (DMD), the concerns she shares with other DMD patient advocates and experts, and the ticking clock as she watches her own son progress and pushes for a new drug now forestalled by the FDA’s refusal late last year to grant it accelerated review.
I want to describe the subject as prosaically as possible, not despite of but because of its high emotional content. Science often offers a refuge when passionate arguments fail to decide the point, but even science allows for many sides in a debate, thus prolonging it. The delay to decision may be academic, or as in this case, the lives of children can hang in the balance.
See? It’s so difficult to avoid the emotional element. The ending clause in the last paragraph was merely a descriptive statement, but for certain readers, it carries huge emotional resonance.
The drug in question is eteplirsen, Sarepto’s exon-skipping treatment for DMD. The story also involves eteplirsen’s exon-skipping cousin, drisapersen, formerly under co-development by GSK and Prosensa before GSK gave up the fight in January. Both drugs work on the assumption that, by restoring the patient’s ability to generate dystrophin, a key protein for connective tissue in muscles, the treatment will improve symptoms and perhaps halt disease progression. Both also use walking stability tests along with dystrophin levels as endpoints.
A Phase 2 trial of drisapersen showed a strong increase in dystrophin levels in 22 percent of boys on drug; eteplirsen, which can be dosed much higher than drisapersen, showed significant increase in all patients in its studies. But in November last year, the agency turned down Sarepta’s request to file an NDA for eteplirsen based on its Phase 2 data while it conducted a Phase 3 confirmatory trial, despite issuing a guidance in July encouraging the application. This time the agency expressed doubts about dystrophin levels as a surrogate marker as well as the significance of walking-test data from the drug’s Phase 2b trial. The consequence will likely be at least a two-year delay in making eteplirsen available to the general population, even if ultimately approved.
I spoke with Mindy Leffler after she responded to a brief description of the eteplirsen case in my February article on Janet Woodcock, where I described a letter to Woodcock from one “leading advocate” for eteplirsen as “petulant.” I did not cite the letter writer by name in the article, however — in fact, it was signed by Steven T. Walker M.S., P.G., Co-Founder, Abigail Alliance for Better Access to Developmental Drugs — but Leffler had also written to Woodcock about the negative decision, so she believed at first that it was her letter I had described as petulant. After we both got over our mutual confusion, Leffler and I were able to begin again with a fresh discussion.
In retrospect, I should not have used the word petulant; it is unfair to imply overbearance in an advocate community when words like passion and perseverance actually apply. Advocates are conducting a rational argument over the meaning of clinical trial data and design for tiny patient populations with a great unmet or poorly met medical need. In particular, the DMD case also appears to be a test of the FDA’s flexibility in considering the data and use of nontraditional trial designs when such populations face a grimly limited timeline.
“I’ve had six meetings with the FDA in the past year, from the director level up to Commissioner Hamburg,” Leffler says.” Nothing has happened on the regulatory front with eteplirsen since then, except an additional year of stability and safety data on the original 12 boys on the drug in the Phase 2 trial. There have been no additional rulings or feedback.”
A HOME RUN THWARTED
Leffler and other parents of patients first met with the agency in February 2013 to discuss why DMD as a disease, and eteplirsen as a drug, were ideal candidates for the then-nascent accelerated review program — one mandated by Congress to speed the availability of badly needed new medicines. The parents listed the characteristics of the disease that qualify it for the fast-review status, including extreme risk/benefit tolerance, unmet need, and a recognized surrogate marker that addresses the root cause. “Our input seemed to be very well received, perhaps because we didn’t come in as hysterical parents,” she says.
As the meetings progressed, the discussions turned to more specific details of the eteplirsen trials such as the patient-reported data, burden of treatment and trial participation, and use of optimum parameters for measuring the progress of DMD patients in the trials against the disease’s natural history. Then, last July, when Sarepta announced that the FDA was receptive to an NDA for eteplirsen based on its Phase 2b data, the advocates believed they had scored a home run. “I thought by this time next year, my son will be on the drug, and he’ll have a chance at life,” says Leffler. “But in November, everything fell apart.”
No one disputes the actual data, but to say it is a matter of interpretation is to over-simplify the actual dispute. The FDA has already said it believes the dystrophin surrogate is questionable enough to disqualify the drug for accelerated review, at least in the eteplirsen and drisapersen studies. The company must now convince the agency of the model’s validity with more data from the Phase 2b trial or an additional trial. It has just submitted some impressive pulmonary data from the Phase 2b and is committed to the confirmatory trial, possibly starting next year.
There are no safety issues with eteplirsen identified so far. Despite the Phase 2b trial’s limited sample, the walking tests showed stabilization in most subjects and improvement in a few. Most patients and their parents would take stabilization as a tremendous benefit considering the rapid, devastating progression of the disease.
Do you see where I’m going with this? Even at worst, NDA approval for eteplirsen at this very moment is a low risk to high benefit proposition. Critics of Sarepta’s Phase 2b study often cite the small patient sample — only 12 boys. But DMD has a prevalence of only about 1.5 per 10,000 males 5-24, according to a four-state study by the CDC. Now, go out and try to find sufficient numbers of clinical trial subjects beyond those already involved in one. It’s not only a matter of how many, but also how quickly you can find, enlist, and qualify patients. Meanwhile, imagine the clock ticking as your own, or your own son’s, essential faculties deteriorate on a daily basis. Are double-blind, placebo trials even ethical is such a situation? If new trial designs are ever called for, isn’t this the perfect place to apply them?
ON THE SIDE OF REASON
Leffler was not content to wait to see if her son might win a 50 percent chance of getting the active drug versus placebo in another year or two, if he qualifies for the planned late-stage trial of eteplirsen. On February 6 of this year, she brought a large group of DMD researchers, all well-known opinion leaders, to a meeting with the FDA. Now she is waiting again, waiting to hear whether the KOL group, representing nearly the full complement of top international DMD experts, has helped the FDA see the existing data with new eyes. When she does, and especially if they do, I will continue the story in this space. Meanwhile, I am happy to correct my previous, unwarranted impression of advocates like Leffler.
“We are not a bunch of zealots eager to buy into any drug for Duchenne that comes along,” she says. “We have worked hard to look at all of the science, and we made a careful decision to support this one.”
Clinical data is hardly ever straightforward. Drugs are frequently approved along with acknowledged ambiguities. On the other hand, the FDA is clearly still calculating its steps in implementing accelerated review. Having been stung by the Iclusig case, and, at the same time perhaps, seeing more applications bearing stronger data, the agency may be raising its standard of evidence. Risk aversion can be a useful tool in drug regulation. But when the risk of doing nothing is so clear, as it is with DMD, it seems reasonable that the FDA’s calculation should put much more weight on even a qualified benefit of action.
The FDA will not comment in direct response to the advocates’ position on the eteplirsen case, of course; whatever it will say in relevance is already out there and easy to find. Thus, I hope this admittedly one-sided account helps the debate, at the least, by shedding light on the inextricable relationship of science and sensitivity to patients in meeting the most urgent unmet needs.