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What Does FDA's ‘Breakthrough’ Pathway Mean for Neurology?

Shaw, Gina

doi: 10.1097/01.NT.0000442993.04668.ab
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Investigators discuss the potential impact of the Food and Drug Administration's latest expedited review program — the breakthrough therapy designation — on the therapy pipeline for Duchenne muscular dystrophy.

Over the past year, the US Food and Drug Administration (FDA) has granted “breakthrough” status to some 22 emerging therapies, a new designation created by the FDA Safety and Innovation Act of 2012. The “breakthrough” status joins three other expedited FDA designations for serious conditions: fast-track, accelerated-approval, and priority-review. [See “FDA Expedited Programs.”]

The newest designation allows that “preliminary clinical evidence [for a serious condition]...may demonstrate substantial improvement over available therapies on a clinically significant endpoint or endpoints,” wrote scientists with the FDA's Center for Drug Evaluation and Research (CDER) in the Nov. 14 New England Journal of Medicine (NEJM). In addition to the benefits of fast-track designation (rolling review, possible priority review, frequent interaction with FDA sources), “breakthrough” drugs also receive “intensive guidance on an efficient drug development program, beginning as early as phase 1” and “organizational commitment involving FDA senior managers.”

Most of the drugs on the breakthrough list are oncology compounds, but three are designed to treat neurologic conditions: amifampridine phosphate for Lambert–Eaton myasthenic syndrome, bimagrumab for sporadic inclusion-body myositis, and drisapersen for Duchenne muscular dystrophy (DMD), the most common and rapidly progressive of the muscular dystrophies.

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What can researchers into these (and potentially other) serious, challenging neurologic conditions expect from this new designation?

It's hard to say at this point. Before the NEJM article went to press, drisapersen's developer, GlaxoSmithKline, announced that the drug had failed to meet its primary endpoint of a statistically significant difference in the six-minute timed walk test, a standard assessment of functional decline in DMD. The 125 boys on the drug did no better on the timed walk than did the 61 on placebo; there was a similar lack of superiority for drisapersen found with secondary endpoints such as the 10-meter walk-run test, the four-stair climb, and the North Star Ambulatory Assessment.

Did the breakthrough designation benefit the drug's developers in any way, even if only by helping it “fail faster?” Neurology Today sought comment from GSK researchers, but was unable to secure a response at press time.

The DMD community would certainly like to know, said Sharon Hesterlee, PhD, vice president of research at the Parent Project Muscular Dystrophy, an advocacy organization that funds research and provides support services to families with children with DMD. “Our understanding is that the breakthrough designation means better access to the FDA and a better turnaround time for getting questions answered, and potentially accelerated approval as well. We'd like to know if the designation improved GSK's timeline on drisapersen and got them answers faster.”

Table FDA

Table FDA

Whether that was the case for GSK or not, the FDA confirms that the breakthrough designation has led to approval of at least one therapy based primarily on phase 2 data. In November, the FDA approved ibrutinib for the treatment of mantle cell lymphoma (MCL), eight months after it had received breakthrough designation for that indication. “The efficacy and safety profile of ibrutinib were primarily evaluated in 111 patients with previously treated MCL in a single-arm phase 2 clinical trial,” said Eric Pahon, a spokesperson for CDER in an e-mail interview with Neurology Today.

Tantalizingly for DMD researchers, the FDA also confirms that a surrogate endpoint — such as dystrophin production — could also be sufficient for the approval of a breakthrough drug. “As a drug designated as a breakthrough therapy may be eligible for the accelerated approval pathway, if the relevant criteria are met, it is possible that surrogate endpoints could be acceptable for approval of a breakthrough designated drug,” Pahon commented.

GSK hasn't pulled the plug on drisapersen yet, said Dr. Hesterlee — they're still analyzing data to see if there are subgroups of responders — but “it's on life support.” [For more on the therapeutic approach used in the DMD drug, see “More on the Exon-Skipping Strategy.”]

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In November, around the same time that drisapersen failed to meet its endpoints, the FDA told Sarepta not to pursue accelerated approval for eteplirsen, in part because of the drisapersen results. (Neurology Today reported on the FDA decision in its Dec. 19 issue: “FDA: Why Eteplirsen Is Not Ready for DMD,”

Earlier in the year, Sarepta had reported what appeared to be promising data from its small phase 2 study involving 12 boys between ages 7 and 10 with deletion mutations correctable by skipping exon 51.

After 84 weeks, the investigators reported, the data showed a continued stabilization of walking ability on the six-minute timed walk among the treated boys. “After 84 weeks, patients in the 30 mg/kg and 50 mg/kg dose cohorts who were able to perform the 6-minute walking test (modified Intent-to-Treat* or mITT population; n=6) showed a statistically significant treatment benefit of 46.4 meters (p≤0.045) when compared to the placebo/delayed-treatment cohort (n=4),” according to a Sarepta release.

They also reported a statistically significant increase (p≤0.001) in dystrophin-positive fibers, to 47 percent of normal. But in a meeting with Sarepta officials, FDA regulators questioned the robustness of the six-minute walk test data and the correlation with dystrophin production resulting from the phase 2 study.

Since then, 96-week data was presented at the World Muscle Society Congress in October, and the results still look promising, said Dr. Hesterlee. “This is a really progressive disease, and the longer the data set shows stabilization, the better and better it looks.”

Sarepta is now planning a larger phase 3 trial, assuming that the accelerated approval pathway may remain unavailable — although they haven't given up hope for a speedier process. “We are now working with the FDA to come to an agreement on a confirmatory study design, and addressing the feedback they provided us to see if a New Drug Application may be a possibility in the future based on phase 2B data,” said Sarepta spokesperson Jim Baker. He said that the new study, in a larger group of patients, will involve sites in the US and Canada and will likely include the six-minute timed walk as its primary endpoint, along with other endpoints including dystrophin levels.



The drug appears to be very safe, said Dr. Hesterlee, and given the stakes with DMD, she is surprised by the level of pushback from the FDA. “They're not bending rules or making allowances. They are saying it's not about safety, it's about efficacy and that we have to be sure that it works. But the parents have kids who are dying. It's a progressive pediatric disease that is fatal, and we feel like we're not getting a lot of the flexibility that has been so touted.”

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Do the recent FDA decisions and trial results mean the end for the exon-skipping technology as a therapeutic strategy for Duchenne muscular dystrophy (DMD)? Exon-skipping uses small bits of DNA called antisense nucleotides to mask or “skip” a malfunctioning exon on the dystrophin gene. It doesn't aim to cure DMD — all 79 exons on the gene must function coherently to produce fully healthy levels of dystrophin protein. But if a damaged exon can be taken out of the equation, the rest of the cellular message can be read, and at least some dystrophin protein can be produced.

“Dystrophin is the scaffolding that holds the membrane of the muscles together. If you have none, or minimal, or it doesn't work, you have Duchenne,” said Ann Tilton, MD, chief of the section of child neurology at Louisiana State University School of Medicine in New Orleans and a member of the Neurology Today editorial advisory board. “If you have an abnormal protein, but it partially works, you have a modified, less severe form of the disease. If you can make it a protein that works somewhat, you have the potential for someone to live much longer.” (Most boys with Duchenne die by the age of 25, usually as a result of lung and heart problems.)

Drisapersen aimed to “skip” exon 51, but it's not the only drug out there targeting this exon. Sarepta's eteplirsen also focuses on this exon, but uses a different chemistry.

—Gina Shaw



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•. Sherman RE, Li J, Shapley S, et al. Expediting drug development — The FDA's new “breakthrough therapy” designation. N Engl J Med 2013; 369(20): 1877–1880.
    •. FDA Safety and Innovation Act of 2012:
      •. Flanigan KM, Voit T, Rosales XQ, et al. Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial. Neuromuscul Disord 2013; E-pub 2013 Sept. 11.
        •. Mendell J, Rodino-Klapac LR, Sahenk Z, et al. for the Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 2013; E-pub 2013 Aug 1.
          •. Ruegg UT.Pharmacological prospects in the treatment of Duchenne muscular dystrophy. Curr Opin Neurol 2013 Oct;26(5):577–584.
            •. Neurology Today archive on exon-skipping therapy, muscular dystrophy:
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