Tuesday, April 26, 2016

Eteplirsen for Duchenne muscular dystrophy

Weighing hard data against patient testimonials, an FDA advisory panel voted 8-5 that a new Duchenne muscular dystrophy (DMD) failed to meet the minimum standards for accelerated approval on Monday.

The Peripheral and Central Nervous System Drugs Advisory Committee's vote signaled a lack of "substantial evidence from adequate and well-controlled studies" to trigger dystrophin production at a level considered "reasonably likely to predict clinical benefit."...

The panel also voted 7-3, with three abstentions, that a single historically-controlled study also did not offer substantial evidence of the drug's efficacy.

In November, the same panel determined in more lopsided votes that the evidence in support of a similar agent, Biomarin's drisapersen, was also weak.

Benjamin Dupree, a 23-year-old with DMD from Dallas, who was the panel's patient representative, voted that the drug met the "substantial evidence" standard in the both questions.

However, the Duchenne patient was deeply conflicted. "The study doesn't provide what I think is adequate evidence to support all of this testimony that I'm seeing in here," he said, referring to extensive public testimony, before breaking down in tears.

Eteplirsen (tentatively branded Exondys 51), a product of Cambridge, Mass.-based Sarepta Therapeutics, has been proposed for treating DMD in patients with a specific verified mutation of the dystrophin gene. The disease is thought to occur when a genetic mutation in exon 51 causes a shortage or lack of dystrophin protein. Eteplirsen is intended to prevent exon 51 from being translated, enabling muscle cells to produce a shortened but still functional form of dystrophin.

The panel's first vote reflected the committee's views regarding the drug's suitability for approval under an accelerated approval pathway -- using dystrophin levels as a surrogate endpoint. The second vote viewed potential approval based on clinical efficacy...

Dunn urged the panel to focus on "whether we can truly conclude that what these few eteplirsen patients are experiencing is clearly outside the natural variability of the disease."

During an unusually long public comment period, many parents pleaded with the committee to speed the drug's approval.

Mindy Leffler, from Seattle, described how her son regained the ability to pull himself into a car after taking eteplirsen. Leffler noted that "regaining definitively lost milestones" was not part of the natural progression for any Duchenne patient...

When, at the end of a long day, Onyike called for an adequate controlled trial, as other panelists and FDA staff had before him, the audience erupted into jeers, shouting "biopsies hurt."

One wheelchair-bound teen, cursing angrily, ran his vehicle through a couple rows of empty chairs before rolling out of the room.

For this application, Sarepta submitted two exploratory studies and a single clinical trial in two phases -- a randomized placebo-controlled study and an open-label extension trial that used data from Italy and Belgium for comparison.

FDA's technical experts noted shortcomings in the sponsor's bioassay methods leading to possible "overestimation" of the percent of dystrophin-positive muscle fibers. The experts also pointed out the inability to distinguish drug-induced dystrophin from naturally-occurring dystrophin in immunofluorescence...

Sarepta's re-analysis of the biopsied tissue by three independent experts found a mean percent of dystrophin positive fibers of 17% [± 10%] at 180 weeks, which was about one-quarter to one-third of Sarepta's initial estimates at 48 weeks.

Similarly, using a Western blot assay, a fourth biopsy from patients at 180 weeks of treatment found dystrophin levels at 0.93% [± 0.84%] of normal muscle. The sub-1% increase was markedly different from the 10- to 20-fold increase with eteplirsen the sponsor initially reported at 12 weeks of treatment.

In the single clinical trial comparing three groups of four patients each at different doses -- eteplirsen 30 mg/kg or 50 mg/kg vs placebo, the drug failed its prespecified endpoints...

Based on the clinical trial, the agency's experts ultimately concluded, "[T]here does not appear to be any evidence of efficacy for eteplirsen."

The FDA is not required to follow the advice of its advisory committees but it often does.



  1. Ten of 12 children with Duchenne muscular dystrophy (DMD) were still walking four years after treatment began with the investigational drug eteplirsen, compared with only one of 13 historical controls with DMD, researchers reported in Vancouver on April 19 at the AAN Annual Meeting...

    At 36 months, the 12 eteplirsen-treated patients demonstrated a statistically significant advantage by being able to walk 151 meters more than the 13 external controls (p < 0.01) during the six-minute walk test (6MWT) and experienced a lower incidence of loss of ambulation. The findings were released in the February issue of Annals of Neurology.The four-year results — along with a letter signed by 36 neurologists and other scientists in support of the drug — are expected to be weighed carefully by the Food and Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee when it meets again on April 25.Sarepta, the drug's manufacturer, is seeking accelerated approval for eteplirsen for patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which represents about 13 percent of all DMD patients.In a briefing document released in January, the FDA took issue with the original three-year study data, however, based mainly on three points: the tiny amount of functioning dystrophin detected in the treated children's muscles; the comparability of the treated children to the historical controls; and the fact that all 10 of the treated children who were still walking four years after treatment had nevertheless shown substantial declines in walking distance.

    The FDA noted in its response that a comparison of dystrophin levels for the two doses and placebo at 12 weeks and 24 weeks showed “a positive finding for only one of the doses (the lower dose) and for just one of the two time points (the later time point). The lack of an effect with the higher dose group tends to undermine the finding in the lower dose group, and the lack of even a positive trend at the earlier time point (with a higher dose) sheds doubt on the finding at a later time point.”Furthermore, the FDA stated: “The mean dystrophin level in patients who had been treated with eteplirsen for some 180 weeks was on average 0.9 percent of normal, far below levels observed in a milder form of muscular dystrophy known as Becker-type muscular dystrophy (BMD). The minimum level of dystrophin that might be reasonably likely to predict clinical benefit in patients with BMD remains unknown, but experts in DMD have stated that levels less than 3 percent of that of normal healthy muscle are generally associated with the typical DMD phenotype.”The FDA also questioned whether the 13 historical controls had received the same intensity of physical therapy and steroid treatment. It stated that “performance on the 6-minute walk test could be influenced by motivation and coaching.” The agency also expressed concern that “open-label trials are susceptible to bias on the part of investigators, patients, and parents.”Perhaps of greatest concern, the FDA stated in its briefing document that the clinical course of the 12 patients treated with eteplirsen “appears to be within the expected natural history of DMD.” Treated children, it stated, “experienced a sequential worsening of functional abilities and muscle weakness, as demonstrated by changes in rise times from the floor and the evolution of North Star Ambulatory Assessment (NSAA) scores.”


  2. Stanley F. Nelson, MD, professor of human genetics, and Carrie Miceli, PhD, professor of microbiology immunology and molecular genetics — co-directors of the Center for Duchenne Muscular Dystrophy at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA) — coauthored a letter of support to the FDA to underscore the importance with which the DMD scientific community regards the drug.

    “We felt perplexed that the data looks good, yet has not been met with a clear path forward for approval,” Dr. Nelson said. “The data are highly supportive of the drug having a positive effect with good safety. I think the effect is substantive but not curative.

    ”The letter to the FDA, which was signed by 34 other scientists, stated that simply on the basis of the three-year data alone these data are “clearly supportive of accelerated approval, however the new four-year data regarding age at loss of ambulation now provide even more compelling data for accelerated approval based on an irreversible morbidity. The hard endpoint of loss of ambulation is not affected by motivational factors.

    ”As to the low level of dystrophin found in the treated patients, the letter stated that “data from studies on BMD and DMD patients and in mouse and canine dystrophinopathy models support the suggestion that relatively low levels of dystrophin can be functionally significant, even if only expressed in a limited number of fibers.

    ”After reviewing the evidence, the letter stated, “we conclude that the aggregate data, described in the briefing documents, are providing substantial evidence of efficacy and use in the greater population of boys amenable to exon 51 skipping is appropriate. We suggest that the most scientifically robust way forward and the most ethical choice for the Duchenne community is in the context of an accelerated approval followed by a confirmatory trial.

    ”Melissa J. Spencer, PhD, a professor of neurology and co-director of the Center for Duchenne Muscular Dystrophy at UCLA who signed the letter to the FDA about the drug, said: “From my point of view, the results are extremely significant. It would be very unlikely to obtain the data they obtained by chance. All the data in the literature suggest that even low levels of dystrophin are likely to be beneficial. How much they need is not clear. More is better obviously.

    ”Whether or not the FDA advisory committee recommends accelerated approval following its April 25 meeting, she said, “The ongoing phase 3 trial will likely be continued as the confirmatory trial where data on efficacy will be collected and evaluated, and under yet to be determined conditions of the FDA, any DMD patient amenable to exon 51 skipping could be able to get the drug through an academic medical center.

    ”Even for an older patient who can no longer walk, she said, “The thinking is that maintenance of muscle mass that is remaining can improve a patient's quality of life.”