Positive New Results for Eteplirsen, Drisapersen in DMD

Pauline Anderson

May 15, 2014

PHILADELPHIA, Pennsylvania — New results of open-label extension trials for 2 emerging drugs in the treatment of Duchenne muscular dystrophy (DMD) — eteplirsen (Sarepta Therapeutics Inc) and drisapersen (Prosensa Holding) — were released here during the recent American Academy of Medicine (AAN) 66th Annual Meeting.

The studies show some positive results over longer follow-up for both agents, even drisapersen, the main study of which did not meet its primary endpoint.

DMD is a progressive disease of skeletal muscle caused by mutation in the gene encoding the protein dystrophin. The 2 drugs are similar in that both induce skipping of exon 51 in the dystrophin pre-messenger RNA to correct this DMD-related mutation, but each uses a somewhat different technology to correct the genetic flaw.

Eteplirsen Update

In his presentation, Jerry Mendell, MD, Departments of Pediatrics and Neurology, Gene Therapy Center, Nationwide Children's Hospital, Columbus, Ohio, shared 120-week results of an open-label extension trial of eteplirsen.

It included boys aged 7 to 13 years who were initially randomly assigned to receive placebo or 30 mg/kg or 50 mg/kg of the drug for 24 weeks, after which they all took the study drug during the open-label phase.

In already-published results to 24 weeks for 12 boys ( Ann Neurol. 2013;74:637-647), the percentage of dystrophin-positive fibers was increased to 23% of normal in the patients receiving 30 mg/kg eteplirsen, with no increase in placebo-treated patients (P ≤ .002). Even greater increases occurred at week 48 in the treated cohorts, suggesting that dystrophin increases with longer treatment.

"They were all biopsied at 1 year, and basically they all produced dystrophin at that time point — all of them, the ones we call delayed who started on placebo then switched, and the 4 patients on 50 mg and the 4 on 30 mg, and there wasn't a significant difference between the 50s and the 30s," said Dr. Mendell. "That demonstrated that more important than the difference between 30 and 50 mg was the time."

The newer results reinforce the importance of treatment time, he said. On the 6-minute walk test (6MWT), the 4 placebo/delayed boys had dropped 20 m from baseline before eteplirsen treatment was initiated at 24 weeks, but then became stable by about week 36. At 120 weeks, their 6MWT distance was –79 m. The 6 patients receiving continuous treatment had a 120-week 6 MWT distance of –14 m, which represented a between-group difference of 65 m (P ≤ .006).

"What's important is that once a patient started on treatment, it took him somewhere between 12 and 24 weeks to start producing dystrophin and at that point, their 6-minute walks were essentially stable," commented Dr. Mendell. "That was true for the placebo delayed group too; when they started, they weren't producing any dystrophin, but at 24 weeks when they rolled over, they dropped down for another 12 weeks and then reached stability and were stable throughout the rest of the study."

Breathing tests (maximum inspiratory and expiratory force) were "very stable" throughout the study, noted Dr. Mendell. "The patients didn't lose any respiratory capacity, and that is different from natural history studies."

Dr. Mendell is clear that these boys should be treated as early as possible, as at some point they develop scar tissue and lose muscle fiber. "If we could take and treat younger boys and reach some degree of stability, we will have even a more profound effect," he said. Ideally, he'd like to see screening of newborns approved.

Eteplirsen, which uses phosphorodiamidate morpholino oligomer-based chemistry, is a "charged neutral" agent and doesn't cause renal or other dose-limiting toxicities, said Dr. Mendell. The other exon-skipping drug in development, drisapersen, a 2'-O-methyl-phosphorothioate antisense oligonucleotide, is "charged negative," he said.

More data on the latter drug was also presented here during the featured Emerging Science session. The main results of a phase 3, double-blind, placebo-controlled trial of drisapersen (DEMAND III), conducted at 47 sites in 20 countries, didn't show a statistically significant or clinically meaningful treatment difference (P = .42) at 48 weeks in its primary endpoint of the 6MWT between the placebo and continuous treatment groups at a dose of 6 mg/kg per week.

There were also no statistically significant or clinically meaningful treatment differences between drisapersen and placebo on most secondary endpoints.

This study, which failed to reach its primary endpoint, thereby raising doubts about the dystrophin biomarker, was among the reasons cited last fall by the US Food and Drug Administration (FDA) that the New Drug Application (NDA) for eteplirsen was considered "premature," according to a statement from Sarepta Therapeutics Inc released at that time.

However, on April 21, Sarepta announced that it will submit another NDA by the end of the year based on a guidance letter from the FDA that proposed a strategy under a potential Accelerated Approval pathway for eteplirsen. The FDA, according to the company, outlined examples of additional data and analysis that, if positive, may enhance the acceptability of an NDA filing by addressing areas of ongoing concern in the existing dataset.

"Additionally, the Agency provided clear guidance on an open-label historically controlled confirmatory study of eteplirsen as well as initial guidance on a placebo controlled study of one or more follow-on DMD drug candidates, which, like the open-label study, could also be considered an acceptable confirmatory study to verify the clinical benefit of eteplirsen in the event of an accelerated approval," the company's press release noted.

Drisapersen Update

Meanwhile, while the main results of the DEMAND III trial were negative, a subgroup of boys aged 7 years or younger in that study showed a non–statistically significant but potentially clinically meaningful treatment difference of 21 m at week 48, and a statistically significant (P < .001) decline in creatine kinase, a potential marker of muscle cell integrity, in the drisapersen group compared with placebo.

New results of an open-label extension study of drisapersen (DEMAND IV) presented here at the AAN meeting suggest that, much like with the alternative agent, giving the drug earlier and treating boys for longer may delay progression of the disease. The study found that patients who were receiving continual treatment could walk farther on the 6MWT than those who took placebo before switching to the drug.

"When you give the drug for a longer time, it makes a difference in the decline of these boys," commented lead researcher Nathalie Goemans, MD, head of the Neuromuscular Reference Center for Children at the University Hospitals Leuven, Belgium, who presented the findings up to 48 weeks. "The values we report here have been proven to be clinically significant."

Dr. Goemans called the new results "very encouraging."

The extension study included 186 boys with DMD at 50 sites in 24 countries who had previously completed 1 of 2 feeder studies (DEMAND II and DEMAND III).

DEMAND II was a phase 2 double-blind, exploratory, placebo-controlled study at 13 sites in 9 countries that assessed 2 dosing regimens of drisapersen for efficacy, safety, tolerability, and pharmacokinetics in ambulatory patients with DMD.

Dr. Goemans noted that patients in DEMAND III were on average older than those in DEMAND II (8 and 8.3 years for drug and placebo groups vs 7.2 and 6.9 years for drug and placebo groups, respectively). They also had more severe disease; for example, boys in DEMAND III had lower mean baseline 6MWT distances (337 and 348 m for drug and placebo groups vs 428 and 403 m, respectively), and also slower mean times for rising from the floor.

Boys who had to withdraw from either feeder study because of safety or tolerability issues were eligible to be enrolled in the current study. This multicenter, uncontrolled extension study included a 4-week run-in period. The primary endpoint was change in 6MWT between weeks 24 and 48.

The mean patient age was 8.8 years. The mean time since first symptoms was 80 months, and the mean time since diagnosis was 67.1 months.

Although there was an overall decline in 6MWT distance at week 48 of this extension study (ie, 96 weeks after the original baseline of feeder studies), the treatment difference in 6MWT distance for patients receiving drisapersen throughout compared with those who received placebo in the feeder studies and started drisapersen at the extension baseline was 46.1 m. The mean change from the original baseline was –66.8 m for the continuous treatment group and –112.9 m for the placebo/delayed treatment group.

Boys with less progressed disease declined less or even improved from baseline with 2-year continuous drisapersen therapy, commented Dr. Goemans. The 6MWT distance for patients under age 7 years (n = 52) treated with drisapersen throughout increased by 8.4 m from baseline vs a decrease of 28.7 m for those receiving placebo in the feeder studies and treated with drisapersen in the extension study. The treatment difference was 37.1 m.

These study results, as well as anecdotes from parents about what boys taking drisapersen, even older ones, were able to accomplish, were quite unexpected, said Dr. Goemans.

"For me, what was interesting was not only how those boys kept their ability to walk, but also the impact on their daily life. Some were starting to do things we would not have expected them to do, for example, one boy was able to do road skipping at the age of 9."

Another 10-year-old boy who had been receiving placebo and been unable to rise from the floor was able to do so in about 12 weeks after enrollment in the extension trial, she added.

For me, what was interesting was not only how those boys kept their ability to walk, but also the impact on their daily life. Dr. Nathalie Goemans

"What is very interesting in this analysis is that when you keep those boys who were more severely affected on treatment, at the end, you see a clinically meaningful difference between the 2 arms. That I think is really encouraging."

These new data support the hypothesis that treating the disease earlier and for a longer duration confers a treatment benefit for boys with DMD, said Giles Campion, MD, PhD, chief medical officer of Prosensa, in a press release. "Early intervention is a potentially crucial component to improving disease outcome."

Drisapersen was generally well tolerated. The most frequent adverse events were associated with injection-site reactions and renal effects (subclinical proteinuria). Moderate to severe thrombocytopenia, which resolved on permanent discontinuation of therapy, was seen in about 3% of treated cases.

Encouraging Signal

Approached for a comment, Robert Griggs, MD, professor, neurology, Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, New York, said that as an open-label study, this drisapersen analysis is subject to possible bias. He also noted the earlier results of the controlled DEMAND study were "disappointing."

However, Dr. Griggs added that the new results represent "a possibly encouraging signal" and pointed out that "any progress, even if needing more careful confirmation, is very exciting in this disease."

Dr. Griggs pointed out that although the eteplirsen study was much smaller — with only 12 patients — it was placebo-controlled and reported "stability on the 6-minute walk test as well as evidence of prominent dystrophin production."

"Both studies have an encouraging element; the advantage of the Mendell study is that it met its primary outcome."

The eteplirsen study was funded by Sarepta Therapeutics. The drisapersen study was funded by GlaxoSmithKline. Dr. Goemans has served on clinical steering committees and/or as a consultant and received compensation from Shire, PTC Therapeutics, Eli Lilly, Italfarmaco, and UCB. Dr. Griggs is a consultant for PTC Therapeutics and for Sarepta. He also holds National Institute of Health, Muscular Dystrophy Association, and Parent Project for muscular dystrophy funding for studies of DMD.

American Academy of Neurology (AAN) 66th Annual Meeting. Emerging Science Platform Session 001, S6.001, S6.002. Presented April 29 and 30, 2014.


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