DMD drugs show promise despite trial’s missing main goal: Sarepta
Company plans to meet with FDA on Amondys 45, Vyondys 53
Exon-skipping therapies Amondys 45 (casimersen) and Vyondys 53 (golodirsen) show “positive and encouraging trends” for people with Duchenne muscular dystrophy (DMD), even though top-line results from a Phase 3 trial testing the treatments showed the study failed to meet its main goal, developer Sarepta Therapeutics said.
Results from the Phase 3 ESSENCE clinical trial may have been affected by disruptions due to the COVID-19 pandemic, Sarepta said. The company said it plans to schedule a meeting with the U.S. Food and Drug Administration (FDA) to discuss the next steps for the treatments.
“This trial enrolled an ultra-rare subset of eligible Duchenne patients,” Louise Rodino-Klapac, PhD, Sarepta’s president of research and development and technical operations, said in a company press release. “The complexity of Duchenne, combined with the heterogeneity of the population and the impact of the COVID pandemic on participation, made this an extraordinary undertaking. We are deeply grateful to the families and investigators whose dedication made this possible, and we remain committed to advancing care for the Duchenne community by delivering options that can change the course of Duchenne.”
DMD is caused by mutations in the gene that encodes dystrophin, a protein that helps to protect muscle fibers from damage. People with DMD make little to no dystrophin protein; as a result, muscles accumulate more damage than normal, leading to symptoms such as muscle weakness and wasting.
Exon skipping
Within a cell’s DNA, the gene encoding dystrophin is composed of exons — the sections that actually provide instructions to make protein — and introns, non-coding regions that help regulate gene function. When the gene is read to produce a protein, the entire sequence is copied into a temporary molecule called messenger RNA. Then the introns are removed and the exons are spliced together to form a mature sequence that can be used for protein production.
Many DMD-causing mutations cause the exons to fall out of alignment, resulting in a garbled sequence that can’t produce protein. The basic idea behind exon-skipping therapies is to remove certain exons from RNA, allowing the remaining exons to be in alignment, which enables the production of a shortened but functional version of the dystrophin protein that can help protect muscles from damage.
Amondys 45 is intended for patients amenable to skipping exon 45, while Vyondys 53 aims to skip exon 53. Both therapies are approved in the U.S. under the FDA’s accelerated approval program.
Under the program, the FDA allowed the therapies to be brought to market based on early clinical data showing they could increase dystrophin protein levels as designed. However, continued approval for this indication, and the potential to transition into full approval, are contingent on additional clinical testing demonstrating that the therapy improves clinical outcomes for patients.
Craig McDonald, MD, an investigator in the ESSENCE study and a professor at the University of California Davis, has seen results. “In the trial and my clinical practice, I’ve followed boys and young men treated with [Amondys 45 and Vyondys 53] since their initial approvals and, in my opinion, these therapies can help preserve critical functions like walking, stair climbing and feeding themselves,” Davis said. “Over time, these gains can translate into a delayed loss of ambulation and even slower respiratory decline, potentially offering these individuals a meaningful path to maintaining quality of life.”
‘Clear treatment effect’
The Phase 3 ESSENCE trial (NCT02500381) hoped to confirm the benefits of Amondys 45 and Vyondys 53. In the trial, boys with DMD aged 6 to 13 who had eligible mutations were assigned to receive the respective therapies or a placebo, weekly for about two years.
The study’s main goal was to determine whether the exon-skipping treatments would lead to better outcomes than a placebo on the four-step ascend velocity test, which measures how quickly patients can walk up four stairs. Results showed that, while patients on exon-skipping therapies tended to be faster, the average difference of 0.05 steps/second wasn’t statistically significant — meaning it could be due to random chance.
The ESSENCE trial launched in the late 2010s, and for 57 of the more than 200 participants, time in the trial overlapped with widespread disruptions due to the COVID-19 pandemic. In exploratory analyses that removed data from these patients, there was an average difference of 0.11 steps per second, favoring the exon-skipping therapies over the placebo. Although this difference wasn’t statistically significant, according to Sarepta, the magnitude of the difference is clinically meaningful.
Safety data from ESSENCE were consistent with the therapies’ known profiles: Almost all reported safety issues were non-serious. Sarepta said these data, together with data collected from patients given the exon-skipping treatments in real-world clinical practice, support the overall benefit-to-risk profile of Amondys 45 and Vyondys 53.
“While the ESSENCE study did not meet statistical significance on its primary endpoint, we believe the results demonstrated a clear treatment effect, showing clinically meaningful functional outcomes for people with Duchenne who have mutations amenable to skipping exons 45 or 53. These topline findings reinforce the potential impact of these therapies to slow muscle weakness and other symptoms,” Rodino-Klapac said. “The results of the study are consistent with the growing body of real-world evidence accumulated over several years. These data, which we have shared with the FDA, strengthen our confidence in the benefit of added dystrophin over time.”
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