AAN 2023: Motor gains with SRP-9001 gene therapy continue for 2nd year

Duchenne patients treated in Phase 2 trial show improving NSAA scores

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Motor function improvements seen in boys with Duchenne muscular dystrophy (DMD) one year after being given the gene therapy SRP-9001 (delandistrogene moxeparvovec) continued for a second year, according to new clinical trial data presented at the recent American Academy of Neurology (AAN) annual meeting.

Mutations that interfere with the production of the muscle protein dystrophin cause DMD. SRP-9001 is designed to deliver a gene encoding a shortened version of the protein, called micro-dystrophin, to muscle cells.

SRP-9001 is currently under priority review by the U.S. Food and Drug Administration (FDA), with a decision expected later this month.

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North Star Ambulatory Assessment (NSAA) scores typically decline over time

Sarepta Therapeutics‘ application for SRP-9001 is supported in part by data from a Phase 2 clinical trial (NCT03769116). Perry Shieh, MD, PhD, of the University of California Los Angeles, shared study data in an AAN presentation titled, “A Phase 2 Clinical Trial Evaluating the Safety and Efficacy of Delandistrogene Moxeparvovec (SRP-9001) in Patients with Duchenne Muscular Dystrophy (DMD).”

The trial, sponsored by Sarepta, SRP-9001’s developer, enrolled 41 boys with DMD, ages 4 to 7. At the start of the study, participants received either SRP-9001 or a placebo, then were followed for about a year.

One-year trial results showed patients given the gene therapy tended to have better scores on the North Star Ambulatory Assessment (NSAA), a standardized measure of motor function. The difference from placebo was not statistically significant in the overall group, which Shieh said might be attributable to differences between the groups prior to treatment.

“The patients who received treatment in [the first part of the study] actually had lower baseline NSAA scores on average, suggesting they may possibly be on a more aggressive [disease] trajectory,” he said.

After that first year, placebo-group participants were treated with SRP-9001, and all were followed for another year. A year after the gene therapy, mean NSAA score increased, indicating gains, by 1.3 points in this second patient group.

For context, Shieh presented an analysis of data from an external group of DMD boys not given the gene therapy, who were selected to have similar features to trial participants around the time they were treated. In the external group, average NSAA scores decreased by 0.6 points after a year.

Among boys given SRP-9001 in the study’s first part, the average NSAA score increased by 1.6 points two years after the treatment. A comparison with external data showed the median NSAA score improved by two points for patients given SRP-9001, compared to a three-point decrease in the external untreated group. The mean (average) scores were not significantly different, though Shieh said this might be due to one outlier in the trial who experienced a substantial drop in scores despite SRP-9001.

“Overall, there was a maintenance of motor function that was observed across two years,” he said. Shieh stressed that this differs from the typical course of DMD, where motor function gradually worsens as the disease progresses.

Results of other SRP-9001 trials also report improving scores

In addition to the Phase 2 study, SRP-9001 has been tested in a proof-of-concept Phase 1/2 study (NCT03375164) in four boys with DMD. These patients show long-term improvements in NSAA scores.

Sarepta is also sponsoring a Phase 1 trial called ENDEAVOR (NCT04626674) to further test the therapy’s safety and micro-dystrophin expression in boys with DMD.

In a separate AAN presentation Craig Zaidman, MD, of Washington University in St. Louis, presented an analysis of combined data from these three clinical trials. The talk was titled, “Integrated Analyses of Data from Clinical Trials of Delandistrogene Moxeparvovec (SRP-9001) in Duchenne Muscular Dystrophy (DMD).”

The analysis included one-year data on a total of 52 boys with DMD, ages 4 to 8 at the time of treatment with SRP-9001 at the dose that’s currently up for FDA approval. For context, outcomes were compared with data from a matched external group of 105 untreated patients.

Results showed that NSAA scores improved by an average of 2.3 points a year after SRP-9001 treatment, whereas in the external cohort, average scores decreased by 0.1 points after one year of follow-up without gene therapy.

According to Zaidman, a two-point improvement in NSAA “is being able to walk up a step, whereas before you could not. So, that is a pretty big deal.”

Average scores on other tests of physical abilities, including the time-to-rise and the time to walk 10 meters, also showed improvements a year after SRP-9001, whereas scores worsened after a year in the external group.

Safety data from these studies have shown that most side effects of SRP-9001 occur soon after the gene therapy is administered. They often included nausea, vomiting, and decreased appetite.

“The majority of patients do vomit … that can happen as early as a day or two after treatment; often it’s in the first week,” Zaidman said.

This side effect usually goes away in a week or two, he noted, and is responsive to anti-nausea medicines like ondansetron (sold as Zofran). However, vomiting can cause issues for patients who need to take oral corticosteroids. If patients can’t keep corticosteroids down, they may need to go into the hospital to get these medicines by into-the-vein infusion.

Out of 84 SRP-9001-treated patients included in the safety analysis, seven experienced serious side effects, including serious vomiting, rhabdomyolysis (a form of muscle damage), and liver injury. Work is ongoing to determine what criteria for trial eligibility might minimize the risk of serious reactions to the therapy, Zaidman said.

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