Sarepta’s SRP-9001 Shows Functional Improvements in DMD Integrated Analysis

Presented at MDA 2023, the gene therapy (also known as delandistrogene moxeparvovec) showed significant improvements on NSAA total score, 10-meter walk/run scores, and time to rise scores relative to an external control cohort.

Crystal M. Proud, MD, a pediatric neurologist at Children’s Hospital of The King’s Daughters

Crystal M. Proud, MD

A comparison of functional data from patients with Duchenne muscular dystrophy (DMD) treated with delandistrogene moxeparvovec (SRP-9001; Sarepta) and an external control cohort of patients that were propensity-score-weighted suggests that the treatment results in a beneficial modification of disease trajectory.1

Those treated with the gene therapy experienced benefits on North Star Ambulatory Assessment (NSAA) total scores, 10-meter walk/run scores, and time to rise scores relative to the external control cohort. Treated patients received 1.33 x1014 vg/kg of delandistrogene moxeparvovec. All told, 1-year postbaseline, the functional analysis cohort (n = 52) showed a change of 2.3 points on the NSAA compared with a change of –0.1 points in the propensity-score-weighted cohort (n = 105) (least-squares mean ∆, 2.4; P <.0001).

On the time to rise assessment, comparisons between the treatment cohort and external controls yielded changes from baseline of –0.53 s and 1.04 s (least-squares mean ∆, –1.57; P <.0001), respectively. For the 10-meter walk/run, the treatment cohort reported a change of –0.23 s compared with 0.51 for the control group (least-squares mean ∆, –0.74; P = .0164). At baseline, both groups displayed similar scores on NSAA total scores (treatment, 22.10 [SD, 3.80]; control, 21.40 [SD, 3.10]), time-to-rise (treatment, 4.48 [SD, 1.80]; control, 4.49 [SD, 1.20]), and 10-meter walk/run (treatment, 5.14 [SD, 1.10]; control, 5.17 [SD, 0.70]).

The data were presented in a poster by Crystal M. Proud, MD, a pediatric neurologist at Children’s Hospital of The King’s Daughters, at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas. “This functional comparison of data from 3 delandistrogene moxeparvovec (SRP-9001) studies with an [external control] cohort contextualizes the findings from these clinical trials, some of which lacked a placebo arm,” Proud and colleagues wrote.1

This integrated analysis included functional data from 52 patients in Study 101 (NCT03375164; n = 4), Study 102 (NCT03769116; n = 28), and cohort 1 of the ENDEAVOR study (NCT24626674; n = 20), compared with the 131-patient external cohort, which included natural history and clinical trial data from the CINRG/DNHS (NCT00468832; n = 16), FOR-DMD (NCT01603407; n = 86), and the Lily study (NCT01865084; n = 29). Study 101 and cohort 1 of ENDEAVOR included ambulatory boys with DMD aged 4 to 8 years, while Study 102 simply included boys with DMD aged 4 to 8 years.

Delandistrogene moxeparvovec is an investigational rAAV-based gene therapy designed to counterweigh missing dystrophin in DMD by delivery of a transgene encoding an engineered protein. Sarepta’s biologics license application (BLA) for the treatment is set for review by May 29, 2023, and just recently, the FDA determined that it will hold an advisory committee on the BLA,2 which was a change in plans based on what was communicated to Sarepta at the midcycle meeting.3

WATCH NOW: Emma Ciafaloni, MD, on the State of Gene Therapy in Neuromuscular Disease

The poster1 also included collective safety data from all patients in Study 101 and Study 102, as well as those from a number of cohorts in ENDEAVOR (n = 84)—both ambulatory and nonambulatory patients. Compared with the cohort of individuals treated with the 1.33 x1014 vg/kg dose (n = 72), safety was deemed consistent. The most common treatment-emergent adverse events (AEs) among all patients were vomiting (n = 52; 61.9%), decreased appetite (n = 40; 47.6%), nausea (n = 34; 40.5%), upper respiratory tract infection (n = 34; 40.5%), pain in extremities (n = 24; 28.6%), upper abdominal pain (n = 23; 27.4%), irritability (n = 23; 27.4%), and procedural pain (n = 22; 26.2%). These AEs occurred at similar rates for the cohort of patients who were treated with the 1.33 x1014 vg/kg dose.

In total, 7 patients (8.3%) experienced treatment-related serious AEs, including 2 events each of vomiting, increased transaminases, and rhabdomyolysis; and 2 event each of liver injury, immune-mediated myositis, and myocarditis. Notably, the latter 2 AEs were new treatment-related serious AEs, both of which occurred in single patients.

Immune-mediated myositis—which has not been observed in other ENDEAVOR cohorts or other studies of the therapy—occurred in a 9-year-old boy with a large mutation in exons 3-43, occurring with severe moving limb impairment and challenges with breathing and swallowing. Proud et al noted that cellular immune response that was detected was specific to this patient’s mutation and informed a protocol amendment.

Myocarditis, meanwhile, occurred in an 11-year-old boy who was admitted for nausea/vomiting, with raised troponin levels noted during hospitalization without signs of systolic dysfunction. The patient had MRI findings consistent with that superimposed on DMD cardiomyopathy. He received 3 days of intravenous methylprednisolone, and had additional chronic cardiac medications added post event. At 1 month, MRI revealed normal function and partial resolution of the changes, with normal systolic function displayed at 4 months post event.

“Delandistrogene moxeparvovec demonstrated a consistent and manageable safety profile across all three clinical trials, with most AEs occurring within the first 90 days following treatment,” Proud et al wrote. “Further ongoing studies are assessing the longer-term safety and efficacy of delandistrogene moxeparvovec.”

Read more coverage of the 2023 MDA Conference here.

1. Proud CM, Zaidman CM, Shieh PB, et al. Integrated analyses of data from clinical trials of delandistrogene moxeparvovec in DMD. Presented at: MDA Clincial & Scientific Conference; March 19-22, 2023; Dallas, TX. Poster 106.
2. Sarepta Therapeutics Announces Advisory Committee Meeting will be Held for SRP-9001. News release. Sarepta Therapeutics. March 16, 2023. Accessed March 21, 2023.
2. Sarepta Therapeutics fourth quarter and full-year 2022 earnings call. News release. Sarepta Therapeutics. February 28, 2023. Accessed March 21, 2023.
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