SRP-9001 Holds Promise as DMD Treatment, MRI Data Suggest

Rebecca J. Willcocks, PhD

Findings from an open-label gene transfer study in adolescent patients with Duchenne muscular dystrophy (DMD) suggest that Microdystrophin gene transfer using recombinant adeno-associated virus serotype rh74 (rAAVrh74), driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7), known as SRP-9001 (Sarepta Therapeutics), is an effective therapeutic option for patients with DMD.¹

Led by Rebecca J. Willcocks, PhD, Department of Physical Therapy, University of Florida, the Systemic Gene Delivery Clinical Trial for DMD showed robust transgene expression on muscle biopsy (74% to 96%) of fibers, but biopsy data reflects a small sample of muscle where muscle quality in large muscle groups can be objectively and noninvasively measured using quantitive MRI (qMRI) and spectroscopy (qMRS), 2 tools used for monitoring disease progression and therapeutic response.

The researchers noted that between qMRI and qMRS data—including muscle fat fraction and bulk MRI transverse relaxation time—could be reduced in children treated with SRP-9001 compared to an age-matched natural history cohort treated with standard of care, as well as a control group of individuals without DMD.

In the case-control trial, 3 patients received qMRI and qMRS evaluation at the University of Florida between 2018-2020, with each imaged 1–2 times, 6–24 months post systemic delivery of SRP-9001, using the MR protocols implemented in the multicenter Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy (Imaging DMD) study. A natural history comparison cohort was used retrospectively from the ImagingDMD study (54 individuals; 110 study visits between 2011-2018). The investigators also retrospectively identified 17 age-matched individuals without DMD for the comparison control cohort.

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In total, minimal fat infiltration was observed on MR images from the SRP-9001 arm compared to participants from the natural history cohort, whose muscles have dark patterning throughout, especially in the biceps femoris long head and adductor magnus.

Additionally, the investigators found spectra from the vastus lateralis (VL) showed a visible fat peak, reflecting an accumulation of intramuscular fat (value, 0.13) in the natural history cohort. In the control and SRP-9001 arms of the trial, this was minimal. Mean VL MRS fat faction in the treatment cohort was lower than what was observed in the natural history cohort. Overall, there were 100 data points (0.02 [0.01] vs 0.11 [0/11]) which were similar to the control group, which included 17 data points (0.02 [0.01]).

VL fat faction was stable over the course of 12 months in 2 participants who received SRP-9001 who had repeated measurements (mean change, 0.00 [0.01]), though, this was not seen in the 42 participants of the natural history cohort with repeated measurements (mean change, 0.05 [0.07]).

Wilcocks et al. also found qT2 across 5 upper and lower leg muscles was greater in the natural history cohort than it was in the SRP-9001 or control cohorts (mean qT2 for VL: natural history, 44.7 [7.7] ms; SRP-9001, 37.3 [2.2] ms; control, 35.1 [3.7] ms).

“These MR data indicate marked sparing and minimal fat infiltration in boys with DMD who received SRP-9001 compared with an age-matched natural history cohort,” they concluded. “qMRI and qMRS biomarkers are valuable adjuncts to clinical assessments because of their sensitivity to subclinical disease progression and lack of dependence on participant growth, maturation, and motivation.”

Last year, results from Study 101, a phase 1/2a nonrandomized controlled trial (NCT03375164) revealed that treatment with SRP-9001 was well-tolerated and had minimal adverse events (AEs) in ambulatory men with Duchenne muscular dystrophy (DMD) without preexisting AAVrh74 antibodies and a stable corticosteroid dose.²

Lead author Jerry Mendell, MD, neurologist, Nationwide Children’s Hospital, and colleagues found that among the 4 patients included in the study, all 53 AEs recorded were either considered mild (n = 33; 62%) or moderate (n = 20; 38%), while also reporting no serious AEs as well. Conducted at the Nationwide Children’s Hospital in Columbus, Ohio, researchers found 18 AEs were considered treatment-related, the most common of which was vomiting (9 of 18 events; 50%). Additionally, 3 patients had transiently elevated y-glutamyltransferase, which resolved with corticosteroids.

With safety as the primary outcome, secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. After 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fiber micro-dystrophin with a mean intensity of 96% at the sarcolemma.

A version of this story originally appeared on NeurologyLive's sister site, HCPLive.

REFERENCES
1. Wilcocks RJ, Forbes SC, Walter GA, et al. Assessment of rAAVrh.74.MHCK7.micro-dystrophin Gene Therapy Using Magnetic Resonance Imaging in Children With Duchenne Muscular Dystrophy. JAMA Netw Open. 2021;4(1):e2031851. doi: 10.1001/jamanetworkopen.2020.31851.
2. 2. Mendell JR, Sahenk Z, Lehman K. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol. Published online June 15, 2020. doi: 10.1001/jamaneurol.2020.1484.