New Data Shows Motor Gains with SRP-9001 Gene Therapy in DMD
Duchenne Muscular Dystrophy (DMD) is a genetic disorder that causes progressive muscle degeneration and weakness. It is the most common form of muscular dystrophy in children, predominantly affecting males. Historically, DMD has resulted in the loss of the ability to walk between ages 7 and 13 years, and death in the teens or 20s. The estimated prevalence of DMD is about 1 in every 5,000 males aged 5-9 years [1].
The Disease Pathway
Source: Romina F, Natasha C (2021) [2]
DMD is caused by mutations in the gene responsible for the production of a protein called dystrophin. This protein plays a crucial role in the structural maintenance of muscle cells. When the production of dystrophin is interfered with, this leads to principal symptoms of DMD such as muscle weakness and degeneration [3].
Study SRP-9001-102 [4]
Against this backdrop, a Phase 2 clinical trial is investigating the potential of SRP-9001 (delandistrogene moxeparvovec), a single-dose gene therapy designed to deliver a gene encoding a shortened version of dystrophin to muscle cells. The study, sponsored by Sarepta Therapeutics, is divided into three parts.
The first part comprised of a 48-week, randomized, double-blind, placebo-controlled trial. During this phase, 41 boys with DMD, aged between 4 to 7 years, were either administered a single infusion of SRP-9001 or a placebo.
The second part of the study, also spanning 48 weeks, included patients (now aged 5 to 8 years) who were initially randomized to the placebo group in Part 1 to receive SRP-9001.
Efficacy Outcomes
The primary efficacy outcome was the North Star Ambulatory Assessment (NSAA) score, a standardized measure of motor function. The NSAA is a 17-item scale that grades the performance of various functional skills on a scale from 0 (unable), 1 (completed independently but with modifications), and 2 (completed without compensation).
Source: NSAA manual
In Part 1 of Study 102, overall maintenance of mean NSAA score was observed 96 weeks after SRP-9001 treatment, a period when functional decline is typically expected based on the natural progression of DMD.
In the second part of the study, the mean NSAA total score increased by 1.3 points at 48 weeks post-treatment in patients who received placebo in Part 1 and SRP-9001 in Part 2.
In a post-hoc analysis, a statistically significant difference of 2 points in mean NSAA total score change from baseline was observed in patients treated in Part 2 versus the propensity-score-weighted external control group (P=0.0009).
In summary, SRP-9001 dystrophin protein expression at 12 weeks post-treatment was achieved in patients treated with delandistrogene moxeparvovec in both Parts 1 and 2. Patients treated in Part 1 continued to express SRP-9001 dystrophin protein after 60 weeks of treatment.
Safety Outcomes
For patients treated in Part 1, most treatment-emergent adverse events (TEAEs) occurred within the first 90 days of treatment. The main adverse events observed were:
- Vomiting (60% in treated vs 19% in placebo)
- Decreased appetite (30% in treated vs 0% in placebo), and
- Nausea (30% in treated vs 9.5% in placebo)
These patients generally did not report treatment-related TEAEs in Part 2.
Of note, five treatment-related serious adverse events (SAEs) were reported in Part 1 of the study, 4 in the group that received delandistrogene moxeparvovec and 1 in the placebo group.
- 3 instances of rhabdomyolysis (2 in patients who received delandistrogene moxeparvovec and 1 in the placebo group) that resolved.
- Increased transaminases in 1 patient and liver injury in another (both in patients who received delandistrogene moxeparvovec).
Similar TEAEs were observed in the treatment group in part 2 of the study:
- Vomiting (76.2% in treated vs 0% in placebo*)
- Decreased appetite (71.4% in treated vs 0% in placebo*), and
- Nausea (47.6% in treated vs 5% in placebo*).
*placebo in this case refers to patients who had already received SRP-9001 in part 1 of the study
In the second part of the study, it was encouraging to note that there were no discontinuations due to an adverse event and no deaths reported. Importantly, no new safety signals have been observed in Study 102.
Ongoing Study – EMBARK, SRP-9001-301
An ongoing phase 3 clinical trial – EMBARK is set to further test the safety and efficacy of SRP-9001. The study will enrol 126 participants with DMD between the ages of 4 to 7. The primary endpoint will assess the change in NSAA total score from baseline to week 52 compared to placebo [5,6].
Looking Ahead
These findings suggest that SRP-9001 holds promise as a potential therapeutic option for DMD patients. The continuation of the study will provide more insights into the long-term efficacy and safety of this gene therapy.
As we continue to monitor the progress of this trial, we remain hopeful that SRP-9001 could represent a significant step forward in the treatment of DMD, offering new possibilities for those affected by this condition.
References:
- Centers for Disease Control and Prevention. (2022, November 21). MD STARnet Data and statistics.
- Romina F, & Natasha C. Empowering Muscle Stem Cells for the Treatment of Duchenne Muscular Dystrophy. Cells Tissues Organs. 2021, 211. 1-14. 10.1159/000514305.
- Duchenne muscular dystrophy (DMD) – diseases. Muscular Dystrophy Association. (2021, April 29).
- Mendell J. et al. A Phase 2 Clinical Trial Evaluating the Safety and Efficacy of Delandistrogene Moxeparvovec (SRP-9001) in Patients with Duchenne Muscular Dystrophy (DMD) (S48.004). Neurology Apr 2023, 100 (17 Supplement 2) 3035; DOI: 10.1212/WNL.0000000000202973
- Sarepta Therapeutics’ investigational gene therapy SRP-9001 for Duchenne muscular dystrophy demonstrates significant functional improvements across multiple studies. Sarepta Therapeutics, Inc.
- A gene transfer therapy study to evaluate the safety and efficacy of SRP-9001 (Delandistrogene Moxeparvovec) in participants with Duchenne muscular dystrophy (DMD) – https://clinicaltrials.gov/ct2/show/NCT05096221
