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Elevidys Gene Therapy Demonstrates Sustained Benefits and Disease Stabilization in Duchenne: Part 2 EMBARK Results
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Key Takeaways
- Elevidys gene therapy showed significant functional improvements in DMD patients, with sustained benefits over two years, including NSAA, TTR, and 10MWR tests.
- The therapy received expanded FDA approval for ambulatory and nonambulatory DMD patients aged 4 and older, contingent on confirmatory trial results.
Crossover-treated patients demonstrated clinically meaningful and statistically significant improvements in functional outcomes despite being older at the time of treatment.
Craig McDonald, MD
New data from Part 2 of the EMBARK study (NCT05096221), a post-marketing trial of Sarepta’s gene therapy, revealed that treatment with the medication led to statistically significant improvements in functional outcomes among crossover patients with Duchenne muscular dystrophy (DMD) previously on placebo, as well as continued benefits in preserving muscle function and disease stabilization over a 2-year period.1
EMBARK, a phase 3, randomized, placebo-controlled study of 125 participants with DMD, comprised of 2 parts. In Part 1 participants were randomized by age (≥4 to <8 years) or NSAA Total Score (>16 to <29) and received either delandistrogene moxeparvovec-rokl (Elevidys; Sarepta)(1.33 x10¹⁴ vg/kg) or placebo, with a 52-week follow-up. In Part 2, participants crossed over, switching treatments while remaining blinded, with another 52-week follow-up.
In comparison with a matched external control, findings showed an improvement of 2.34 points from baseline in NSAA 52 weeks after treatment with Elevidys (P <.0001). The crossover group (n = 59), while 1 year older (average age, 7.18) than those treated in Part 1 (average age, 5.98 years), demonstrated clinically meaningful and statistically significant function benefits in NSAA, Time to Rise (TTR; –2.70 seconds [improvement]; P <.0001), and 10-meter walk walk/run (10MWR) function test (–1.07 seconds [improvement]; P = .0001).
"As a neuromuscular medicine specialist who has seen patients with Duchenne muscular dystrophy for over three decades, I’ve witnessed firsthand the positive impact of gene therapy on the trajectory of Duchenne," investigator Craig McDonald, MD, professor and chair of the UC Davis Health Department of Physical Medicine and Rehabilitation, said in a statement.1 “These longer-term results are even more striking when compared to external control given the progressive nature of the disease, and we’d expect to see this divergence grow over time. The efficacy of Elevidys gives me great hope as we continue to follow these patients and see others treated in the clinical setting.”
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After 2 years of treatment, those who originally received gene therapy in Part 1 demonstrated clinically meaningful and statistically significant functional benefit in NSAA (+2.88 points; P = .0001), TTR (–2.06 seconds [improvement]; P = .0033), and 10MWR (–1.36 seconds [improvement]; P = .0028) in comparison with the external control. Notably, the square means (LSM) differences between the patients treated in Part 1 and the external control group increase from year 1 to year 2 for all 3 functional outcomes, suggesting continued divergence from the natural history of DMD. Furthermore, findings on functional outcomes were also supported by consistent and sustained expression of Elevidys micro-dystrophin observed at week 64 and measured by western blot.
Elevidys, an adeno-associated vector-based gene therapy, was originally approved under the accelerated approval pathway in June 2023.2 Nearly a year later, the therapy was granted traditional approval for ambulatory patients with DMD, as well as had its label expanded to include patients aged 4 years and older with the disease. During that expansion, the agency also granted it accelerated approval for nonabulatory patients, with continued approval that was contingent on a verification of clinical benefit in a confirmatory trial.3
Additional data from Part 2 of EMBARK showed minimal progression in underlying muscle pathology for those treated in Part 1, which was consistent with the functional benefits observed. Furthermore, the safety of the therapy was consistent and manageable, with no new safety signals documented.
"We’re very encouraged to see the results from Part 2 of EMBARK as they further elucidate the impact Elevidys has on disease progression in a blinded, controlled study. Skeletal muscle MRI demonstrates the importance of preserving muscle, and the functional outcome results show disease stabilization sustained through two years after treatment," Louise Rodino-Klapac, PhD, executive vice president, head of Research & Development, and chief scientific officer at Sarepta, said in a statement.1 "Over time, we continue to observe a statistically significant difference favoring Elevidys compared to a well-matched external control on NSAA and timed tests. The consistency and totality of evidence supporting a long-term and clinically meaningful treatment benefit with ELEVIDYS continues to grow. We look forward to sharing more details with the clinical community in upcoming scientific forums."
Topline data from Part 1 of EMBARK, announced in October 2023, showed that treatment with Elevidys did not meet the primary end point of statistically significant improvement in NSAA total score after 52 weeks. Those in the study demonstrated an improvement of 2.6 points whereas those on placebo improved 1.9 points, a difference of 0.65 points that was not significant between groups (P = .24). Despite this, treatment with the therapy results in robust changes on all key pre-specified secondary end points over the treatment period.4
Among secondary endpoints, Elevidys demonstrated a significant LSM difference of –0.64 (P = .0025) in TTR compared to placebo. Treatment effects were more pronounced in patients aged 6-7 years (LSM difference, –0.78; P = .0291) than in those aged 4-5 years (LSM difference, –0.50; P = .0177). Clinically meaningful benefits were also observed on the 10-meter walk test, with an LSM difference of –0.42 (P = .0048) overall, showing greater impact in patients aged 6-7 years (LSM difference, –0.52; P = .0363) compared to those aged 4-5 years (LSM difference, –0.33; P = .0319).
