Exon-Skipping Therapy Golodirsen Prolongs Ambulation in DMD, Long-Term Study Shows


Median time to loss of ambulation for golodirsen-treated patients was 1968 days vs 1092 days for external control patients.

Eugenio Mercuri, MD, PhD

Eugenio Mercuri, MD, PhD

New findings from a long-term trial (NCT03532542) showed that golodirsen (Vyondys 53; Sarepta) treatment for up to 6 years was favorable among patients with Duchenne muscular dystrophy (DMD), with observed prolonged ambulation compared with matched exon 53 skipping-amenable external control patients. Presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, these data represented the longest follow-up of a declining DMD population treated with golodirsen.

Study 4045-302 was a 3-year, multicenter, open-label extension (OLE) study assessing the long-term safety and efficacy of golodirsen 30 mg/kg in patients with DMD amenable to skipping of exon 53. At the last assessment before prior golodirsen initiation, 25 patients received treatment at a mean age of 8.2 (SD, 2.2) years; 18 of the 25 patients completed the OLE up to 338.6 weeks (6.49 years). Over the 6-year period, the exon-skipping agent was well tolerated, with treatment emergent adverse events (TEAEs) that includes diarrhea (18 of 25; 72%), vomiting (18 of 25; 72%), cough (16 of 25; 64%), rhinitis (16 of 25; 64%), nasopharyngitis (15 of 25; 60%), and pyrexia (15 of 25; 60%).

Led by senior author Eugenio Mercuri, MD, PhD, professor of pediatric neurology at Catholic University Rome, loss of ambulation after 3 years occurred in 4 of the 25 treated patients (16.0%) compared with 12 of the 54 (22.2%) matched external controls. Ultimately, this represented a 91.1% risk reduction (HR, 0.089; P = .022). At 6 years, 15 golodirsen-trated patients experienced loss of ambulation, with 7 patients still ambulant at OLE completion (12.4-20.3 years old).

Compared with matched external control patients (n = 19), golodirsen-treated patients experienced a median delay in time to loss of ambulation of around 2.4 years, suggesting a 47.4% risk reduction (HR, 0.526; P = .149). The authors noted that because of the unavailability of follow-up in the matched external control cohort at 6 years, the analysis should be interpreted with caution. In addition, treatment with golodirsen resulted in attenuated pulmonary decline, demonstrated through forced vital capacity assessments (2.9% vs 6.67%; P <.01).

READ MORE: SRP-9001 Improves Duchenne Muscular Dystrophy Disease Trajectory Despite Failing to Meet Primary End Point in Phase 3 EMBARK Trial

During the 6-year period, there were no evidence of kidney toxicity and no TEAEs that led to treatment discontinuation. Additionally, there were no deaths in the study. Of the 25 patients, 8 experienced 11 severe TEAEs, which included fractures (n = 4), loss of ambulation (n = 6), and scoliosis (n = 1); however, none were attributable to golodirsen. The same amount of patients experienced 17 serious AEs, which included fractures (n = 4), pyrexia (n = 1), and convulsion (n = 1). None of these were considered related to treatment. Of note, there were no port-related infections documented among the 8 patients with implanted ports.

Coming into the study, the cohort observed had a mean weight of 28.4 kg and a mean height of 120.6 cm. Patients on golodirsen were mainly taking prednisole or prednisolone (40%) and had a mean body mass index of 18.9 kg/m2. Aside from the noted severe TEAEs, most of the TEAEs were either mild or moderate in severity.

Golodirsen, previously known as SRP-4053, was approved by the FDA in 2019 as a treatment for those with DMD with genetic mutations subject to skipping exon 53. It’s estimated that about 8% of patients with DMD. After originally receiving a complete response letter, the regulatory go-ahead was granted based on data showing a statistically significant increase in dystrophin production in skeletal muscle in those treated with the agent, enough so to indicate benefit. A post-marketing, placebo-controlled confirmatory trial, dubbed ESSENSE, is expected to be completed in 2024.

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1. Mercuri E, Muntoni F, Seferian AM, et al. Six-year long-term safety and efficacy of golodirsen in patients with DMD vs mutation-mediated external controls. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER M162
2. Sarepta Therapeutics Announces FDA Approval of VYONDYS 53™ (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53. Sarepta Therapeutics; Published December 12, 2019. Accessed March 4, 2024. sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-vyondys-53tm.
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