Interim Real-World Data From Phase 4 EVOLVE Study Demonstrate Sustained Treatment Effect of Eteplirsen


In a real-world study, eterplirsen was safe for patients with Duchenne muscular dystrophy, with sustained or improved status in function.

Katherine Mathews, MD, a professor of pediatrics–general neurology at the University of Iowa

Katherine Mathews, MD

At the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, investigators presented real-world, interim data from the phase 4 EVOLVE trial, a confirmatory study assessing the treatment effects of eterplirsen (Exondys 51; Sarepta Therapeutics). All told, in a subgroup of patients, treatment with the exon-skipping agent demonstrated persisted effects and a safety profile that was consistent with previous clinical trials.

The interim analysis included patients who were nonambulatory at eteplirsen treatment initiation of became nonambulatory after eteplirsen initiation. Of the 123 eteplirsen-treated patients enrolled in the study as of December 2021, 41 (33%) were nonambulatory at treatment initiation (mean age, 18.4 years; duration of treatment, 4.2 [SD, 1.2] years). Over the 5-year period, upper limb function in patients with at least a 2 on Brooke score evaluations suggested a maintenance of function in 14 of 18 (78%) of nonambulatory patients and maintenance/improvement of function in 12 of 15 (80%) of patients who lost ambulation after eteplirsen initiation.

Senior author Katherine Mathews, MD, a professor of pediatrics–general neurology at the University of Iowa, and colleagues observed that one-fourth (n = 31) of patients lost ambulation after eteplirsen initiation (mean age, 14.7 years; mean duration of treatment, 6.1 [SD, 1.9] years). At the time of the analysis, all patients that were nonambulatory at treatment initiation or lost ambulation after eteplirsen initiation (n = 72), persisted on eteplirsen (mean duration of treatment, 5.0 [SD, 1.8] years; mean duration of follow-up in EVOLVE, 1.1 [SD, 0.8] years). In addition to maintenance/improvement of function, there were no treatment-related serious adverse events with eteplirsen.

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This was not the first time data from EVOLVE had been released. At the 2022 Congress of the World Muscle Society, an interim analysis of EVOLE described the usage, safety, and clinical outcomes of eteplirsen, along with golodirsen (Vydonys; Sarepta) and casimersen (Amondys 45; Sarepta), in patients with DMD in routine clinical practice. Golodirsen was approved for patients with a confirmed mutation amenable to exon skipping 53 while casimersen, an antisense oligonucleotide, was approved for patients amenable to skipping exon 45.2

Across the 3 PMOS, patient age at treatment initiation ranged from 1 to 33 years old. The mean total duration of PMO treatment received was equal to 4.7 years for eteplirsen-treated, 1.3 years for golodirsen-treated, and 0.3 years for casimersen-treated patients. Similar to the analysis presented at MDA 2024, the safety of the therapies was consistent with what was previously seen in clinical trials. In total, 17.1% (21 of 123) of eteplirsen-treated and 5.9% (1 of 17) of golodirsen-treated patients experienced a treatment-emergent AE of special interest. No patients on casimersen experienced a treatment-related AE of special interest to date observed (December 2021).

Eteplirsen’s approval was met with controversy related to the pivotal trial, which enrolled 12 patients and demonstrated small increases in the surrogate measure end point of dystrophin levels, raising questions about its clinical benefit. Two years after its approval, the Committee for Human Medicinal Products of the European Medicines Agency gave a negative opinion for eteplirsen treatment. After Sarepta appealed and a new evaluation was initiated, including a scientific advisory group meeting involving DMD experts and patient representatives, the opinion of the CHMP remained negative.3

The efficacy and safety of eteplirsen continues to be evaluated in the phase 3 MIS51ON study (NCT03992430). This 2-part study, comprised of a dose-escalation portion and a dose-finding/dose comparison portion, is expected to conclude sometime in 2024.

Click here for more coverage of MDA 2024.

1. Grabich S, Waldrop MA, Santra S, et al. Interim analysis of EVOLVE: evaluating eteplirsen treatment in nonambulatory patients in routine clinical practice from a phase 4 observational study. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER M180.
2. Ricchetti-Masterson K, Santra S, Hornibrook S, et al. Interim analysis of EVOLVE: a long-term observational study evaluating eteplirsen, golodirsen, or casimersen in routine clinical practice. Presented at: 2022 World Muscle Society; LSVP.31
3. Sarepta receives negative CHMP re-examination opinion for eteplirsen. Sarepta Therapeutics. September 21, 2018. Accessed March 3, 2024.
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