Duchenne Therapy Eteplirsen Safe in Infants as Young as 6 Months, Study Shows


Patients with Duchenne muscular dystrophy between ages of 6 and 24 months old demonstrated a similar safety profile on eteplirsen than those between 24 and 48 months of age.

New data from a long-term open-label extension (OLE) of a phase 2 trial (NCT03218995) showed that treatment with eteplirsen (Exondys 51; Sarepta Therapeutics) was safe in infants with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping as young as 6 months old. All told, investigators reported no discernible differences in safety signals at 162 weeks for patients aged 24 to 48 months vs those 6 to 24 months old.1

Presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, the most commontreatment-emergent adverse events (TEAEs) reported were cough, pyrexia, rhinorrhea, and nasopharyngitis, which were consistent with what has been seen in pediatric populations. Patients were on the therapy for a mean of 120.1 (SD, 35.79) weeks, and saw a reduction in the frequency and severity of TEAEs compared with the parent study.

Led by Ihor Sehinovych, PharmD, Sarepta Therapeutics, the dose-escalation study featured 9 patients aged 24 to 48 weeks (cohort 1) and 6 patients aged 6 to less than 24 months (cohort 2) who were treated with once-weekly 30 mg/kg intravenous eteplirsen for up to 5 years. Fourteen (93.3%) of the 15 patients were enrolled in the OLE when the study was terminated by the sponsor to reduce trial burden and ensure continued treatment if desired. In addition, around one-fourth (26.7%; 4 of 15) entered the OLE on corticosteroids and 11 patients received corticosteroids throughout the OLE.

In addition to the common TEAEs observed, 3 patients experienced mild treatment-related TEAEs of catheter-site swelling, chromaturia, and abnormal urine albumin/creatinine ratio. One case of influenza, unrelated to eteplirsen, was reported as a serious TEAE. There were no port-related infections, treatment-related discontinuations, deaths, or evidence of kidney toxicity observed.

The original study, published in Neuromuscular Disorders, in March 2023, highlighted the pharmacokinetic and safety profile of the agent in both cohorts of infants with DMD. Those in the trial received ascending doses (2, 4, 10, 20, 30 mg/kg) of once-weekly eteplirsen over 10 weeks, continuing at 30 mg/kg up to 96 weeks. Most participants experienced an infusion-related reaction; however, all were mild in severity and most (43 of 44) were assessed as unrelated to study drug by the investigator.2

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This was the first study to utilize a phosphorodiamidate morpholino oligomer (PMO) in boys with DMD as young as 6 months of age, with extensive kidney testing showing no evidence of kidney toxicity as observed in other studies of eteplirsen. Despite a limited sampling approach from all participants, pharmacokinetic parameters of the agent were shown to be consistent with clinical studies in older boys with DMD.

"This model demonstrated that eteplirsen exposures in the younger age groups (including ages 0.5 to < 4 years) were within the exposure range in adolescents when using the weight-based dosing regimen of 30 mg/kg that is associated with biological efficacy in older boys," the study authors wrote.2 "Of note, the data continue to support that urinary excretion is the major pathway of eteplirsen clearance."

Eteplirsen, a PMO treatment designed to increase dystrophin by skipping exons, was the first approved in its class in 2016. The therapy was approved under the accelerated approval pathway, and is currently being assessed in the phase 4 MIS51ON trial (NCT03992430) to confirm its clinical benefit. According to clinicaltrials.gov, the trial is expected to complete later this year.

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1. Sehinovych I, Mercuri E, Seferian AM, et al. Safety and tolerability of eteplirsen in patients 6-48 months old with DMD amenable to exon 51 skipping: an open-label extension study. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Orlando, FL. POSTER M173
2. Mercuri E, Seferian AM, Servais L, et al. Safety, tolerability, and pharmacokinectics of eteplirsen in young boys aged 6-48 months with Duchenne muscular dystrophy amenable to exon 51 skipping. Neuromusc Disord. 2023;33(6):476-483. doi:10.1016/j.nmd.2023.03.008
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