Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6–48 months with Duchenne muscular dystrophy amenable to exon 51 skipping

• Published in: Neuromuscular disorders : NMD Vol. 33; no. 6; pp. 476 - 483
• Main Authors: Mercuri, E., Seferian, A.M., Servais, L., Deconinck, N., Stevenson, H., Ni, X., Zhang, W., East, L., Yonren, S., Muntoni, F., Deconinck, Nicolas, Van Coster, Rudy, Vanlander, Arnaud, Seferian, Andreea, De Lucia, Silvana, Gidaro, Teresa, Brande, Laura Vanden, Servais, Laurent, Kirschner, Janbernd, Borell, Sabine, Mercuri, Eugenio, Brogna, Claudia, Pane, Marika, Fanelli, Lavinia, Norcia, Giulia, Muntoni, Francesco, Brusa, Chiara, Chesshyre, Mary, Maresh, Kate, Pitchforth, Jaqueline, Schottlaender, Lucia, Scoto, Mariacristina, Silwal, Arpana, Trucco, Fedrica
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01-06-2023
• Subjects: Child, Preschool; Clinical trial; Duchenne muscular dystrophy; Dystrophin - genetics; Eteplirsen; Exons; Humans; Infant; Male; Morpholinos - therapeutic use; Muscular Dystrophy, Duchenne - drug therapy; Muscular Dystrophy, Duchenne - genetics; Mutation; Safety; Clinical trial; Safety; Duchenne muscular dystrophy; Eteplirsen
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2023.03.008

•First clinical trial of eteplirsen in patients with DMD aged 6 to 48 months.•Safety experience was consistent with the known safety profile of eteplirsen.•Eteplirsen was well tolerated with no evidence of kidney toxicity.•Eteplirsen pharmacokinetics was comparable with that of boys older than 4 years.
Eteplirsen is FDA-approved for the treatment of Duchenne muscular dystrophy (DMD) in exon 51 skip-amenable patients. Previous studies in boys > 4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with matched natural history cohorts. Here the safety, tolerability and pharmacokinetics of eteplirsen in boys aged 6–48 months is evaluated. In this open-label, multicenter, dose-escalation study (NCT03218995), boys with a confirmed mutation of the DMD gene amenable to exon 51 skipping (Cohort 1: aged 24–48 months, n = 9; Cohort 2: aged 6 to < 24 months, n = 6) received ascending doses (2, 4, 10, 20, 30 mg/kg) of once-weekly eteplirsen intravenously over 10 weeks, continuing at 30 mg/kg up to 96 weeks. Endpoints included safety (primary) and pharmacokinetics (secondary). All 15 participants completed the study. Eteplirsen was well tolerated with no treatment-related discontinuations, deaths or evidence of kidney toxicity. Most treatment-emergent adverse events were mild; most common were pyrexia, cough, nasopharyngitis, vomiting, and diarrhea. Eteplirsen pharmacokinetics were consistent between both cohorts and with previous clinical experience in boys with DMD > 4 years of age. These data support the safety and tolerability of eteplirsen at the approved 30-mg/kg dose in boys as young as 6 months old.