Journal Article

Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia

Saini, Rajnish, Lipshutz, Gerald S., Leuchars, Mary, Li, Lerong, Sikirica, Vanja, Geberhiwot, Tarekegn, Grunewald, Stephanie, Jin, Ling, Koeberl, Dwight, Schulze, Andreas, Liang, Min, Sondheimer, Neal, Luo, Junxiang

2024

نظرة عامة

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period. Interim data from a clinical trial of mRNA-3927—an mRNA therapeutic for propionic acidaemia—provide early indications of the safety and efficacy of the treatment, and suggest that this approach might be applicable to other rare diseases.

• الناشر: Nature Publishing Group UK,Nature Publishing Group
• موضوع: 13 / 38/1 / 45/71 / 45/90 / 49/47 / 692/308 / 692/699 / Coenzyme A / Drug dosages / Enzymes / Humanities and Social Sciences / Metabolism / Metabolites / mRNA / multidisciplinary / Optimization / Pancreatitis / Polyethylene glycol / Science / Science (multidisciplinary)