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.

丙酸血症是一种罕见疾病，由丙酰辅酶 A 羧化酶 α 或 β（PCCA 或 PCCB）亚基缺陷引起，导致有毒代谢物积累，并导致反复出现危及生命的代谢失代偿事件。在此，我们报告了一项首次人体、1/2 期、开放标签、剂量优化研究的中期分析，以及一项评估 mRNA-3927（编码 PCCA 和 PCCB 的双重 mRNA 疗法）安全性和有效性的扩展研究。截至 2023 年 5 月 31 日，共有 5 个剂量组的 16 名参与者入组。 16 名参与者中有 12 名完成了剂量优化研究并参加了扩展研究。在总计 15.69 人年的治疗中，总共注射了 346 剂 mRNA-3927 静脉注射剂。没有发生剂量限制性毒性。 16 名参与者中有 15 名 (93.8%) 报告了治疗引起的不良事件。初步分析表明，在 12 个月的预处理期间报告代谢失代偿事件的 8 名参与者中，随着剂量的增加，mRNA-3927 的暴露量增加，代谢失代偿事件的风险降低了 70%。