{Reference Type}: Journal Article
{Title}: Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia.
{Author}: Koeberl D;Schulze A;Sondheimer N;Lipshutz GS;Geberhiwot T;Li L;Saini R;Luo J;Sikirica V;Jin L;Liang M;Leuchars M;Grunewald S;
{Journal}: Nature
{Volume}: 628
{Issue}: 8009
{Year}: 2024 Apr 3
{Factor}: 69.504
{DOI}: 10.1038/s41586-024-07266-7
{Abstract}: 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.