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

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.

Fig. 1. PCCA and PCCB genes, the propionate pathway and the mechanism of action of mRNA-3927.

a, PA is caused by pathogenic variants in the PCCA or PCCB genes, resulting in a deficiency of the mitochondrial enzyme PCC. PCC deficiency leads to the accumulation of toxic metabolites, including 2-MC and 3-HP. b, LNP-encapsulated mRNAs encoding the human PCCA and PCCB subunits are delivered to target cells in the liver. After entry into the cytoplasm, the mRNAs are translated into the PCCA and PCCB subunits, forming the PCC enzyme complex, which localizes to the mitochondria to function in the propionate metabolic pathway. MUT, mutase. The illustration in b was adapted from ref. , Elsevier, under a Creative Commons licence CC BY 4.0.

Fig. 2. Dose-optimization study design and participant information.

a, Study schema. Participant eligibility was assessed during the screening period, followed by an observation period during which baseline PA disease status was monitored. The enrolment of participants into each cohort was staggered using a sentinel dosing strategy. Three participants were enrolled into a cohort, treated and monitored for safety for at least 14 days by a Safety Monitoring Committee. After confirmation that no DLTs occurred, enrolment and dosing of the next cohort began. After the treatment period, participants could roll over into the extension study or enter a two-year follow-up period. Q2W, every two weeks; Q3W, every three weeks. b, CONSORT diagram. ^aAn additional participant was enrolled in cohort 1 per protocol after the discontinuation of one participant after their first dose owing to the withdrawal of participant consent. ^bSeven individuals failed the initial screening; two of these individuals were rescreened and met eligibility criteria for inclusion in the study. ^cOne participant switched to 0.60 mg per kg every two weeks dosing.

Fig. 3. PK exposure to PCCA mRNA after dose 1 (PK analysis population).

Blood samples were collected before dosing and at the indicated time points for up 21 days after dose 1. Samples were submitted to the PPD central laboratory for quantification of PCCA mRNA through branched DNA analysis. For graphing purposes, cohorts 1 and 2 (both 0.30 mg per kg) were combined before the dosing frequency changed for dose 2. Data are mean + s.d.

Fig. 4. MDE profiles (intention-to-treat population).

MDEs, defined as the presence of exacerbated PA symptoms, the need for emergency care and evidence of biochemical abnormalities, were assessed 12 months before treatment and in the post-treatment period. Note that the definition of MDEs was updated during the study in response to discussions with regulatory agencies. MDEs that were reported by investigators before this update might not fully align with this current definition.