Model-Informed Dose Selection for mRNA-3927 in Participants with Propionic Acidemia (PA)

Objectives: To develop population pharmacokinetic/pharmacodynamic (PKPD) models for mRNA-3927 to characterize PCCA mRNA pharmacokinetics and the pharmacodynamic response of disease-related biomarkers, 3-hydroxypropionic acid (3-HP) and 2-methylcitric acid (2-MC), in participants with propionic acidemia (PA), and to use these models to support dose selection for ongoing clinical studies [ 1, 2]. Methods: Population PK modeling of PCCA mRNA was performed using serum concentration data from participants in the ongoing Phase 1/2 clinical trial mRNA-3927-P101. An indirect inhibition Kin model was used to describe the PD response of 3-HP and 2-MC. Simulations were conducted for a biweekly mRNA-3927 dosing regimen (0.3~1.5 mg/kg) in a virtual population of 1000 pediatric and adult participants aged 0–36 years, based on body weight distributions from participants with propionic acidemia in both mRNA-3704-P001 (non-interventional natural history study) and mRNA-3927-P101 studies. Modeling and simulation were conducted using NONMEM and R. Results: PK and PD models were successfully developed using interim data from the participants with propionic acidemia. The final PK model estimated a typical clearance of 0.266 L/hr and volume distribution of 13.9 L for PCCA mRNA. The PD models captured dose-dependent reductions in biomarker levels. Simulations indicated that a 0.6 mg/kg biweekly dose resulted in meaningful reductions in 3-HP and 2-MC across age groups. This dose was predicted to offer an effective and practical balance between biomarker response and clinical feasibility. Conclusions: Population PKPD modeling and simulation of mRNA-3927 support the selection of 0.6 mg/kg administered once every two weeks as the dose for participants over 1 year old in future trials. These models provide a robust framework for guiding dose optimization in this rare disease population.