Translational Pharmacokinetic/Pharmacodynamic Model for mRNA-3927, an Investigational Therapeutic for the Treatment of Propionic Acidemia

Abstract

Propionic acidemia (PA) is an ultrarare disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), composed of PCCA and PCCB subunits. An enzyme replacement therapy is being developed using dual messenger RNA (mRNA) therapy composed of lipid nanoparticles (LNPs) encapsulating mRNAs encoding PCCA and PCCB subunits of the PCC enzyme. We herein report on development of a translational semimechanistic pharmacokinetic (PK) and PK/pharmacodynamic (PD) model to quantify the relationship between the mRNA components of mRNA-3927 (an LNP encapsulating PCCA and PCCB mRNAs) and dose levels; PCCA/B mRNA PK and PD responses were assessed as circulating levels of primary disease markers 2-methyl citrate, 3-hydroxypropionate, and propionyl carnitine normalized to acetyl carnitine (C3/C2 ratio) to inform the first-in-human dose range and regimen selection. The translational PK/PD model was developed using preclinical data available in mice with PA, Sprague Dawley rats, and cynomolgus monkeys at dose levels ranging from 0.2 to 9 mg/kg. PCCA/B mRNA PK in mice, rats, and monkeys was adequately described using allometric scaling of volume and clearance parameters. The interspecies preclinical model was scaled allometrically to humans to predict the dose-response relationship in adult and pediatric patients with PA to guide selection of dose range and regimen for the Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT04159103).

Keywords: lipid nanoparticles; mRNA therapy; propionic acidemia; propionyl-CoA carboxylase.

FIG. 1.

PK/PD model schematic. k₁₂, transfer rate from plasma compartment 1 to tissue compartment; k₂₀, rate of elimination from tissue compartment; k₂₃, transfer rate from tissue compartment to plasma compartment 2; k₃₂, transfer rate from plasma compartment 2 to tissue compartment; Ce, effect compartment concentration of mRNA-3927; k_deg, PCC protein degradation rate; k_e0, equilibrium rate constant for effect compartment; k_q, intercompartmental rate constant for PCC protein; k_syn, PCC protein synthesis rate; PCC, propionyl-CoA carboxylase.

FIG. 2.

Observed and fitted (A) concentration–time profiles of mRNA-3927 in mice, rats, and monkeys, and (B) PCC protein–time profile after 1 mg/kg IV bolus dose of hPCCA+hPCCB mRNA in PCC-deficient mice. Black lines indicate population predicted, blue lines indicate individual predicted, and closed circles indicate observations. DV, dependent variable (plasma concentration); IV, intravenous; mRNA, messenger RNA; PCC, propionyl-CoA carboxylase.

FIG. 3.

PK model goodness-of-fit plots. Blue lines indicate linear fit. CWRES, conditional weighted residuals; DV, dependent variable (plasma concentration); IPRED, individual predicted; IVAR, independent variable (time); PK, pharmacokinetic; PRED, population predicted; TAD, time after dose.

FIG. 4.

Goodness-of-fit plots for the plasma (A) 2-MC, (B) 3-HP, and (C) C3/C2 PD model. Blue lines indicate linear fit. 2-MC, 2-methyl citrate; 3-HP, 3-hydroxypropionate; C2, acetyl carnitine; C3, propionyl carnitine; CWRES, conditional weighted residuals; DV, dependent variable (plasma concentration); IPRED, individual predicted; IVAR, independent variable (time); PD, pharmacodynamic; PRED, population predicted.