Quantitative systems pharmacology model of mRNA lipid nanoparticle for two programs at the preclinical to clinical transition

Crigler-Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in UGT1A1 enzyme activity.

ALXN1540 (hUGT1A1-RNA delivered via LNP) is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in CN1 patients. In vivo mechanism of action and clinical pharmacology is unknown.

Here, we develop a QSP model to support translation from preclinical to clinical studies, and for FIH studies, by understanding the hUGT1A1-RNA mechanisms.

The QSP model was based on first principles as a system of elementary mass-action, mechanistic PKPD, ordinary differential equations.

The model reactions describe elimination of LNP from the plasma due to liposomal instability, uptake of LNP by endocytosis into liver hepatocytes, release of mRNA from the endosome into the cytoplasm, transcription of the mRNA to produce UGT1A1 protein, and glucuronidation of bilirubin by UGT1A1 leading to the increased clearance of bilirubin.

The QSP model was populated primarily with mechanistic parameters from literature, as shown here.

Mui, B. L. et al (2013). Influence of Polyethylene Glycol Lipid Desorption Rates on Pharmacokinetics and Pharmacodynamics of siRNA Lipid Nanoparticles. Molecular Therapy. Nucleic Acids, 2(October), e139.

Preclinical: This model helped guide the selection of preclinical candidates, accelerate the termination of a program based on predicted low therapeutic window, reduced the number of in vivo studies, optimized in vivo studies, and provided insight into the mechanism of action of mRNA LNP.

Clinical: This model helped justify elimination of some biomarkers, inform recommended safe starting dose, impacted clinical strategy in term of patient populations for Ph1, and helped project consequences of nonlinear parameters that do not follow typical allometric scaling rules to inform first-in-human dose.