PI-093 - TRANSLATIONAL PHARMACOKINETIC/PHARMACODYNAMIC MODEL FOR NOVEL MRNA-MODALITY SUPPORTING ENZYME REPLACEMENT THERAPY.

S. Al Rihani¹, M. Zimmer², J. Zhuo², Y. Liu³, L. Van⁴; ¹Moderna, Inc., Moderna, Inc., Cambridge, Massachusetts, USA, ²Moderna, Inc., Cambridge, Massachusetts, United States of America, ³Moderna, Inc., Moderna, Inc., Cambridge, Massachusetts., United States of America, ⁴Moderna, Inc., Cambridge, MA, United States.

Background: The purpose of this analysis is to develop a PKPD model using the experimental data (single- and multiple-dose) obtained after intravenous (IV) administration in both wild-type and disease mouse model. Specifically, the aims will be to develop a PK model to describe mRNA concentrations in mice. Second to develop a PKPD model to describe the transcribed protein concentrations after the administration of mRNA in disease mice. Third to perform calculations of FIH doses based on simulation from the PKPD model.

Methods: Data from three different pre-clinical studies conducted in wild type (WT) and disease mice were used. mRNA concentrations in plasma and protein concentrations in liver were used.

Results: A 2-compartment distribution model with linear mRNA elimination best described the data. Inter-individual variability was estimated for both the volume of distribution of the central and peripheral compartments of mRNA. To calculate the FIH dose needed for expressing protein concentrations of functional enzyme, a unique bridging method using a correlation curve derived from western blot and mass spectroscopy for protein expression levels in mice was applied. A predefined WT expression percentage levels were set and converted to a specific protein concertation in ng/g tissue, which is more relevant for clinical target threshold. Accordingly, three different scenarios based on the principles of allometric scaling were explored to support FIH dose calculations.

Conclusion: The developed PKPD model was able to adequately describe both the mRNAs and protein concentrations in mice after single and multiple dose administration. The preclinical model was allometrically scaled to humans to predict the dose-response relationship in adult patients using a bridging metric to calculate efficacious protein level for the enzyme replacement therapy in absolute units of ng/g than percentage of WT levels. Subsequently, a target above a predefined clinically relevant threshold was established and will be used to guide dose selection for FIH.