PI-054 - DEVELOPMENT OF A PHARMACOKINETIC-PHARMACODYNAMIC MODEL FOR MRNA-0184, AN INVESTIGATIONAL MRNA THERAPEUTIC ENCODING HUMAN RELAXIN-2-VLK FOR THE TREATMENT OF HEART FAILURE.

N. Kaushal, M. Liang, M. Iqbal, R. Saini, H. Attarwala; Moderna Therapeutics, Inc., Cambridge, MA, USA.

Background: The objective of this analysis was to develop a translational semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model of an investigational mRNA therapeutic, mRNA-0184, to quantify the relationship between mRNA-0184 dose, PK, and PD of the long-acting human relaxin-2-vlk (Rel2-vlk) fusion protein. The PK/PD model was applied to estimate the first-in-human therapeutic dose range and regimen selection in patients with stable heart failure.

Methods: Preclinical PK or PK/PD studies were conducted in cynomolgus monkeys (N=68) at doses ranging from 0.1-5 mg/kg. Plasma concentration-time profiles of mRNA-0184 in monkeys were modeled using a semi-mechanistic PK model. Rel2-vlk protein production rate was evaluated using an inhibitory response PD model via an effect compartment as a linear function of plasma mRNA-0184 concentration with covariates. A final model (with covariates) was selected for human PK/PD prediction.

Results: The PK and PK/PD models converged successfully with plausible model parameters, estimated with reasonable %RSE ( < 30%). The Rel2-vlk protein t1/2 was about 4 days in non-human primates (NHPs). Inter-individual variability of the protein synthesis rate was 14%. The steady-state Rel2-vlk AUEC associated with the efficacious dose (0.15 mg/kg QW) in NHPs was used as a benchmark of efficacy. The preclinical Rel2-vlk protein PK/PD model was scaled to humans via allometric scaling of model parameters to predict Rel2-vlk protein exposure in humans. Human efficacious dose range and regimen were selected based on non-inferiority of the predicted Rel2-vlk AUEC relative to the efficacy benchmark in NHPs.

Conclusion: The PK/PD model adequately described observed responses without any systematic bias and was used for guiding dose range and regimen selection for the planned phase 1 clinical study.