PII-015 - MODELING AND SIMULATION ANALYSIS TO SUPPORT DOSE SELECTION FOR MAM01, A NOVEL ANTI-CIRCUMSPOROZOITE PROTEIN MONOCLONAL ANTIBODY, IN UPCOMING TRIALS

M. Levi¹, S. Watson¹, J. Huleatt², S. Miller¹, C. Wells¹, K. Andrews¹; ¹Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA, ²Bill and Melinda Gates Medical Research Institute, Bill and Melinda Gates Medical Research Institute, USA.

Background: Malaria continues to pose a serious global health issue, with an estimated 249 million cases and around 580,000 deaths in 2022. Innovative approaches to help combat this disease are in development, including the creation of monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein. MAM01 is an investigational extended half-life mAb developed for passive immunoprevention. The objectives of this work were to characterize MAM01 pharmacokinetics (PK) using a population approach and to perform simulations to support dosing strategies for a second Controlled Human Malaria Infection (CHMI) challenge. The model was also used to project exposures in a virtual African pediatric population to support dose selection for a subsequent pediatric phase 1b trial.

Methods: Thirty-six healthy adult volunteers were randomized to receive a single dose of MAM01 at various doses (1.5, 5, 10, and 40 mg/kg intravenous or 5 mg/kg subcutaneous) or placebo (NCT05891236). A preliminary population PK model was developed to characterize the interim MAM01 PK concentration time profiles in serum prior to the CHMI challenge. The model was then used in a simulation model to predict the PK profiles in US adults and in the virtual African pediatric population.

Results: A 2-compartment model with linear elimination adequately described MAM01 data, with central and intercompartmental clearances, central and peripheral distribution volumes, and a half-life of 0.0441 L/day, 0.528 L/day, 2.39 L, 1.73 L, and 65.7 days, respectively. Model-based simulations suggested that SC doses of 450, 600, and 900 mg in adults could achieve pre-CHMI concentrations of 30-100 µg/mL which are in the expected range of the effective concentration to achieve protection in 80% of the CHMI participants (EC80). Simulations of the fraction of participants expected to be above an assumed EC80 of 30 µg/mL in the virtual African pediatric population indicated that a single 150 mg SC dose may potentially be efficacious for at least 180 days in infants aged 3-12 months. Doses of 190 mg SC for children aged 12-24 months, 225 mg SC for 24-36 months, to maintain efficacy for at least 180 days.

Conclusion: Investigational MAM01 showed a favorable pharmacokinetic profile, and simulations were conducted to guide dose selection for a future clinical trial.