PI-017 - CONCENTRATION-RESPONSE RELATIONSHIP OF MAM01, AN INVESTIGATIONAL MONOCLONAL ANTIBODY TARGETING THE CIRCUMSPOROZOITE PROTEIN (CSP), IN A CONTROLLED HUMAN INFECTION MODEL (CHIM) STUDY.

A. Abulfathi¹, M. Trame², M. Dodds², M. Levi³, S. Watson⁴, K. Andrews⁴, J. Huleatt⁵, S. Miller⁴; ¹Certara USA, Norristown, PA, USA, ²Certara USA, Radnor, PA, USA, ³Bill & Melinda Gates Medical Research Institute, Montclair, New Jersey, USA, ⁴Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA, ⁵Bill and Melinda Gates Medical Research Institute, Bill and Melinda Gates Medical Research Institute, USA.

Background: Malaria remains a significant global health burden, with 249 million cases and ~608,000 deaths in 2022. Novel strategies for global malaria control are being explored, including monoclonal antibodies (mAbs) targeting Plasmodium falciparum circumsporozoite protein. MAM01 is an investigational extended half-life mAb developed for passive immunoprevention. Our objectives were to characterize MAM01 pharmacokinetics (PK) using a population approach in adults and to perform exposure-response analysis to understand the critical threshold concentration for protection in a controlled human malaria infection (CHMI) model.

Methods: Thirty-six healthy 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)). MAM01 PK was characterized using a population PK model. Model-derived post-hoc exposures were used for time-to-parasitemia (TTE) analysis via Kaplan-Meier (K-M) and Cox-proportional hazard (Cox PH) modeling.

Results: A 2-compartment model with linear elimination adequately described MAM01 preliminary data, with central (0.057 L/day) and intercompartmental (0.53 L/day) clearances, central (3.69 L) and peripheral (1.73 L) distribution volumes, and an initial terminal half-life estimation of 67 days. The K-M analysis showed that the optimal threshold for prevention of parasitemia was 35.5 µg/mL, separating the population into two groups with the most significant difference in median TTE (28 days vs 10 days, p-value < 0.01). The Cox PH model elaborated on this result, binning MAM01 concentrations into tertiles: low (0-3.65 µg/mL, n=10), middle (3.65-15.3 µg/mL, n=9), and high (15.3-158 µg/mL, n=9). The Cox PH model demonstrated that MAM01 was superior to placebo and that concentration was a significant predictor of TTE, with higher concentrations linked to lower hazards of parasitemia. The hazard ratio (95% confidence interval) for parasitemia was 0.37 (0.14-0.98) for the middle tertile and 0.2 (0.07-0.58) for the high tertile relative to the low tertile group.

Conclusion: MAM01 demonstrated concentration-response in TTE in a CHMI model and a favorable PK profile with a preliminary 67-day half-life, supporting further investigations in vulnerable populations.