Characterizing the pharmacokinetics of MAM01, an extended half-life monoclonal antibody for the prevention of malaria using a population approach

Objectives: Malaria remains a major global health concern, with 263 million cases and approximately 597,000 deaths reported in 2023 [ 1]. Most cases occur in sub-Saharan Africa, where children under 5 years are disproportionately affected. To combat malaria, novel strategies are being explored, including the use of monoclonal antibodies (mAbs) that target the Plasmodium falciparum circumsporozoite protein. One such investigational mAb is MAM01, designed for passive immunoprevention. The extended half-life of MAM01 allows for a single dose administration during malaria season in endemic regions or after severe malaria hospitalization, providing an opportunity to prevent morbidity and mortality associated with malaria in high-risk populations. We aimed to characterize MAM01 pharmacokinetics (PK) using a population PK model, quantify variability in PK parameters, and identify covariates that explain this variability. Methods: The trial consisted of two parts (A and B). Part A was a double-blind trial that enrolled 61 healthy participants, randomized to receive placebo or a single dose of MAM01 at escalating dose levels (1.5, 5, 10, and 40 mg/kg intravenous [IV] or 5 mg/kg subcutaneous [SC]). Participants who received the 5 mg/kg IV or SC dose also received a second dose of 5 mg/kg SC at Week 30. Part B trial enrolled 18 healthy participants randomized to receive a single dose of MAM01 at 450-900 mg SC. Data was modeled in NONMEM©. One- and two-compartment models were explored. Between-subject variability (BSV) was added on PK parameters using log-normal distribution. Different error models were explored. Covariates such as baseline body weight (BWT), age, serum albumin, sex, race, and dose effect were explored. Model selection was based on goodness-of-fit (GOF) statistics and GOF plots. Results: Overall, 351 serum concentrations were collected from 49 subjects (n=31 from Part A and n=18 from Part B), of which, 51% are female with median (range) age and body weight of 31 years (21, 49 years) and 75.4 kg (46.6, 96 kg), respectively. The observed MAM01 PK profiles show mono-exponential decline in the log-space, whereas the dose-normalized profiles suggested MAM01 exhibits linear PK. MAM01 PK was adequately described using a one-compartment model parameterized with a linear clearance from the central compartment (CL=0.051 L/day), apparent volume (V=5.63 L), first-order absorption rate constant (KA=0.578 1/day) for SC administration, and SC bioavailability (F=0.679). The estimated half-life is approximately 76.5 days. BSV on CL, V and KA were 29.2%, 14.1% and 35.5%, respectively. Covariance was included between BSV of CL and V, and KA and V. Residual error was modeled with combined proportional (7.9%) and additive (0.867 mg/L) errors. Mahmood age-dependent exponent [ 2] was implemented on CL, BWT/70 on V, and dose on F. Conclusions: MAM01 shows favorable PK with linear elimination and a prolonged half-life of approximately 76.5 days, supporting the potential for single dose administration during high transmission season in malaria endemic regions. These findings provide valuable insights into the PK profile of MAM01 and support its further development as a tool for preventing malaria in high-risk populations.