Maximum effect of drug (maximum parasite killing rate). Emax used in the PK/PD model comes from the mean viable parasite elimination half-life of cohort 1 as estimated in the parasite viability report as Emax was not clearly observed in the cohort 2 parasitemia profiles.

Half Maximal Effective Concentration PK/PD dataset contains the individual information from all arms including date and time of inoculum administration, MMV367 dose; MMV367 plasma PK concentrations; total parasitemia counts by 18S qPCR; gametocytemia counts by pfs25, pfMGET and pfSBP-1 if relevant; and typical covariates such as age, body weight, height, sex and race, to build the model and derive outcome results.

MIC is defined as the concentration when drug killing equals the parasite growth, i.e., the time at which the minimum parasite concentration is observed. Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan.

MPC90 is defined as the concentration at which the clearance effect is at 90% of the maximum. Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan. PK/PD dataset contains the individual information from all arms including date and time of inoculum administration, MMV367 dose; MMV367 plasma PK concentrations; total parasitemia counts by 18S qPCR; gametocytemia counts by pfs25, pfMGET and pfSBP-1 if relevant; and typical covariates such as age, body weight, height, sex and race, to build the model and derive outcome results.

PRR48 is given as the reduction of values on log10 transformed scale. Only MMV\_MMV367\_22\_01 data was used. PRR48 provides an estimate of the efficacy of an anti-malarial treatment. It is the ratio of parasite density over a 48-hour period, estimated using the slope of the optimal fit of the log-linear relationship of parasitemia decay. Optimal fit is derived using geometric mean parasitemia data (i.e. 18S qPCR measuring all blood stage malaria parasites). The optimal fit of the log-linear parasitemia decay by time relationship is determined using left and right censoring to systematically remove potential lag and tail phases of parasitemia decay. PRR48 was calculated for each participant using daily PCR data. If the model fit was adequate (overall model p-value\<0.001), the slope and corresponding SE from the log-linear regression was used to calculate overall dose-specific PRR48. Participants without adequate model fits were excluded from all dose-specific PRR48 calculations.