Phase IIa Proof of Concept Study of M5717-Pyronaridine in Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1)

Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.

Time frame: Day 1 up to Day 29

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, and coagulation.

Time frame: Day 1 up to Day 29

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

Number of participants with clinically significant change from baseline in vital signs. Clinical Significance was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.

Time frame: Day 1 up to Day 29

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

An adverse event (AE) was defined as any untoward medical occurrence in a participant. TEAEs are defined as AEs which started at or after the administration of study intervention (study treatment) or which started prior to the first administration of study intervention but worsened after the dose intake, until the last scheduled assessment will be regarded as treatment-emergent, but before established rescue antimalarial treatment is administered, if required. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was considered to be related if a causal relationship between study treatment and the TEAE is at least reasonably possible.

Time frame: Day 1 up to Day 43

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

PCR-adjusted ACPR 28 days after first treatment (i.e., on Day 29) was defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of Early treatment failure (ETF), Late clinical failure (LCF), or Late parasitological failure (LPF).

Time frame: At Day 29

Population: The Full Analysis Set included all enrolled participants. ACPR could not be assessed for 1 participant due to missing parasites assessment at Day 28. Here Number Analyzed is equivalent to the number of participants evaluable for this outcome measure.

Crude ACPR 28 and 42 days after first dose is defined as absence of parasitemia (parasite count = 0) from thick smear/microscopy, irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF.

Time frame: Day 28 and 42

Population: The FAS included all enrolled participants.

t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The apparent total body clearance of study intervention following extravascular administration. CL/ F was calculated by oral dose divided by Area under the plasma concentration curve 0- infinity.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The apparent volume of distribution during the terminal phase following extravascular administration. Vz/F = Dose/(AUC0-∞\*λz) following single dose.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. Calculated as AUC0-inf = AUC0-tlast + Clast pred/ lambda z.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The Pharmacokinetics (PK) analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide more than equal to (\>=) 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The AUC from time zero (dosing time) to 24 hours post dose was calculated using the mixed log linear trapezoidal rule (linear up, log down) using the nominal dosing interval.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The AUC from time zero (= dosing time) to the time of the last quantifiable concentration (tlast), calculated using the mixed log linear trapezoidal rule (linear up, log down)

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The dose normalized AUC from time zero extrapolated to infinity. Normalized using dose, using the formula AUC0-∞ /Dose.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The dose normalized AUC from time zero to 24 hours post dose. Normalized using the dose, using the formula AUC0-24/Dose.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The dose normalized AUC from time zero to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Normalized using the dose, using the formula AUC0-tlast /Dose.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

The dose normalized maximum concentration. Normalized using the dose, and the formula Cmax /Dose.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

Cmax was taken directly from the observed concentration-time curve.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

Parasite clearance time defined as time from dosing to the first negative (no parasites) film

Time frame: Day 1 up to Day 43

Population: The FAS included all enrolled participants.

Early treatment failure (ETF) was defined as meeting any of the following : 1. Danger signs or severe malaria 1, 2, or 3 days after treatment, in the presence of parasitemia2. Parasitemia 2 days after treatment higher than on day of treatment, irrespective of axillary temperature • Parasitemia 3 days after treatment with temperature ≥ 37.5°C 3. Parasitemia 3 days after treatment ≥ 25% of count on day of treatment. ETF rate will be estimated with 95% confidence intervals. Confidence intervals was derived by use of Wilson's score method.

Time frame: Up to Day 3 post treatment on Day 1

Population: The Full Analysis Set (FAS) included all enrolled participants.

Late clinical failure (LCF) was defined as:1. Danger signs or severe malaria in the presence of parasitemia on any day between 4 and 28 days after treatment (i.e., between Days 5 and 29) in participants who did not previously meet any of the criteria of ETF. 2. Presence of parasitemia on any day between 4 and 28 days after treatment with temperature ≥ 37.5°C in participants who did not previously meet any of the criteria of ETF. LCF was estimated with 95% confidence intervals. Confidence intervals will be derived by use of Wilson's score method.

Time frame: Day 1 up to Day 29

Population: The FAS included all enrolled participants.

Late parasitological failure (LPF) was defined as: Presence of parasitemia on any day between 7 and 28 days after treatment (i.e., between Days 8 and 29) with temperature \< 37.5°C in participants who did not previously meet any of the criteria of ETF or LCF. LPF was estimated with 95% confidence intervals. Confidence intervals will be derived by use of Wilson's score method.

Time frame: From Day 8 to Day 29

Population: The FAS included all enrolled participants.

Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

Fever clearance time was defined as the time from first dosing to the first measurement of temperature \< 37.5°C for 2 consecutive temperature readings plus confirmed normal temperature 24 h after the first normal body temperature reading. This analysis was done on participants with fever.

Time frame: Day 1 up to Day 29

Population: The FAS included all enrolled participants. Here Number Analyzed is equivalent to the number of participants evaluable for this outcome measure.

tmax was obtained directly from the concentration versus time curve.

Time frame: Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43

Population: The PK analysis set included all participants, who received more than equal to 1 dose of study intervention, have no clinically important protocol deviations or important events affecting PK and provide \>= 1 measurable post-dose concentration. Dose wise results have been reported for M5717 and Pyronaridine as per the planned analysis.

PCR-adjusted ACPR 28 and 42 days after treatment defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF.

Time frame: Day 28 and 42

Population: The FAS included all enrolled participants. ACPR could not be assessed for 1 patient due to missing parasites assessment at Day 28.

An adverse event (AE) was defined as any untoward medical occurrence in a participant. TEAEs are defined as AEs which started at or after the administration of study intervention (study treatment) or which started prior to the first administration of study intervention but worsened after the dose intake, until the last scheduled assessment will be regarded as treatment-emergent, but before established rescue antimalarial treatment is administered, if required. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was considered to be related if a causal relationship between study treatment and the TEAE is at least reasonably possible.

Time frame: Day 1 up to Day 43

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.