Malaria is an acute fever infection caused by Plasmodium parasite types especially P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. According to the latest estimates, there were about 247 million cases of malaria and an estimated 619,000 deaths worldwide in 2022 (WHO Malaria Report, 2022). Most deaths (77%) occurred among children less than 5 years of age, most of them living in sub-Saharan Africa. Prevention of malaria or infection is one of the key strategies to decrease the malaria burden. For this purpose, there are few number of medicines available for use in high-risk populations in areas where malaria occurs throughout the year. Most efforts in malaria drug development have focused on treatment of cases; the development of new treatments targeting prevention and transmission are becoming increasingly important. The latest WHO report has highlighted for the first time in decades a rise in the number of malaria cases and deaths, highlighting and reinforcing the needs for innovative approaches for prevention and treatment. M5717 is a new class of drugs being tested for the treatment and prevention of malaria. Pyronaridine is an antimalarial drug marketed in combination with artesunate as Pyramax. M5717 and pyronaridine are intended to be developed as a fixed-dose combination for either the treatment of acute uncomplicated malaria or for the prevention of symptomatic malaria in populations living in areas where malaria occurs. The initial step of the clinical development plan of the combination is to generate initial safety, efficacy, and exposure data in symptomatic malaria patients and asymptomatic, malaria-infected individuals through the conduct of a Phase 2 study. There is a clear need to accelerate the development of dedicated drug combinations for malaria prevention. A reduction of more than 50% of malaria cases was observed in regions where malaria preventive treatments were systematically applied leading to a significant reduction in death in the population. WHO has recently published new treatment policies to reinforce the use of prevention, which combined with the increasing development of resistance against the 2 main standards of care, highlights the need for dedicated new therapies. This study will evaluate the efficacy of a single dose of M5717 plus pyronaridine in clearing current Plasmodium falciparum (P. falciparum) infections and protecting against recurrent infections in asymptomatic adults and adolescents. This study intends to establish the duration of protection provided by M5717 plus pyronaridine to develop the right dose for prevention of malaria. Prevention in the context of this study is defined as prevention of malaria parasites in adults and adolescents with a P. falciparum infection but without symptoms at time of recruitment and living in malaria countries. This Phase 2 study will be in multiple sites and you will know which drug you receive study. The study population will include adults and adolescents (≥ 12 and ≤ 55 years of age) with P. falciparum malaria without symptoms. The maximum study period per participant will be 12 weeks including a prescreening period of a maximum of 2 weeks and a follow-up period of up to 63 days. Up to 192 participants will be recruited and given study drug by chance with approximately 180 being assessed for results. The VIBRI site will enrol and follow-up about 50 participants in the study.

Human malaria is an acute febrile infection caused by Plasmodium parasite species especially P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. According to the latest estimates, there were about 247 million cases of malaria and an estimated 619,000 deaths worldwide in 2022 (WHO Malaria Report, 2022). Most deaths (77%) occur among children < 5 years of age, most of them living in sub-Saharan Africa. Prevention of clinical malaria or infection is one of the key strategies to decrease the malaria burden. For this purpose, there is a limited number of medications available for use in high-risk populations in malaria endemic areas. Most efforts in malaria drug development have focused on case management; the development of new treatments targeting prevention and transmission are becoming increasingly important. The latest WHO report has highlighted for the first time in decades a rise in the number of malaria cases and deaths, highlighting and reinforcing the needs for innovative approaches for prevention and treatment.

M5717 is a first-in-class New Chemical Entity (NCE) targeting the Plasmodium cytosolic protein synthesis for the treatment and prevention of malaria due to the activity in the liver and blood stage of the parasite life cycle. Pyronaridine tetraphosphate is an antimalarial drug marketed in combination with artesunate as Pyramax. Pyronaridine is a drug that interferes with the digestive system of P. falciparum and P. berghei and inhibits the production of complexes with β-hematin to enhance hematin-induced human blood cell lysis (Croft 2012). M5717 and pyronaridine are intended to be developed as a fixed-dose combination for either the treatment of acute uncomplicated malaria or for the prevention of symptomatic malaria in populations living in endemic areas. The initial step of the clinical development plan of the combination is to generate initial safety, efficacy, and exposure data in symptomatic malaria patients and asymptomatic, malaria-infected individuals through the conduct of 2 Phase 2a PoC studies (CAPTURE-1 and CAPTURE-2) in order to prioritize the final indication for Phase 2b and Phase 3. There is a clear need to accelerate the development of dedicated drug combinations for malaria prevention. A reduction of > 50% of malaria cases was observed in regions where malaria preventive treatments were systematically applied leading to a significant reduction in mortality in the population. WHO has recently published new treatment policies to reinforce the use of chemoprevention, which combined with the increasing development of resistance against the 2 main standards of care, highlights the need for dedicated new therapies.

This study will evaluate the efficacy of a single dose of M5717 plus pyronaridine tetraphosphate in clearing current Plasmodium falciparum (P. falciparum) infections and protecting against recurrent infections in asymptomatic adults and adolescents. This study intends to establish the duration of protection provided by M5717 plus pyronaridine for developing the future dose regimen for chemoprevention. Prevention in the context of this study is defined as prevention of parasitemia in asymptomatic adults and adolescents with a P. falciparum infection at time of recruitment and living in malaria endemic countries. This Phase 2a study is a multicenter, parallel, randomized, open-label study. The study population will include adults and adolescents (≥ 12 and ≤ 55 years of age) with asymptomatic P. falciparum malaria. The maximum study duration per participant will be 12 weeks including a prescreening period of a maximum of 2 weeks and a follow-up period of up to 63 days. Up to 192 participants will be randomly assigned to study intervention with approximately 180 evaluable participants. The VIBRI site will enrol and follow-up about 48 participants in the trial.