Safety, pharmacokinetics, and antimalarial efficacy of single-dose cabamiquine–pyronaridine combination therapy for the treatment of adults and adolescents with acute uncomplicated Plasmodium falciparum malaria (CAPTURE 1): a prospective, multicentre, open-label, phase 2a study

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BACKGROUND: Novel antimalarial combinations are needed to address the threat of emerging resistance to artemisinins. This study evaluated the safety, tolerability, pharmacokinetics, and efficacy of a single oral dose of cabamiquine-pyronaridine for the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: This two-part, multicentre, open-label, phase 2a study (CAPTURE 1) enrolled patients aged 12-55 years from five hospitals in four countries across Africa with acute uncomplicated P falciparum monoinfection, defined by microscopically confirmed parasitaemia, with parasite densities of 1000-50 000 asexual parasites per μL in part A and 1000-150 000 asexual parasites per μL in part B; exclusions included mixed Plasmodium infections, severe malaria, liver abnormalities, and previous antimalarial use. In part A, patients received a single oral dose of 330 mg cabamiquine free base and 360 mg pyronaridine tetraphosphate. In part B (cohort B0), patients received 660 mg cabamiquine and 720 mg pyronaridine adjusted for bodyweight. Additional planned cohorts B1, B2, and B3 (control) were not initiated owing to early trial termination after cohort B0 in part B following higher-than-predicted cabamiquine exposure, data monitoring committee concerns about 2-day dosing, and high observed efficacy in the studied cohorts. The primary outcomes were safety and tolerability, assessed through the incidence, severity, and seriousness of study intervention-related treatment-emergent adverse events (TEAEs), and day 28 post-treatment efficacy in treated patients assessed using PCR-corrected adequate clinical and parasitological response (ACPR). This study is registered with ClinicalTrials.gov, NCT05689047, and is complete. FINDINGS: Between March 29, 2023, and May 8, 2024, 75 patients were screened, of whom 38 patients were enrolled (12 in part A and 26 in part B) and treated in the study. TEAEs occurred in 25 (65·8%) of the 38 patients and were predominantly mild or moderate in severity (grade 1 or 2), and no serious adverse events or deaths were reported. The day 28, PCR-corrected ACPR in part A was 91·7% (11 of 12 patients [95% CI 64·6-98·5]) and 92·3% (24 of 26 patients [95% CI 75·9-97·9]) in part B. INTERPRETATION: A single dose of cabamiquine-pyronaridine showed promising safety and efficacy in this proof-of-concept trial in adults and adolescents, which supports further development for combination therapy in larger trials and in children. FUNDING: Merck KGaA, the EDCTP2 Programme, and the Swedish International Development Cooperation Agency (Sida).