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Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands - 28/09/23

Doi : 10.1016/S1473-3099(23)00212-8 
Johan L van der Plas, MD a, b, , Vincent P Kuiper, MD b, , Wilhelmina M Bagchus, PhD e, Matthias Bödding, PhD f, Özkan Yalkinoglu, PhD f, Aliona Tappert, MD f, Andrea Seitzinger, PhD f, Thomas Spangenberg, PhD g, Deon Bezuidenhout, RN MSc h, Justin Wilkins, PhD i, Claude Oeuvray, PhD g, Satish K Dhingra, PhD j, Vandana Thathy, PhD k, David A Fidock, PhD k, l, Lisanne C A Smidt, MD a, Geert V T Roozen, MD b, Jan Pieter R Koopman, MD b, Olivia A C Lamers, MD b, Jeroen Sijtsma, BSc b, Roos van Schuijlenburg, Ing BSc b, Els Wessels, PhD c, Pauline Meij, PhD d, Ingrid M C Kamerling, PhD a, b, Meta Roestenberg, MD PhD b, , Akash Khandelwal, PhD f
a Centre for Human Drug Research, Leiden, Netherlands 
b Department of Infectious Diseases and Parasitology, Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands 
c Department of Medical Microbiology, Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands 
d Center for Cell and Gene Therapy, Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands 
e Merck Institute for Pharmacometrics, Merck Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Lausanne, Switzerland 
f The healthcare business of Merck KGaA, Darmstadt, Germany 
g Global Health Institute of Merck, Ares Trading (a subsidiary of Merck KGaA, Darmstadt, Germany), Eysins, Switzerland 
h Merck (Pty) (an affiliate of Merck KGaA, Darmstadt, Germany), Modderfontein, South Africa 
i Occams, Amstelveen, Netherlands 
j Hemogenyx Pharmaceuticals, New York, NY, USA 
k Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA 
l Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA 

* Correspondence to: Prof Meta Roestenberg, Department of Infectious Diseases and Parasitology, Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, Netherlands Department of Infectious Diseases and Parasitology Leiden University Center for Infectious Diseases Leiden University Medical Center Leiden RC 2300 Netherlands

Summary

Background

Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose–exposure–response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoites in malaria-naive, healthy volunteers.

Methods

This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study performed in Leiden, Netherlands. Malaria-naive, healthy adults aged 18–45 years were divided into five cohorts and randomly assigned (3:1) to receive cabamiquine or placebo. Randomisation was done by an independent statistician using codes in a permuted block schedule with a block size of four. Participants, investigators, and study personnel were masked to treatment allocation. A single, oral dose regimen of cabamiquine (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 h (early liver-stage) or 96 h (late liver-stage) after DVI. The primary endpoints based on a per-protocol analysis set were the number of participants who developed parasitaemia within 28 days of DVI, time to parasitaemia, number of participants with documented parasite blood-stage growth, clinical symptoms of malaria, and exposure–efficacy modelling. The impact of cabamiquine on liver stages was evaluated indirectly by the appearance of parasitaemia in the blood. The Clopper–Pearson CI (nominal 95%) was used to express the protection rate. The secondary outcomes were safety and tolerability, assessed in those who had received DVI and were administered one dose of the study intervention. The trial was prospectively registered on ClinicalTrials.gov (NCT04250363).

Findings

Between Feb 17, 2020 and April 29, 2021, 39 healthy participants were enrolled (early liver-stage: 30 mg [n=3], 60 mg [n=6], 80 mg [n=6], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=6]; late liver-stage: 60 mg [n=3], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=3]). A dose-dependent causal chemoprophylactic effect was observed, with four (67%) of six participants in the 60 mg, five (83%) of six participants in the 80 mg, and all three participants in the 100 and 200 mg cabamiquine dose groups protected from parasitaemia up to study day 28, whereas all participants in the pooled placebo and 30 mg cabamiquine dose group developed parasitaemia. A single, oral dose of 100 mg cabamiquine or higher provided 100% protection against parasitaemia when administered during early or late liver-stage malaria. The median time to parasitaemia in those with early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of cabamiquine, respectively, compared with 10 days for the pooled placebo. All participants with positive parasitaemia showed documented blood-stage parasite growth, apart from one participant in the pooled placebo group and one participant in the 30 mg cabamiquine group. Most participants did not exhibit any malaria symptoms in both the early and late liver-stage groups, and those reported were mild in severity. A positive dose–exposure–efficacy relationship was established across exposure metrics. The median maximum concentration time was 1–6 h, with a secondary peak observed between 6 h and 12 h in all cabamiquine dose groups (early liver-stage). All cabamiquine doses were safe and well tolerated. Overall, 26 (96%) of 27 participants in the early liver-stage group and ten (83·3%) of 12 participants in the late liver-stage group reported at least one treatment-emergent adverse event (TEAE) with cabamiquine or placebo. Most TEAEs were of mild severity, transient, and resolved without sequelae. The most frequently reported cabamiquine-related TEAE was headache. No dose-related trends were observed in the incidence, severity, or causality of TEAEs.

Interpretation

The results from this study show that cabamiquine has a dose-dependent causal chemoprophylactic activity. Together with previously demonstrated activity against the blood stages combined with a half-life of more than 150 h, these results indicate that cabamiquine could be developed as a single-dose monthly regimen for malaria prevention.

Funding

The healthcare business of Merck KGaA, Darmstadt, Germany.

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Vol 23 - N° 10

P. 1164-1174 - octobre 2023 Retour au numéro
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