Volunteer infection studies accelerate the clinical development of novel drugs against malaria

• Published in: The Lancet infectious diseases 2022-06, Vol.22 (6), p.753-754
• Main Authors: Daubenberger, Claudia, Burrows, Jeremy N
• Format: Article
• Language: English
• Subjects: Antimalarial agents; Blood; Children; Clinical trials; Collaboration; Drug development; Drug dosages; Drugs; Economic development; Gametocytes; Genetic markers; Genomes; Infections; Infectious diseases; Insects; Malaria; Mode of action; Morbidity; Parasites; Pharmacodynamics; Pharmacokinetics; Vector-borne diseases; Volunteers
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(21)00722-2

Malaria-related morbidity and mortality is highest in young children and pregnant women, and WHO estimated that in 2020, 627 000 humans died of malaria, mainly from Plasmodium falciparum infections.1 Malaria elimination will foster economic development of affected countries and allow reallocation of around US$3·0 billion currently spent yearly for malaria control.1 Malaria elimination is thought to be achieved by a combination of interventions targeting the insect transmitting vector and the human host, including deployment of highly efficacious malaria drugs.2 In 2010, AstraZeneca and Medicines for Malaria Venture (MMV) entered into a collaboration to discover novel compounds that kill the asexual blood-stage of P falciparum, resulting in 500 000 compounds being screened on P falciparum 3D7 in Brisbane, QLD, Australia by Prof Vicky Avery's group. Promising hits were further worked on by scientists at AstraZeneca in Bangalore, India—led by Shahul Hameed, Vasan Sambandamurthy, Suresh Solapure, and Shridhar Narayanan—and the triaminopyrimidine series were selected for their chemical and biological novelty.3 ZY-19489, a first-in-class antimalarial with a novel mode of action, fulfills the criteria for the malaria treatment target candidate profile 1:4 it is a fast-killing, asexual blood-stage antimalarial with high potency also against early gametocyte stages (unpublished) but not against mature gametocytes nor liver stages. Results obtained from the IBSM indicate that ZY-19489 has potent activity against blood-stage P falciparum, with single oral doses of 200, 300, or 900 mg resulting in a parasite clearance half-life of 6·6–7·1 h. Recrudescent parasites were recovered ex vivo, cultivated, and whole-genome sequenced, with no genetic markers of resistance found.