The candidate inhibits two essential enzymes required for the growth of malaria parasites and the spread of the disease through human-to-mosquito transmission.
The initiation of this first-in-human trial is a crucial step in the development of a novel agent for the fight against malaria – a disease that kills more than 600,000 people each year.
This initial first-in-human study is designed to assess safety, tolerability and pharmacokinetics. The results from this study will inform the need for clinical development of this compound.
In pre-clinical studies the dual-targeting mechanism appears to confer a high barrier to the generation of resistance, an important criterion for malaria drug candidates.
Malaria remains one of the largest killers of pregnant women and children under the age of five in most resource-poor countries. One child in Africa dies from malaria approximately every two minutes, according to the World Health Organization (WHO).
Professor Alan Cowman, an international malaria expert who recently won the CSL Florey Medal for his outstanding research contributions to the field, said that the preclinical profile observed to date makes it a promising new antimalarial drug candidate.
“In pre-clinical studies we’ve shown this compound inhibits two enzymes that process and activate key proteins that enable the parasites to move in and out of red blood cells,” Professor Cowman, deputy director at WEHI and a Laboratory Head in the Infectious Diseases and Immune Defence Division, said.
“The pre-clinical studies indicate that inhibiting these two enzymes – Plasmepsin IX (PMIX) and Plasmepsin X (PMX) – effectively disables the parasite from carrying out its key function of replicating and multiplying in the bloodstream.
“The successful initiation of these first-in-human trials is an important milestone towards developing urgently-needed new treatments that could alleviate this major global health burden.”
As new malaria parasites increasingly becoming resistant to available drugs, the development of vaccines and novel antimalarial compounds to block transmission is vital in the fight against this killer disease.
MSD scientist and US team lead Dr David Olsen said: “Efforts to develop drugs for malaria typically focus on disrupting a novel parasitic process or pathway to avoid pre-existing drug resistance and, ideally, are active at multiple stages of the lifecycle.
“By inhibiting two essential parasitic enzymes, this molecule met both criteria with the potential to provide a high barrier for the development of drug resistance.”
The compound is the result of an eight-year collaboration between WEHI and MSD, dedicated to discovering new widely applicable malaria drug candidates.
In 2022, the research collaboration published findings from preclinical experiments that revealed how a new class of antimalaria compounds worked to stop parasites from spreading in the blood.
The team plans to present the results from this initial clinical trial at a future scientific meeting and further clinical trials are being planned.
The research underpinning this work was supported by the Wellcome Trust (grant: 202749/Z/16/C), the Victorian Government and the National Health and Medical Research Council (NHMRC).
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