GSK484 raises the bar for all future preclinical candidates.
Today, at an online meeting of MMV’s Expert Scientific Advisory Committee (ESAC), the MMV Project of the Year 2021 was officially awarded to a discovery team led by Dr Laura Sanz at GSK and Dr Stephen Brand at MMV, for the discovery of GSK484, a compound with potential for treatment of patients with uncomplicated malaria.
'Irresistible’ compound exhibits rapid parasite clearance
MMV’s ESAC recommended GSK484 for this award owing to its high quality, including its fast and potent antimalarial activity against drug sensitive and resistant strains and ‘irresistibility’ i.e., no detectable resistance selection in vitro1 which makes it a potentially important public health tool as part of a future combination to drive the treatment, control and eradication of malaria.
New antimalarial therapeutics are needed to ensure that malaria cases can continue to be treated effectively, as emerging parasite resistance to frontline chemotherapies threatens control programmes in Africa2. GSK484, approved as a preclinical candidate in 2021, is a novel chemotype which exhibits rapid parasite clearance in vitro and in vivo3, and is predicted to have a low clinical dose. This exciting molecule comes from a novel structural series, and although the mode of action is not yet known it has a different overall profile to current antimalarials in clinical use or in MMV’s portfolio.
Finding the right candidate
“GSK Tres Cantos in Madrid performed a screening of a large collection of GSK compounds against the parasite and identified thousands of hit compounds with good potency. From that point, GSK worked on multiple chemical series aiming to improve the many characteristics required to turn them into effective treatments. One of these series, the pyrazines, was particularly interesting because of its irresistibility. After several years of work to improve the key properties, we were able to identify GSK484,” explained Dr Brand in an interview for MMV’s Annual Report.
A potential antimalarial for use during pregnancy
“Given the compound’s non-clinical safety profile – demonstrated by a toxicology programme, including selectivity profiles and evaluation of safety pharmacology, genetic toxicology, general toxicology and even developmental toxicity – it has the potential to be considered as a treatment for pregnant women,” said Dr Sanz.
A successful collaboration
“The collaboration between GSK and MMV has been key in identifying this new antimalarial opportunity,” added Dr Sanz.
“If it weren’t for GSK’s commitment to global health and Laura and her team’s capability in malaria research, we wouldn’t have this candidate,” acknowledged Dr Brand.
MMV has had a discovery collaboration with GSK since 2003.
1. A laboratory process that is not conducted in a living organism.
2. Evidence of Artemisinin-Resistant Malaria in Africa: https://www.nejm.org/doi/full/10.1056/NEJMoa2101746
3. Studies in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and plants, as opposed to a tissue extract or dead organism.