Elaine Bignell – University of Exeter, United Kingdom
Tom Harrison – St George’s University, London, United Kingdom
Liliane Mukaremera– University of Exeter, United Kingdom
Serisha Devi Naicker – Wits Health Consortium (Pty) Ltd, South Africa
William Hope – University of Liverpool, United Kingdom
Andy Borman – UK National Mycology Reference Laboratory, United Kingdom
Joe Jarvis – London School of Hygiene and Tropical Medicine, United Kingdom
David Lawrence – London School of Hygiene and Tropical Medicine, United Kingdom
Henry Mwandumba – Malawi-Liverpool-Wellcome Trust Unit in Blantyre, Malawi
Nelesh Govender – University of the Witwatersrand, South Africa
Mark Jones – Basilea Pharmaceutica International Ltd., Switzerland
Global, but training delivered to South Africa
Microbial Pathogenesis
Cryptococcus neoformans
Cryptococcal meningitis (CM) is an invasive fungal infection that remains a leading cause of mortality among people living with HIV, accounting for almost 20% of all AIDS deaths globally, especially in LMIC territories that are disproportionately impacted by fungal diseases.
Significant treatment failures account for persistently high mortality of CM and are due to limited availability and supply of antifungals, emergence of antifungal resistance, and requirement for intravenous administration of some drugs. Simpler, rapidly effective treatment, that can be taken as tablets, and to which the infection does not become resistant are urgently needed.
A new drug, BAL2039, is the most promising antifungal treatment in development, and animal experiments suggest BAL2039 could be effective when used on its own, however, many antifungal drugs rapidly lose effectiveness when used in isolation and our previous work has shown that the use of combination treatments (combinations of 2 or 3 different drugs) improve survival and prevent resistance. We have safe, affordable partner drugs, and optimisation of combination antifungal approaches is critical to safeguard the utility and resilience of BAL2039 before its entry into clinic.
We now have a unique window of opportunity, while BAL2039 toxicity and phase 1 studies are completed, to undertake essential preclinical work that will empower the design of phase 2 and 3 clinical development plans, and thus ensure that the potential of BAL2039 is fully realised for the long-term benefit of patients with cryptococcal infection.
Therefore, our aims are:
1. To find the best BAL2039-containing drug combinations in laboratory “in vitro” experiments. Using a large collection of cryptococcal isolates from a recent trial, we will test how well BAL2039 alone, and in 2 and 3-drug combinations, inhibits or kills cryptococcal cells. We will determine rates of fungal growth or killing, as a function of drug concentration, and visualise and quantify the response of fungal cells to the drugs, to determine whether Cryptococcus is able to adapt to drug exposure, and how we can prevent this.
2. To test selected BAL2039-containing drug combinations in a mouse model of systemic cryptococcosis, to find: the best-performing tablet treatment for patients with early cryptococcal infection.
