Advance the development of sustained-release flucytosine to simplify inpatient and outpatient treatment of cryptococcal infections
current phase of drug development
updated 18 Mar 2024
Cryptococcal meningitis is one of the leading causes of death in people with advanced HIV. About 180,000 people a year, mostly in Africa, die from HIV-related cryptococcal meningitis. While undiagnosed and untreated fungal meningitis is fatal, over 70 percent of people can survive if they receive early and optimal treatment.
Flucytosine (5FC) is a key, life-saving component of the new WHO-recommended first- and second-line treatments. However, standard formulations of the drug – delivered in four divided doses per day – are poorly adapted for use in under-staffed and overburdened hospitals in resource-limited settings. The drug also often needs to be crushed and given by nasogastric intubation. This project aims to deliver a simpler, sustained-release formulation of flucytosine that is easier to administer and better suited to resource-constrained settings. The project also aims to strengthen local capacities in conducting clinical trials in South Africa, Tanzania, and Malawi.
Renowned scientists and institutions from Africa and Europe are working on this project led by DNDi and funded by the European & Developing Countries Clinical Trials Partnership (EDCTP).
In parallel with activities to develop new field-adapted treatment tools, DNDi and partners are also carrying out work to facilitate the scale-up of 5FC immediate-release formulations included in the latest WHO treatment guidelines in African low- and middle-income countries. Although significant progress has been made, 5FC is currently not registered or not available in many African countries. The 5FC access project provides the opportunity to advocate, together with in-country and international partners, to change this and to develop a framework for a comprehensive access plan for treatment and diagnostics for cryptococcal meningitis in the context of advanced HIV disease.
Dr Irene Mukui, Former Head of HIV Disease, DNDiWe are excited about working towards an improved formulation of life-saving treatment for cryptococcal meningitis, which causes the suffering and death of so many. If successful it should be made accessible and affordable to people in areas where the need is greatest.
Project updates
2023
The second Phase I trial was completed at FARMOVS in Bloemfontein, South Africa in May 2023. The safety and pharmacokinetic data confirmed the dose of the identified sustained-release 5FC formulation, supporting the development of a twice-daily regimen for patients with cryptococcal meningitis. This sustained-release regimen (6 grams, administered twice per day) will be tested in a Phase II study in Tanzania and Malawi to determine its suitability as a substitute for the current immediate-release regimen of 5FC, which is administered four times per day. The study protocol was submitted to ethics committees and health authorities in the two countries and is expected to start in early 2024.
2022
The first Phase I trial kicked off at FARMOVS in Bloemfontein, South Africa, in early 2022. The data generated enabled the selection of a sustained-release prototype formulation for further development and testing. The second Phase I trial began at FARMOVS in November 2022 and is expected to be completed in early 2023. Review of Phase I safety and pharmacokinetic data established the dosage of the sustained release formulation required to obtain the optimum level of flucytosine exposure. Preparation for the Phase II study, to take place in Tanzania and Malawi in 2023, also began in 2022.
2021
Preparations for the Phase I trial continued through 2021 and the study began at FARMOVS in South Africa in early 2022. Phase II studies in Tanzania and Malawi will take place in subsequent years.
2020
A consortium was established to implement project activities with support from EDCTP. Preparations to initiate Phase I studies are now underway. The application to conduct the first Phase I study in South Africa has been submitted to the South African Health Products Regulatory Authority (SAHPRA) for review, in collaboration with consortium member, FARMOVS, a partner clinical research organization affiliated to the University of the Free State in South Africa. FARMOVS will be leading the Phase I study in South Africa.
2019
Pharmaceutical development studies were performed to evaluate the feasibility of development of a new sustained-release formulation of flucytosine, physiologically based pharmacokinetic modelling was carried out to support prototype selection, and a quality target product profile was developed.
News & resources
- 18 September 2024 - Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis, Clinical and Translational Science
- 28 March 2024 - 2023 R&D portfolio in review: HIV
- 15 March 2024 - Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers, Clinical and Translational Science
- 17 June 2022 - Improving cryptococcal meningitis treatment in Africa, The Lancet Microbe
- 8 March 2022 - Cryptococcal meningitis: An improved formulation of a lifesaving treatment
- 25 February 2022 - Expert consortium begins study in South Africa to develop an optimized treatment for cryptococcal meningitis
- 13 May 2021 - Ending deaths from cryptococcal meningitis in a decade is possible – but more action needed before UN meeting on HIV/AIDS
- 30 November 2020 - Ending deaths from HIV-related cryptococcal meningitis by 2030, The Lancet Infectious Diseases
- 25 October 2018 - Leave no one behind: Response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries, The Lancet Infectious Diseases
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