A consortium of leading scientists and institutions in Africa and Europe has launched a project with funding from the European & Developing Countries Clinical Trials Partnership (EDCTP) aimed at delivering an improved formulation of a lifesaving treatment for cryptococcal meningitis – one of the leading causes of death in people with advanced HIV.
About 180,000 people a year, mostly in African countries, die from cryptococcal meningitis, a fungal infection which invades the lining of the brain. People with advanced HIV are particularly susceptible to it because they have weakened immune systems. Of the 180,000 annual deaths from cryptococcal meningitis, 135,000 are in sub-Saharan Africa.
‘We are excited about collaborating with committed and outstanding research partners across two continents to develop a better adapted treatment for this devastating illness,’ said Carol Ruffell, project leader of the 5FC Sustained Release (SR) development programme and Head of the Southern Africa Office of the non-profit research organization, Drugs for Neglected Diseases initiative (DNDi), which is coordinating the consortium.
The consortium recently launched a Phase I study at FARMOVS, a clinical research facility in Bloemfontein, South Africa, to develop a new formulation of the existing treatment, known as flucytosine (5FC). This new sustained release formulation (5FC SR) would only need to be administered twice a day instead of four times a day, as it is the case now.
‘It would make a huge difference to give the patient flucytosine only twice a day, especially as we have so many patients to look after in our hospitals. It would help not having to administer the treatment in the middle of the night,’ said Ida Oliphant, a nurse who treats cryptococcal meningitis patients at Khayelitsha hospital in Cape Town. ‘Being able to take the treatment only every 12 hours would also encourage patients to complete the course once they are discharged from hospital.’
While undiagnosed and untreated fungal meningitis is fatal, over 70 percent of people can survive if they receive early, safe, and effective treatment with a combination of medicines including flucytosine.
‘I thought I was going to die when I had cryptococcal meningitis. The pain from terrible headaches was unbearable. Treatment gave me back my life and I no longer have any fear of dying. I’m so grateful. Treatment is the best thing I can ever advise to anyone. It saved my life,’ said Zikhona Mboto, a former cryptococcal meningitis patient.
The Phase I study will assess the comparative bioavailability of three candidate 5FC SR formulations in healthy study participants. The formulation is being developed so that it can be used as pellets which can be taken with water as well as via nasogastric tube. A Phase II study will follow in 2023 and 2024 in sites in Malawi and Tanzania, where cryptococcal meningitis patients will be enrolled in a randomized, controlled clinical trial to assess the 5FC SR formulation.
The consortium comprises a selected group of partners with an excellent track record of success delivering new tools and treatment strategies with an impact on public health: DNDi; FARMOVS; investigators from St George’s University of London; the National Institute for Medical Research (NIMR), Tanzania; the Lilongwe Medical Relief Fund Trust (LMRFT) in a partnership with the Kamuzu Central Hospital, Malawi; and the Luxembourg Institute of Health (LIH).
‘Cryptococcal meningitis is one of the unacceptably under-studied and under-funded HIV related comorbidities, especially in sub-Saharan Africa. To address this critical gap in such vulnerable populations, EDCTP provides funding to improve treatment and access to essential drugs, as well as diagnosis of cryptococcal infections, as an integral part of healthcare systems. We are very encouraged by the start of this very promising 5FC HIV-Crypto consortium,’ said Michael Makanga, Executive Director of European & Developing Countries Clinical Trials Partnership (EDCTP).
In tandem with the clinical trial work, the consortium will mobilize support for a combination of lifesaving treatments to be more widely available, particularly in African countries that are hard-hit by the disease.
Access to treatment for cryptococcal meningitis is urgently needed but is severely limited. The consortium will carry out focused work to support a strategy to increase access to the currently used immediate release formulation of flucytosine, and then, once developed, the new sustained release formulation. It will work with supporting partners, organizations, and the CryptoMAG advocacy group to get flucytosine registered in more African countries, expand access to people who need it, and save lives.
The European & Developing Countries Clinical Trials Partnership (EDCTP) funds clinical research for medical tools to detect, treat and prevent poverty-related infectious diseases in sub-Saharan Africa. The 5FC Sustained Release project is part of the EDCTP2 programme supported by the European Union (grant number RIA2018CO-2516).
About the EDCTP Consortium partners
DNDi is an international not-for-profit research and development organization which discovers and develops new treatments for neglected patients. DNDi has delivered nine treatments since its inception in 2003.
FARMOVS is a full-service clinical research organization in Bloemfontein, South Africa. It has conducted over 3,000 clinical trials that have facilitated the registration of pharmaceutical products and has submitted to a variety of regulatory authorities, including the FDA (USA), EMA (Europe), WHO, and MHRA (UK).
The investigators from St George’s University of London, National Institute for Medical Research (NIMR), Tanzania, and the Lilongwe Medical Relief Fund Trust (LMRFT) in partnership with the Kamuzu Central Hospital, Malawi, have designed and implemented a series of Phase II to IV trials that have transformed the treatment of cryptococcal meningitis and led to updated WHO treatment guidelines.
The Luxembourg Institute of Health (LIH) is a biomedical research centre whose main mission is to support translational research. Its Competence Centre for Methodology and Statistics is a well-known centre for data management and statistics in global health. LIH involvement is supported by the National Research Fund from Luxembourg (INTER/EDCTP/19/13991296/5FC HIV-Crypto).
Cape Town, South Africa: Kim Cloete
+27 82 4150736
Geneva, Switzerland: Frédéric Ojardias
+41 79 431 62 16
EDCTP: Ilona van den Brink
Photo credit: Karin Schermbrucker-DNDi