Neglected Diseases
Cryptococcal meningitis is an opportunistic infection that causes inflammation of the tissue covering the brain and spinal cord. It is caused primarily by Cryptococcus neoformans, a microscopic and easily inhaled fungus found throughout the world.
In healthy individuals, inhalation of the fungal spores rarely leads to serious illness; but for immunocompromised individuals, such as those with HIV/AIDS, cryptococcal infection (cryptococcosis) can be serious and even deadly. Cryptococcosis can affect multiple organs, but the primary site of infection is usually the lungs. Cryptococcal meningitis occurs when the infection spreads to the brain and central nervous system, with symptoms including headaches, fever, neck pain, light sensitivity and altered mental state (ranging from confusion to coma). Mortality rates for cryptococcal meningitis can be as high as 70%.
Antifungal medications used for treating cryptococcal meningitis are effective, but poorly suited for use in developing countries. Amphotericin B is expensive and requires administration at a hospital, and flucytosine – another repurposed antifungal – requires careful blood monitoring. As a result, most developing countries resort to fluconazole use, which is only partially effective. Notwithstanding the AMBITION-cm findings, there remains a need for affordable, efficacious oral drugs, adapted for resource-poor settings. New antifungal agents, repurposed drugs and immunotherapies targeting various biochemical processes are in different stages of development, with many candidates showing promising activity against cryptococcal meningitis. One such candidate, Mycovia Pharmaceutical’s VT 1598, is in an ongoing Phase I trial. Monoclonal antibodies and immunomodulators alone or in combination with antifungal agents have been investigated, but there are currently no biological candidates in clinical trials.
There are seven cryptococcal meningitis drugs in the pipeline, the most advanced of which is Matinas BioPharma’s MAT2203, which began its pivotal non-inferiority Phase III trial of in January 2023. The drug is a lipid nanocrystal formulation of amphotericin B. This non-toxic oral formulation of MAT2203 is more suitable to low-resource settings than the standard amphotericin B, which is expensive, requires careful toxicity monitoring and is administered intravenously. The current trial builds on positive Phase II results, which demonstrated similar survival rates in people living with HIV infected with cryptococcal meningitis as when treated with intravenous amphotericin B.