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Evaluation of a novel sustained release formulation of flucytosine for treatment of HIV-related cryptococcal meningitis

Award Number: K23NS151985
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Evaluation of a novel sustained release formulation of flucytosine for treatment of HIV-related cryptococcal meningitis - PROJECT SUMMARY / ABSTRACT Cryptococcal meningitis remains a leading cause of mortality among people with advanced HIV, accounting for approximately 19% of AIDS-related deaths globally. Adjunctive flucytosine (5FC) during induction therapy significantly improves survival; however, optimal dosing strategies are unknown, and the current immediate- release formulation requires four-times-daily dosing, creating barriers to adherence and consistent drug exposure. Emerging pharmacokinetic/pharmacodynamic (PK/PD) data suggest that cerebrospinal fluid (CSF) drug exposure, rather than time above MIC alone, may be a critical determinant of antifungal efficacy. The Drugs for Neglected Diseases Initiative (DNDi) has developed a novel sustained-release formulation of flucytosine (5FC-SR) administered twice daily, which achieves higher plasma exposure while remaining below toxicity thresholds. The overall objective of this K23 proposal is to evaluate the antifungal efficacy, patient- centered outcomes, and PK/PD profile of 5FC-SR in a randomized clinical trial for the treatment of HIV- associated cryptococcal meningitis while providing mentored training in clinical trials and PK/PD principles. This K23 project will conduct a phase II randomized clinical trial nested within the ongoing PLATFORM-CM trial (n=80). Specific Aim 1 will determine whether 5FC-SR is non-inferior to standard flucytosine in early fungicidal activity, measured by the quantitative rate of CSF cryptococcal clearance. Aim 2 will assess overall patient benefit using a Desirability of Outcome Ranking (DOOR) composite endpoint incorporating survival, toxicity, and serious adverse events. Aim 3 will characterize PK/PD relationships between CSF 5FC exposure with the CSF inflammation, neurocognitive outcomes at 12 weeks, and survival at 18 weeks. The primary objective of the career development plan is to transition the candidate into an independent physician-scientist with expertise in global health clinical trials for neglected infectious diseases. The plan emphasizes advanced training in clinical trial design, implementation, and analysis. A second objective is to develop deep expertise in PK/PD principles to optimize therapeutics for opportunistic infections in advanced HIV. The candidate will also build multidisciplinary collaborations across academia, public health agencies, and international partners. Structured mentorship, didactic coursework, and hands-on leadership of a phase II trial will position the candidate to successfully compete for future independent NIH R01 funding. This research addresses a critical gap in cryptococcal meningitis therapeutics and will inform future dosing strategies and international treatment guidelines. Concurrently, this K23 award will provide structured mentorship and advanced training in clinical trial design, PK/PD analysis, and networking for diseases of global importance while supporting the candidate's transition to an independent investigator focused on improving outcomes for neglected infectious diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $239,760 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/15/2026	NEW	$239,760
														Subtotal = $239,760

Grand Total All Awards = $239,760

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Evaluation of a novel sustained release formulation of flucytosine for treatment of HIV-related cryptococcal meningitis

Award Number: K23NS151985

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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