Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial

Author:

Boulware David R1ORCID,Atukunda Mucunguzi2,Kagimu Enock2,Musubire Abdu K2,Akampurira Andrew2,Tugume Lillian2,Ssebambulidde Kenneth23,Kasibante John2,Nsangi Laura2,Mugabi Timothy2,Gakuru Jane2,Kimuda Sarah2,Kasozi Derrick2,Namombwe Suzan2,Turyasingura Isaac2,Rutakingirwa Morris K2,Mpoza Edward2,Kigozi Enos4,Muzoora Conrad4,Ellis Jayne2,Skipper Caleb P1,Matkovits Theresa5,Williamson Peter R3,Williams Darlisha A1,Fieberg Ann6,Hullsiek Kathy H6,Abassi Mahsa1,Dai Biyue6,Meya David B12

Affiliation:

1. Department of Medicine, University of Minnesota , Minneapolis, Minnesota , USA

2. Infectious Diseases Institute, Makerere University , Kampala , Uganda

3. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland , USA

4. Department of Medicine, Mbarara University of Science and Technology , Mbarara , Uganda

5. Matinas Biopharma Nanotechnologies , Bedminster, New Jersey , USA

6. Division of Biostatistics, School of Public Health, University of Minnesota , Minneapolis, Minnesota , USA

Abstract

Abstract Background Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. Methods In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus–associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). Results We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10  Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin. Grade 3–4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). Conclusions This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. Clinical Trials Registration NCT04031833.

Funder

NIH

Matinas BioPharma

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

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