Efficacy of an oral lipid nanocrystal formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis.

Invasive mucormycosis (IM) is associated with high mortality and morbidity. MAT2203 is an orally administered lipid nanocrystal formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to Rhizopus arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. In R. arrhizus var. delemar-infected mice, 15 mg/kg of MAT2203 qd was as effective as 10 mg/kg of LAMB in prolonging median survival time vs placebo (13.5 and 16.5 days for MAT2203 and LAMB, respectively, vs 9 days for placebo) and enhancing overall survival vs placebo-treated mice (40% and 45% for MAT2203 and LAMB, respectively, vs 0% for placebo). A higher dose of 45 mg/kg of MAT2203 was not well tolerated by mice and showed no benefit over placebo. Similar results were obtained with mice infected with M. circinelloides. Furthermore, while both MAT2203 and LAMB treatment resulted in a significant reduction of ~1.0-2.0log and ~2.0-2.5log in Rhizopus delemar or M. circinelloides lung and brain burden vs placebo mice, respectively, LAMB significantly reduced tissue fungal burden in mice infected with R. delemar vs tissues of mice treated with MAT2203. These results support continued investigation and development of MAT2203 as a novel and oral formulation of amphotericin for the treatment of mucormycosis.

Efficacy of an oral lipid nanocrystal (LNC) formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis.

Invasive mucormycosis (IM) is associated with high mortality and morbidity and commonly afflicts patients with weakened immune systems. MAT2203 is an orally administered lipid nanocrystal (LNC) formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to R. arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. Treatment with placebo (diluent control), oral MAT2203 administered as BID and QD or intravenous LAMB for 4 days, began 16 h post infection and continued for 7 and 4 days, respectively. Survival through Day +21 and tissue fungal burden of lung or brain in animals euthanized on Day +4 served as a primary and secondary endpoint, respectively. In both infection types, MAT2203 was as effective as LAMB in prolonging median survival time (MST) and enhancing overall survival vs. placebo-treated mice ( P <0.05 by Log-Rank). Furthermore, both MAT2203 and LAMB treatment resulted in significant ∼1.0-1.5-log reduction and ∼2.0-2.2-log in R. delemar or M. circinelloides lung and brain burden, vs. placebo mice, respectively. These results support the potential efficacy of oral MAT2203 as an alternative to LAMB. Continued investigation and development of this novel oral formulation of the amphotericin B for the treatment of mucormycosis is warranted.

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

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.

Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis.

Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC. OPC and VVC were modeled in Act1-/- mice, and mucosal tissue fungal burden was assessed after once-daily treatment with CAMB, vehicle, or AMB-deoxycholate (AMB-d). Four patients with azole-resistant CMC enrolled in a phase 2 CAMB dose-escalation study. The primary endpoint was clinical improvement at 2 weeks followed by optional extension for long-term CMC suppression to assess safety and efficacy. CAMB-treated mice had significantly reduced tongue and vaginal fungal burdens compared to vehicle-treated mice and exhibited comparable fungal burden reduction relative to AMB-d-treated mice. All CAMB-treated patients reached clinical efficacy by 2 weeks, three at 400 mg twice daily and one at 200 mg twice-daily dosing. All patients continued to the extension phase, with three having sustained clinical improvement of OPC and esophageal candidiasis (EC) for up to 60 months. One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical responses were not seen for onychomycosis or VVC. CAMB was safe and well-tolerated, without any evidence of nephrotoxicity. In summary, oral CAMB reduced tongue and vaginal fungal burdens during murine candidiasis. A proof-of-concept clinical trial in human CMC showed efficacy with good tolerability and safety. This study has been registered at ClinicalTrials.gov under identifier NCT02629419.

Phase I EnACT Trial of the Safety and Tolerability of a Novel Oral Formulation of Amphotericin B.

Amphotericin B deoxycholate (AMB) has substantial toxicities. A novel encochleated amphotericin B deoxycholate (cAMB) formulation has oral bioavailability, efficacy in an animal model, and minimal toxicity due to targeted drug delivery into macrophages, where intracellular fungi reside. We conducted a phase I, ascending-dose trial of cAMB administered at 1.0 g, 1.5 g, or 2.0 g per day in 4 to 6 divided doses among HIV-positive survivors of cryptococcosis (n = 9 per cohort). We assessed the tolerability of cAMB and the adverse events (AEs) associated with cAMB treatment over 3 days. A second trial (n = 9) assessed the tolerability of 1.5 g/day given for 7 days. In the single-ascending-dose study, all subjects received their full daily dose without vomiting (100% tolerability). The cohort receiving 1.0 g had 4 transient clinical AEs in 2 subjects within 48 h and 8 laboratory AEs (n = 6 grade 2, n = 2 grade 1). The cohort receiving 1.5 g had 7 clinical AEs in 1 subject attributed to acute gastroenteritis (n = 4 grade 2) and 5 laboratory AEs (n = 1 grade 2). The cohort receiving 2.0 g had 20 clinical AEs among 5 subjects within 48 h (n = 3 grade 2) and 11 laboratory AEs (n = 2 grade 2, n = 1 grade 3). From a qualitative survey, 26 of 27 subjects (96%) preferred their experience with oral cAMB over their prior experience with intravenous (i.v.) AMB. The second, multiple-dose cohort received 1.5 g/day for 1 week, with 98.4% (248/252) of the doses being taken. Overall, 5 clinical AEs (n = 5 grade 1) and 6 laboratory AEs (n = 6 grade 1) occurred without kidney toxicity. Oral cAMB was well tolerated when given in 4 to 6 divided daily doses without the toxicities commonly seen with i.v. AMB. (This study has been registered at ClinicalTrials.gov under registration no. NCT04031833.).

FV-100 versus valacyclovir for the prevention of post-herpetic neuralgia and the treatment of acute herpes zoster-associated pain: A randomized-controlled trial.

This prospective, parallel-group, randomized, double-blind, multicenter study compared the efficacy and safety of FV-100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, ≥50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ-associated pain, were randomized 1:1:1 to a 7-day course of either FV-100 200 mg QD (n = 117), FV-100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post-herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV-100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV-100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments.