Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis

Abstract

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 One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study.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.

Keywords: amphotericin B; chronic mucocutaneous candidiasis; cochleated; mouse model; mucosal candidiasis; phase 2 trial.

FIG 1

Cochleated amphotericin B (CAMB) exhibits comparable efficacy with AMB deoxycholate (AMB-d) in mouse models of invasive (IC), oropharyngeal (OPC), and vulvovaginal candidiasis (VVC). (a) Mice were treated daily with CAMB via oral gavage, AMB-d intraperitoneally, or the vehicle control starting at day 1 postinfection. (b) C. albicans was injected intravenously in C57BL/6 mice and survival was monitored (n = 5 per group). (c) Act1^−/− mice were infected with C. albicans in models of OPC (n = 4 to 11 per group) and VVC (n = 4 to 8 per group). At day 5 postinfection, the mice were euthanized and tongue (for OPC) or vaginal tissue (for VVC) was harvested to quantify fungal burden. *, P < 0.05; **, P < 0.01 as determined using a log-rank test (b), one-way ANOVA with Tukey’s multiple-comparison test (panel c, OPC), or Kruskal-Wallis test with Dunn’s multiple-comparison test (panel c, VVC). Data are summary of one (b) or two independent experiments (c).

FIG 2

Clinical efficacy of CAMB in patients with azole-resistant chronic mucocutaneous candidiasis (CMC). (a) Shown are the clinical severity scores for corresponding manifestations of CMC at baseline and during CAMB treatment, at the primary endpoint evaluation. (b) Evolution of clinical score over time following initiation of CAMB treatment.

FIG 3

Pharmacokinetic data of CAMB administration in patients with CMC. (a and b) Plasma concentrations of amphotericin B (in ng/mL) measured over serial time points, as indicated, (a) at day 1 after initiation at 100 mg, (b) at day 14 after continuation at 200 mg/day, and at day 27 after the first dose of the 400 mg twice-daily CAMB dosing for Patients 1, 3, and 4 or after continuation of 200 mg twice daily for Patient 2.

FIG 4

Long-term administration of CAMB in patients with CMC does not cause renal impairment or anemia. (a) Serum levels of creatinine and potassium (left panel) and hemoglobin (right panel) over time after initiation of CAMB treatment. Horizontal dashed lines depict the normal range of creatinine values, and horizontal dotted lines depict the normal range of potassium (left panel) and hemoglobin (right panel) values. (b) Serum levels of erythropoietin after initiation of CAMB treatment in patient 1 (day 1,214 from CAMB initiation), patient 2 (days 148, 203, and 574 from CAMB initiation), and patient 4 (days 28, 88, 220, 674, and 796 from CAMB initiation). Horizontal dotted lines depict the normal range of erythropoietin.

FIG 5

Schematic representation of the CAMB dose escalation in the phase 2 clinical study.