PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections

Abstract

Disease due to pulmonary Aspergillus infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is a novel triazole antifungal agent, a potent inhibitor of CYP51, purpose-designed to be administered via inhalation for high local lung concentrations and limited systemic exposure. In preclinical testing, PC945 is potent versus Aspergillus spp. and Candida spp. and showed two remarkable properties in preclinical studies, in vitro and in vivo. The antifungal effects against Aspergillus fumigatus accumulate on repeat dosing and improved efficacy has been demonstrated when PC945 is dosed in combination with systemic anti-fungal agents of multiple classes. Resistance to PC945 has been induced in Aspergillus fumigatus in vitro, resulting in a strain which remained susceptible to other antifungal triazoles. In healthy volunteers and asthmatics, nebulised PC945 was well tolerated, with limited systemic exposure and an apparently long lung residency time. In two lung transplant patients, PC945 treated an invasive pulmonary Aspergillus infection that had been unresponsive to multiple antifungal agents (systemic ± inhaled) without systemic side effects or detected drug-drug interactions.

Keywords: Aspergillus fumigatus; inhalation; triazole.

Figure 1

Chemical Structure of PC945.

Figure 2

Effects of intranasally dosed PC945, posaconazole or voriconazole in temporarily neutropenic mice infected with A. fumigatus. Compounds were dosed on day 0 (30 min before infection) and on days 1, 2, and 3 post infection, and lungs and BALF were collected 6 h after the final dose. Shown are galactomannan levels in BALF (A), and haematoxylin-eosin (H&E) staining and Grocott fungus staining (magnification, ×200) of lung sections (B). In controls 3 days after Aspergillus infection (upper panels) the following features were noted: abundant hyphae growing in alveoli, infiltrating the lung parenchyma; parenchymal destruction and necrosis; scarce inflammatory cell recruitment (cellular inflammatory responses were primarily foamy and activated macrophages, lymphocytes with a few neutrophils). By contrast, in PC945-treated lungs (lower panels) the following features were noted: few or no fungal hyphae; no major disruption of alveoli; parenchymal structure preserved; limited number of foamy macrophages. 1 control animal in PC945 experiment was dropped out before sample collection on day 3 post infection. 3 control mice in posaconazole experiment were taken for preliminary histology analysis. ** p < 0.01, *** p < 0.001 vs. each infection control. Adapted from [47].

Figure 3

PK:PD relationship for PC945 in Aspergillus-infected, temporarily neutropenic mice. PC945 (0.56 µg/mouse) was administered once daily intranasally from day 7 to day 0 or from day 1 to day 0 before A. fumigatus inoculation, and BAL was collected 24 h or 72 h after the last dose and A. fumigatus inoculation. BAL cells and BAL supernatant were separated by centrifugation. The levels of PC945 in BAL cell extracts are shown in panel (A). (B) Non-infected intact mice were given PC945 (0.56 µg/mouse) once daily for 7 days or for 2 days, or PC945 (14 µg/mouse) for 3 days, and PC945 concentration in BAL cell extracts was measured at 6, 24, 48, 72 and/or 240 h post the last dose. (C) The relationship between PC945 in BAL cell extracts and inhibition of galactomannan (GM) in BAL in Aspergillus-infected, temporarily neutropenic mice (E). Each horizontal bar is presented as mean ± SD. 5 mice per group. * p < 0.05, **** p < 0.0001 by ANOVA-unpaired t-test with Welch’s correction. V: vehicle. Adapted from [48].

Figure 4

Pharmacodynamic responses to PC945 in an in vitro model of the human alveolus. (A) An illustration of the 2-cell model, showing combined treatment with PC945 in the upper (apical chamber and posaconazole in the lower (basolateral chamber. (B) effects of treatment with PC945 (0.1 µg/mL) or posaconazole (0.01 µg/mL) alone or in combination versus azole-susceptible fungus on Day 2 post infection; (C) effects of treatment with PC945 (0.1 µg/mL) or posaconazole (0.1 µg/mL) alone or in combination versus azole-resistant fungus on day 2 post infection; (D) effects of treatment with PC945 (0.1 µg/mL) or micafungin (1 µg/mL) alone or in combination versus azole-susceptible fungus on day 2 post infection. POS: posaconazole, MFG: Micafungin. Adapted from [52,53].

Figure 5

Refractory Invasive Pulmonary Aspergillosis Post Lung Transplant. Pre-exposure images (A–D) and response to Nebulised PC945 Treatment (E–H). Bronchoscopic images of the anastomosis: (A) Refractory infection pre-PC945 treatment, (E) After 8 weeks of PC945 treatment. Chest CT scans: (B–D) CT angiogram pre-PC945 treatment, (F–H) CT scan after 6 weeks of PC945 treatment. Adapted from [59] (and CT scans from Dr P Dalal, personal communication).