Effects of inhaled PC945 on fungal load in mouth wash collected from healthy subjects in the first-in-human study (NCT02715570)

Author:

L Daly, K Woodward, M Coates, L Cass, P Strong, A Murray, G Rapeport, K Ito

Author address:

Pulmocide Ltd., London, United Kingdom

Full conference title:

AAAM 2020

Date: 26 February 2020

Abstract:

Purpose: A first in human (FIH) study of PC945, a novel inhaled antifungal triazole, was conducted to evaluate the safety and pharmacokinetics of PC945 delivered as a suspension formulation by nebulisation (NCT02715570). During this study, mouth wash and pharyngeal swabs were collected for exploratory investigation of the impact of PC945 treatment on observed fungal loads.

Methods: Healthy volunteers (HVs) received Placebo or PC945 as either single ascending doses (0.5-10 mg) (SAD Cohort) or 5 mg once daily for 7 days (repeat dose [RD] cohort). Mild asthmatics received a single dose of PC945, 5 mg or Placebo (asthma cohort). Mouth wash and pharyngeal swabs were collected pre- and 48hrs post dose.   Mouth wash was cultured in Potato dextrose agar (PGC) and CHROMAgar, and the presence of Candida albicans assessed using polymerase chain reaction (PCR). Yeasts were identified using CHROMAgar, PCR and Maldi-Tof MS analysis

Results: Fungal detection rates and fungal burden in both cohorts of healthy volunteers were very low. In addition, fungal burden distribution was poorly randomised. In the SAD and asthma cohorts, no yeasts or moulds were detected in culture in the Placebo groups pre-dose. The commonest yeast species observed was Candida albicans and, for mould species, Aspergillus fumigatus, Penicillium rubens and Penicillium chrysogenum were detected.

In the SAD cohort, PC945 dose-dependently inhibited yeast load detected in PGC agar and CHROMagar up to 5mg dose. Overall, treatment with PC945 statistically significantly inhibited Candida culture load (p=0.023) and PCR signal (p=0.009) (paired comparison pre- versus post-dose) in samples yeast positive pre-dose.  In the RD and asthma cohorts, no yeast was detected in the Placebo treated group, but the trend of PC945 inhibition of yeasts post-dose was observed in the asthma cohort compared with pre-dose.  In all cohorts, mould detection was limited, and no conclusive data were obtained. In addition, almost no or little yeast and mould PCR signal was detected in pharyngeal swabs.

Conclusion: Samples taken during this FIH study allowed a first exploratory investigation of PC945’s antifungal activity in humans, although the study was neither powered nor appropriately randomised for this purpose. The results do, however, suggest a trend of PC945 treatment-dependent inhibition of oral yeasts which may warrant further clinical study.

Abstract Number: 80

Link to conference website:

Link Conference abstract: 

AAAM 2020

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