595. Olorofim (OLO) for treatment of invasive mould infections in patients with limited or no treatment options: PK data from a Phase 2b open-label study (NCT03583164, Study 32)
Authors: Cornelissen Karen , Wright James G , Cristinacce Andrew , Galbraith Hal , Bruggemann Roger , Maertens Johan A , Thompson George R , Chen Sharon C , Rex John H 
Published: December 2022

Abstract

Background
OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. In preclinical PKPD studies, a plasma level ≥ 0.2 µg/mL was required for efficacy similar to mould-active azoles.

Methods
Patients in Study 32 (N=100) received OLO (30 mg tablets) guided either by therapeutic drug monitoring (TDM) based on baseline bodyweight and OLO pre-dose plasma levels (180 to 300 mg/day x 1 d to load then 120 to 240 mg/day, given BID or TID as appropriate) or a fixed dose (150 mg BID for 1d then 90 mg BID). For each subject, OLO PK profiles were determined over 1 or 2 dosing intervals, an additional 8 to 9 scheduled pre-dose samples were taken during the initial 84 days and every 1-3 months thereafter. Food intake was not constrained.

Results
Geometric mean steady-state OLO PK parameters in the 90 evaluable subjects were similar between the TDM and fixed dosing groups (Table). Mean OLO pre-dose concentrations were similar over time for all 100 patients regardless of group and regimen; drug concentration variability was slightly greater when TDM was not utilized (Figure).
Pre-dose levels were greater than the Cmin observed over a dosing interval in most subjects (range of pre-dose: Cmin ratio of 1 to 15.8). which may be due to food-triggered release from a deep compartment such as the liver. Exposures exceeding the PD target (≥ 0.2 µg/mL) were consistently achieved.
PK parameters predicted by population PK modelling of Phase II data were in reasonable agreement with observed data (Table).
Table: OLO Systemic Exposure at Steady-State [median (5th – 95th percentiles)]
1 based on 90 mg BID

Conclusion
OLO is a novel mechanism oral antifungal with broad-spectrum mould activity. When administered as a fixed dose (90 mg BID), adequate exposure for efficacy against invasive mycoses is achieved, without the need to confirm by TDM

Disclosures
Karen Cornelissen, PhD, F2G: Employee James G. Wright, PhD, F2G: Advisor/Consultant Andrew Cristinacce, MSc by Research, F2G: Advisor/Consultant Roger Bruggemann, Pharm, PhD, Amplyx: Advisor/Consultant|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant|Mindipharma: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant.