# P-1187. Olorofim for the treatment of Central Nervous System (CNS) invasive fungal infections (IFI) in patients with limited or no treatment options: a sub-analysis of an open-label, single-arm, Phase 2b trial (Study 32; NCT03583164)

## TL;DR

Olorofim shows promise as a treatment for hard-to-treat fungal infections in the brain, with some success in patients with limited options.

## Contribution

This study evaluates olorofim's effectiveness in treating CNS fungal infections, particularly in patients with filamentous molds or coccidioidomycosis.

## Key findings

- Olorofim achieved global response rates of 12.5% to 62.5% in patients with CNS fungal infections.
- Patients with coccidioidomycosis showed no global response at Day 42 and Day 84.
- Extended treatment improved outcomes, especially for filamentous mold infections.

## Abstract

CNS IFIs are associated with high mortality rates. They affect immunocompetent and immunosuppressed hosts and are challenging due to limitations of licensed agents (poor CNS penetration; resistance).Table 1.Baseline Characteristics of patients treated with olorofim in patients with CNS infectionTable 2.Outcomes in patients with CNS IFI, excluding coccidioidomycosis*

Baseline Characteristics of patients treated with olorofim in patients with CNS infection

Outcomes in patients with CNS IFI, excluding coccidioidomycosis*

Study 32, an open-label trial of oral olorofim (first-in-class orotomide with activity against difficult-to-treat rare and dimorphic moulds), included 48/203 patients with proven CNS IFI. Global response (GR; composite of radiological, mycological, and clinical responses [CR]) was adjudicated by a Data Review Committee (DRC; Day 42 and Day 84) or the investigator (> Day 90) using MSG/EORTC 2008 criteria.a,b,c Olorofim beyond D90 was permitted in an Extended treatment Phase (EP).Table 3.Outcomes in patients with coccidioidomycosis

Outcomes in patients with coccidioidomycosis

Causative pathogens (Table 1) included Coccidioides (n=32), Aspergillus (n=12), Scedosporium (n=3), and Lomentospora (n=1). In patients with filamentous molds (FM; table 2), DRC-adjudicated successful GR was 12.5% (2/16) and 18.8% (3/16) at D42 and D84, respectively, when improvement was required in all three components. When stable disease was judged as success, DRC-adjudicated GR was 62.5% (10/16) and 56.3% (9/16) at D42 and D84, respectively. Successful CR, including stable disease, were seen in 50% (8/16) and 56.3% (9/16) at D42 and D84, respectively. In patients with coccidioidomycosis (table 3), GR was 0% at D42 and D84 due to slow resolution of serologic findings, even in those who achieved complete CR. For the 38 patients (Coccidioides n=29, FM n=9) who entered EP, Investigator-adjudicated CR at End of Treatment (InvEP-EOT) showed higher success and less failure rates than DRC D84, especially in patients with FM. All-cause mortality at both D42 and D84 was 31.3% (5/48); all deaths were in patients with FM IFI.

For the full cohort (N=203), the main AE was LFT alterations, judged at least possibly related to olorofim in 9.9% (20/203); 3% (6/203) requiring discontinuation.

Oral olorofim was well tolerated with positive treatment outcomes in patients with CNS infections, even those on extended therapy. MSG/EORTC assessments at D42 and D84 may be insufficient to evaluate clinical outcomes, especially in patients infected with coccidioidomycosis.

George R. Thompson III, MD, Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Advisor/Consultant|GSK: Grant/Research Support|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Royce Johnson, MD, CDC: Travel|F2G: Advisor/Consultant|NIH: Grant/Research Support Martin Hoenigl, MD, AiCuris: Advisor/Consultant|F2G: Grant/Research Support|F2G: Honoraria|Gilead: Honoraria|Melinta: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Honoraria|Scynexis: Grant/Research Support|Shionogi: Honoraria Johan A. Maertens, MD PhD, Amgen: Consulting fees and non-financial support|Astellas Pharma: Honoraria|Astellas Pharma: Consulting fees and non-financial support|Basilea: Consulting fees and non-financial support|Bio-Rad: Grant/Research Support|Bio-Rad: Consulting fees and non-financial support|Cidara: Consulting fees and non-financial support|F2G: Honoraria|F2G: Consulting fees and non-financial support|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Gilead Sciences: Consulting fees and non-financial support|Merck: Grant/Research Support|Merck: Consulting fees and non-financial support|Merck Sharpe & Dohme: Honoraria|Mundipharma: Honoraria|Pfizer: Grant/Research Support|Pfizer: Honoraria|Pfizer: Consulting fees and non-financial support|Schering-Plough: Consulting fees and non-financial support|Scynexis: Consulting fees and non-financial support|Shire/Takeda: Consulting fees Andrej Spec, M.D., MSCI, Astellas Global Development Pharma, Inc: Grant/Research Support|Cidara: Grant/Research Support|Mayne Pharma: Grant/Research Support|Scynexis: Grant/Research Support Andrea Deschambeault, PharmD, F2G: Employee of company Valerie Ravenna, PharmD, F2G: Employee of company Daniela Zinzi, MD, F2G: Employee of company Omar Fernandez, MD, F2G: Employee of company John H. Rex, MD, F2G Limited: Employee|F2G Limited: Stocks/Bonds (Private Company)