Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study

Abstract

Background: Only a small number of antifungal therapies for invasive fungal disease (IFD) are currently available, and many pathogens are resistant to one or more of these therapies. Olorofim, the first orotomide antifungal agent to be developed, is active against fungi that are resistant to registered therapies. It impairs fungal pyrimidine biosynthesis, leading to cell death. We sought initial data on the efficacy and safety of olorofim as a therapy for IFD. Methods: In this single-arm, open-label, phase 2b study, patients aged 16 years or older with few or no treatment options for proven IFD or probable invasive pulmonary aspergillosis were recruited from 22 centres in 11 countries. The first 58 patients received a weight-based loading dose of oral olorofim 180–300 mg in two to three divided doses on day 1 followed by 120–240 mg daily in two to three divided doses from day 2 onwards. On the basis of pharmacokinetic data from the first 25 patients, dosing was simplified from patient 59 onwards to a loading dose of 150 mg twice on day 1 followed by a fixed maintenance dose of 90 mg twice a day up to day 84 (main treatment phase) with extended therapy as needed. The primary endpoint was global response rate (based on a composite of clinical, radiological, and mycological responses) at day 42, determined as success (complete or partial improvement in all three components) or failure (stable disease or progression on any one component or death from any cause) by a data review committee (DRC). Secondary efficacy endpoints included global response rate at day 84 and all-cause mortality at day 42 and day 84. Global response rate with stable disease classified as success and response rate in the clinical component of the global response at day 42 and day 84 were also assessed. Efficacy was analysed for all patients who were confirmed by the DRC to have an IFD and who received at least one dose of olorofim (the modified intention-to-treat population). Safety was analysed in all patients who received at least one dose of olorofim (the safety population). This trial is registered with ClinicalTrials.gov, NCT03583164, and is completed. Findings: Between June 6, 2018, and Sept 8, 2022, 204 patients were enrolled. Of these, 203 were treated with olorofim and 202 (124 male, 78 female) had DRC-adjudicated IFD. Causative pathogens were Aspergillus spp (n=101, including 22 azole-resistant strains), Lomentospora prolificans (n=26), Scedosporium spp (n=22), Coccidioides spp (n=41), and other fungi (n=12). Successful global response was confirmed in 58 of 202 patients (28·7%, 95% CI 22·6–35·5) at day 42 and in 55 patients (27·2%, 21·2–33·9) at day 84. Successful global response with stable disease included in the definition of success was seen in 152 patients (75·2%, 68·7–81·0) at day 42 and in 128 patients (63·4%, 56·3–70·0) at day 84. A successful clinical response was seen in 121 patients (59·9%, 52·8–66·7) at day 42 and in 109 patients (54·0%, 46·8–61·0) at day 84. All-cause mortality was documented in 24 patients (11·9%, 7·8–17·2) at day 42 and in 33 patients (16·3%, 11·5–22·2) at day 84. Mean dosing duration was 73 days (SD 25) for the 203 patients in the main treatment phase (median 84 days [range 2–99, IQR 78–87]) and 361 days (SD 220) for the 114 patients who received extended treatment after the main phase (median 309 days [38–988, 180–502]). Medically significant liver enzyme elevations adjudicated to be at least possibly due to olorofim occurred in 20 (10%) of 203 patients and were managed to resolution by dose modification in 14 (7%) patients or by discontinuation of treatment in six (3%). Gastrointestinal intolerance, which occurred in 20 (10%) patients, was predominantly reported as mild or moderate and self-limiting. There were no treatment-related deaths. Interpretation: Olorofim showed efficacy and good tolerability in patients with IFD with few or no treatment options. Further studies will be needed to fully delineate the role of this new antifungal agent. Funding: F2G.