Olorofim shows promise in invasive fungal disease

In patients with invasive fungal disease (IFD) who have few or no treatment options, olorofim demonstrates efficacy and good tolerability, according to the results of a single-arm, open-label phase IIb study.

The study included patients at least 16 years of age who had few or no treatment options for proven IFD or probable invasive pulmonary aspergillosis. The first 58 patients received a weight-based loading dose of olorofim 180–300 mg, administered orally 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.

Pharmacokinetic data from the first 25 patients were used to simplify dosing for 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 allowed if needed.

The primary endpoint of global response was assessed based on a composite of clinical, radiological, and mycological responses at day 42. Response was defined as success (ie, complete or partial improvement in all three components) or failure (ie, 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.

The analysis included 204 patients. Of these, 203 received treatment with olorofim and 202 had DRC-adjudicated IFD. Aspergillus spp (n=101) was the most common causative pathogen. Others were Lomentospora prolificans (n=26), Scedosporium spp (n=22), Coccidioides spp (n=41), and other fungi (n=12).

Successful global response occurred in 28.7 percent of patients at day 42 and in 27.2 percent at day 84. The rate of all-cause mortality was 11.9 percent at day 42 and 16.3 percent at day 84. Mean dosing duration was 73 days for the 203 patients in the main treatment phase and 361 days for the 114 patients who received extended treatment after the main phase.

Medically significant elevations in liver enzyme adjudicated to be at least possibly due to olorofim were documented in 10 percent of patients and were resolved by dose modification in 7 percent or by treatment discontinuation in 3 percent. There were 10 percent of patients who had gastrointestinal intolerance, which was mainly mild or moderate and self-limiting. There were no reports of treatment-related deaths.