754. Olorofim for treatment of invasive fungal infections (IFI) due to moulds in patients with limited or no treatment options: Interim results from a Phase 2b open-label study (NCT03583164, Study 32)

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Abstract

Background

Olorofim, the first orotomide antifungal, selectively inhibits fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in fungal pyrimidine biosynthesis. Olorofim is active against Aspergillus (including azole-resistant and cryptic species), resistant moulds (e.g., Lomentospora prolificans, Scopulariopsis) and dimorphic fungi (e.g., Coccidioides). The drug is given orally and cleared by multiple CYP450 isoenzymes.

Serial images via bronchoscope of Scopulariopsis infection at the anastamosis in a lung transplant patient, pre- and post-olorofim therapy.

After lung transplant, airway obstruction at the anastomosis due to Scopulariopsis was unresponsive to available antifungal agents. The airway was clear by day 10 on olorofim monotherapy. Infection was cured with 84 days of olorofim.

Methods

Patients with limited or no treatment options for proven invasive mycoses or probable pulmonary invasive aspergillosis (IA, as per 2020 EORTC-MSGERC criteria) received olorofim (loading dose of 150mg BID on day 1, followed by 90mg BID) for up to 90 days, with extended therapy beyond day 90 allowed. The primary endpoint was DRC-adjudicated overall response rate by pathogen at day 42 using the EORTC-MSG response criteria.

Results

At database lock for the first 100 cases, infecting fungi were Aspergillus species (53, including 13 azole-resistant species), L. prolificans (17), Scedosporium (11), Coccidioides (11), and other fungi (8). Success (complete or partial response) was 44% at day 42 and 39% at day 84. When stable disease was counted as success, the success rate was 69% and 59% respectively. Response was seen in patients with highly active, uncontrolled infection (Figure). Overall all-cause mortality was 14% and 19% at day 42 and 84 respectively (IA: 23% and 30%; non-IA infections 4% and 6% respectively).

Safety: Olorofim was well tolerated over the 84d median dosing duration (max 722 days). Altered hepatic biochemistry possibly due to olorofim was seen in 8% of study subjects and managed by dose reduction/pause and led to discontinuation in 2%. Mild, self-limiting GI intolerance was noted in 2%.

Conclusion

Olorofim is an oral, mechanistically novel anti-mould agent with activity against a range of mould infections which are difficult to treat. Olorofim has a positive risk-benefit profile in a well-defined population of patients with infections due to moulds including species considered resistant to all approved antifungals.

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Journal

Title: Open Forum Infectious Diseases

Publisher: Oxford University Press (OUP)

ISSN (Electronic): 2328-8957

Publication date Created: December 01 2022

Publication date Created: December 15 2022

Publication date Other: December 01 2022

Publication date (Print): December 15 2022

Publication date (Electronic): December 15 2022

Volume: 9

Issue: Supplement_2

Article

DOI: 10.1093/ofid/ofac492.039

SO-VID: 14589941-45b8-4b76-8009-2d42c5487093

License:

https://creativecommons.org/licenses/by/4.0/

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