MSG-10: a Phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis

Abstract

Objectives To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable β-glucan synthase inhibitor, in subjects with invasive candidiasis versus the standard of care (SOC) and to identify the dose to achieve target exposure (15.4 μM·h) in >80% of the intended population. Methods In a multinational, open-label study, patients with documented invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of novel oral ibrexafungerp or the SOC treatment following initial echinocandin therapy. Plasma samples were collected to evaluate exposure by population pharmacokinetic (PK) modelling. Safety was assessed throughout the study and global response at the end of treatment. Results Out of 27 subjects enrolled, 7 received ibrexafungerp 500 mg, 7 received ibrexafungerp 750 mg and 8 received the SOC. Five did not meet criteria for randomization. Population PK analysis indicated that an ibrexafungerp 750 mg regimen is predicted to achieve the target exposure in ∼85% of the population. The rate of adverse events was similar among patients receiving ibrexafungerp or fluconazole. Similar favourable response rates were reported among all groups: 86% (n = 6) in the ibrexafungerp 750 mg versus 71% (n = 5) in both the fluconazole and ibrexafungerp 500 mg treatment arms. The one subject treated with continued micafungin had a favourable global response. Conclusions The oral ibrexafungerp dose estimated to achieve the target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a favourable global response rate, similar to the SOC.

Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

“…Animal studies looking at the tissue distribution of ibrexafungerp achieved high concentrations in the skin, an attribute that may be of importance to limit C. auris skin colonization, with a potential impact of limiting transmission. Ibrexafungerp demonstrates activity across a range of invasive fungal diseases as a monotherapy but also in combination [ 58 , 59 ]. Early clinical evidence from an emergency-use Phase 3 study of ibrexafungerp for invasive candidiasis due to C. auris is promising.…”

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

“…Phase II studies previously utilized a 1250 mg PO once loading dose. It has been well-tolerated in studies and primarily limited to gastrointestinal adverse effects, with several studies identifying no significant difference from placebo arms [20].…”

“…It is currently being evaluated in an open-label, non-comparator, single arm phase III study as treatment of invasive fungal disease refractory or intolerant to standard-of-care therapy (FURI; NCT03059992), a phase III study vs placebo in patients with recurrent vulvovaginal candidiasis (CANDLE; NCT04029116). Interim analysis of the study has identified clinical benefit in 17 of the 20 evaluated patients [20].…”

Invasive Candidiasis

“…This drug might be considered for future randomized trials as an oral stepdown agent. 82 Fosmanogepix (previously APX001) is a first-in-class broad-spectrum antifungal drug with in vitro and in vivo activity against Candida, including C. auris. Its active moiety APX001A targets the highly conserved fungal enzyme Gwt1, which mediates the cross-linking of cell-wall mannoproteins to β-1,6-glucan.…”