Phase 2 trial demonstrates novel investigational antifungal Fosmanogepix is tolerated and efficacious in patients with renal Insufficiency.
A novel, first-in-class antifungal, fosmanogepix, demonstrated efficacy in a phase 2 candidemia trial, and was well tolerated in a subset of patients with renal insufficiency, according to results presented at the 2020 IDWeek virtual conference.
“Fosmanogepix demonstrated high level treatment success with no evidence of drug-related nephrotoxicity, with no dose adjustments required,” reported Pierre Bulpa, MD, Head, Clinical Department, Mont-Godine University Hospital, Yvoir, Belgium.
Fosmanogepix is described by the manufacturer and sponsor of the phase 2 trial, Amplyx Pharmaceuticals, as a unique antifungal with a novel mechanism of action and broad spectrum activity, including against strains such as C auris that are resistant to the 3 available antifungal classes of polyenes, azoles and echinocandins.
The mechanism of action of fosmanogepix involves inhibition of the fungal enzyme Gwt1 by the active moiety, manogepix. The manufacturer indicates that Gwt1 is highly conserved across fungal strains and is essential for trafficking and anchoring manoprotein to the outer cell wall in fungi; with mannoproteins integral to fungal cell wall integrity, adhesion, pathogenicity, and for evading host defenses.
As a substantial number of patients with candidemia also suffer from renal insufficiency, Bulpa and colleagues conducted a subset analysis of those patients from an open-label, non-comparative phase 2 trial of the safety and efficacy of the agent as first-line treatment.
All participants had a positive blood culture for Candida spp within 96 hours prior to study entry, and had not received antifungal treatment within the previous 2 days.Patients with neutropenia, C krusei infection, deep-seated Candida infections, or those on hemodialysis were excluded.
Participants received fosmanogepix for up to 14 days, as 1000mg intravenously (IV) twice daily for 1 day, then 600mg IV daily for at least 2 days, followed by either 600mg IV or 700mg orally daily.Fluconazole was to be administered to any participants who required antifungal treatment beyond the 14 day regimen with fosmanogepix.
Of the 21 participants, 14 had some degree of renal insufficiency: 7 had mild insufficiency with glomerular filtration rate (GFR) of 60-89; 5 had moderate insufficiency with GFR 30-59; and 2 had severe renal insufficiency with GFR 15-29.
Twelve of the 14 (85%) with renal insufficiency completed the study treatment, and treatment was successful for each of the 12 at the end of the 14 day regimen.Successful outcome was defined as survival with clearance of Candida from blood cultures with no additional antifungal treatment.
“Decline in renal function was not observed at end of study treatment,” Bulpa reported, and“there were no treatment-related adverse events.”
There was worsening of renal function observed in the follow-up period in 4 patients, however, although none required dialysis.Bulpa indicated that renal impairment had not increased “the exposure” (ie, increased serum levels) of fosmanogepix, and so no dose adjustments were required.
“These preliminary data support the continued evaluation of foxmanogepix in patients with candidemia and renal dysfunction as an alternative to potentially nephrotoxic antifungal agents,” Bulpa reported.
The results were reported at the 2020 IDWeek virtual conference, Poster 1157: “Clinical Safety, Efficacy, and Pharmacokinetics of Fosmanogepix, a Novel First-in-class Antifungal, in Patients with Renal Insufficiency: Subset Analysis from a Phase 2 Candidemia Trial.