Phase 1b safety and pharmacokinetics of intravenous and oral fosmanogepix in patients with acute myeloid leukaemia and neutropenia

by Selleckchem | Dec 13 2023

Objectives: Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/μL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix.

Methods: Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data.

Results: Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers.

Conclusions: Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.

Comments:

Title: **Safety, Tolerability, and Pharmacokinetics of Fosmanogepix in Patients with Acute Myeloid Leukemia and Neutropenia Undergoing Chemotherapy: A Phase 1b Study**

**Abstract:**
This open-label, multicentre Phase 1b study aimed to evaluate the safety, tolerability, and pharmacokinetics (PK) of fosmanogepix, a first-in-class antifungal prodrug, in adult patients with acute myeloid leukemia (AML) and neutropenia undergoing remission induction chemotherapy. Fosmanogepix was administered intravenously (IV) at a dose of 600 mg once daily or orally (PO) at a dose of 500 mg once daily for 14 days, with a 28-day follow-up period. The study also assessed fosmanogepix-related adverse events (AEs) and compared PK parameters between IV and PO administration.

**Methods:**
Twenty-one adult AML patients with neutropenia (<500 cells/μL; >10 days) undergoing remission induction chemotherapy were enrolled. Ten patients received IV fosmanogepix, and 11 patients received oral fosmanogepix. All patients also received AML remission induction chemotherapy (S-HAM or 7 + 3 regimen) and invasive fungal disease prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was applied to manogepix plasma data.

**Results:**
A total of 26 fosmanogepix-related AEs were observed in 9 patients (42.9%). None of these events were serious or led to fosmanogepix discontinuation. The most common fosmanogepix-related AEs were Grade 1/2 nausea (14.3%), vomiting, ALT increase, and delirium (9.5% each). One patient experienced fosmanogepix-related Grade 3 hypertension. The dose-corrected geometric mean ratio of area under the curve (PO-to-IV) was 95%. The elimination half-lives of fosmanogepix (approximately 2 days) were consistent with previous studies in healthy volunteers.

**Conclusions:**
Fosmanogepix was found to be safe and well-tolerated in AML patients with neutropenia undergoing remission induction chemotherapy. The safety and PK profiles of fosmanogepix in these patients were comparable to those observed in healthy volunteers. These findings support the continued development of fosmanogepix for the treatment of invasive fungal diseases in this patient population.