DISCUSSION
nausea, acute myeloid leukemia, critically ill, neutropenia, toxicity, toxicities, candidiasis, TEAEs, candidemia, nonneutropenic, NCT03604705
ACUTE MYELOID LEUKEMIA, CRITICALLY ILL, NEUTROPENIA, CANDIDIASIS, CANDIDEMIA, GASTROINTESTINAL DISORDERS
Despite the high unmet medical need for new antifungal drugs with a unique mechanism of action, no new drug classes have been commercialized for IFI since the launch of the first echinocandin in 2001 (FMGX is a first-in-class investigational antifungal prodrug. The active moiety, MGX, has a novel mechanism of action that disrupts the integrity of the cell wall through inhibition of the conserved inositol acylase Gwt1. Due to its unique mechanism of action, target-based cross-resistance with other classes of drugs (azoles, echinocandins, polyenes) is not observed. FMGX and MGX have also demonstrated broad-spectrum The results presented here from two phase 1 studies that evaluated single and multiple doses of FMGX up to 1,000 mg administered via the i.v. or p.o. route highlight additional characteristics of FMGX, such as predictable linear and dose-proportional PK and maintenance of plasma exposures during the transition from i.v. to oral dosing. Oral FMGX may be administered with or without food for the convenience of ambulatory patients or those who have been discharged and continue treatment at home. Single oral dosing of FMGX demonstrated improved tolerability with food as indicated by a lower number of TEAEs related to gastrointestinal disorders (mainly nausea). At the i.v. dose levels of 10 mg to 1,000 mg and oral dose levels of 100 mg to 500 mg evaluated in these studies, FMGX use was generally well tolerated and safe, not accompanied by any serious/unexpected concerns. Most AEs were mild, transient, and resolved without intervention. No dose-limiting toxicities were observed, and no AEs or laboratory safety test results met any of the predefined criteria that prevented dose escalation. In earlier preclinical toxicity studies, no target organ toxicities were observed. Although target MGX exposures for Treatment with FMGX resulted in predictable and consistent PK profiles. Dose proportionality (linear PK) was demonstrated via high correlation between FMGX dose and MGX FMGX has high oral bioavailability (>90%), making it an ideal candidate for developing i.v. and p.o. formulations. The i.v. therapy may be more appropriate for a patient who is critically ill or unable to reliably absorb oral medications. However, for other patients, the oral formulation may be preferred (while switching from i.v. to oral therapy or to initiate treatment with oral medication only). For some drugs (antimicrobials such as clindamycin, cephalexin, amoxicillin, cloxacillin, and antifungal voriconazole), switching from the i.v. to p.o. route of administration has the potential to lower the plasma exposure to ineffectual levels and result in treatment failure (Taken together, these drug characteristics suggest that FMGX could be a novel antifungal treatment option for patients with life-threatening IFIs. Other open-label, multicenter studies to evaluate FMGX in patients undergoing chemotherapy for acute myeloid leukemia with neutropenia (NCT03333005), nonneutropenic patients with candidemia (NCT03604705), and patients with candidemia/invasive candidiasis caused by 