Clinical safety and efficacy of novel antifungal, fosmanogepix, for the treatment of candidaemia: results from a Phase 2 trial.

BACKGROUND: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration. METHODS: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (<96 h of treatment start) composed the modified intent-to-treat (mITT) population. Primary efficacy endpoint was treatment success at the end of study treatment (EOST) as determined by the Data Review Committee. Success was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at the EOST. RESULTS: Treatment success was 80% (16/20, mITT; EOST) and Day 30 survival was 85% (17/20; 3 deaths unrelated to fosmanogepix). Ten of 21 (48%) were switched to oral fosmanogepix. Fosmanogepix was well tolerated with no treatment-related serious adverse events/discontinuations. Fosmanogepix had potent in vitro activity against baseline isolates of Candida spp. (MICrange: CLSI, 0.002-0.03 mg/L). CONCLUSIONS: Results from this single-arm Phase 2 trial suggest that fosmanogepix may be a safe, well-tolerated, and efficacious treatment for non-neutropenic patients with candidaemia, including those with renal impairment.

Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris: Results from a Phase 2 Trial.

Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. In vitro susceptibility of Candida isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent in vitro activity against all C. auris isolates (MIC range: 0.008 to 0.015 µg/mL [CLSI]; 0.004-0.03 µg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.

Safety and Pharmacokinetics of Intravenous and Oral Fosmanogepix, a First-in-Class Antifungal Agent, in Healthy Volunteers.

Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (Cmax) (SAD: 0.16 to 12.0 µg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 µg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 µg · h/mL). With single and repeat p.o., dose-proportional increases in Cmax (SAD: 1.30 to 6.41 µg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 µg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 µg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens.

Changes in cognitive symptoms after a buspirone-melatonin combination treatment for Major Depressive Disorder.

Cognitive deficits are often associated with acute depressive episodes and contribute to the functional impairment seen in patients with Major Depressive Disorder (MDD). Many patients sustain residual cognitive deficits after treatment that may be independent of the core MDD disorder. We tracked changes in cognitive deficits relative to antidepressant treatment response using the patient self-rated Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) during a 6-week, double-blind trial of a combination antidepressant treatment (buspirone 15 mg with melatonin-SR 3 mg) versus buspirone (15 mg) monotherapy versus placebo in MDD patients with acute depressive episodes. The CPFQ includes distinct cognitive and physical functioning dimension subscales. Treatment response was determined using the Inventory of Depressive Symptomatology (IDSc30). Treatment responders improved significantly more on the total CPFQ than non-responders (p < 0.0001) regardless of treatment assignment. The cognitive dimension of the CPFQ score favored the combination treatment over the other two groups (ANCOVA: p = 0.050). Among the treatment non-responders, the effect size for the CPFQ cognitive dimension was 0.603 favoring the combination treatment over the over two groups and 0.113 for the CPFQ physical dimension. These preliminary findings suggest that a combination of buspirone with melatonin may benefit cognitive function distinct from mood symptoms and that some aspects of cognition may be specific targets for treatment within a population of patients with MDD.

A comparative analysis between site-based and centralized ratings and patient self-ratings in a clinical trial of Major Depressive Disorder.

We compared scores from three different ratings methods in a clinical trial of patients with Major Depressive Disorder (MDD). The Quick Inventory of Depressive Symptoms (QIDS-SR16) was compared to site-based clinician and centralized (site-independent) ratings of the Inventory of Depressive Symptoms (IDSc30). An extracted QIDSc16 was used for a matched comparison with the QIDS-SR16. Patient self-ratings were more depressed at baseline than either site-based ratings (p = 0.131) or centralized ratings (p = 0.005), but significantly less depressed at the end of double-blind treatment than either site-based (p = 0.006) or centralized ratings (p = 0.014), and after 12 weeks (site-based ratings: p = 0.048; centralized ratings: p = 0.004). The matched comparisons with patient self-ratings revealed ICC of r = 0.55 (site-based raters) and r = 0.49 (centralized raters) at baseline. After baseline, the correlations between the two different clinician ratings and patient self-ratings improved to r-values between 0.78 and 0.89. At the end of double-blind treatment, site-based raters separated the combination treatment from placebo on the IDSc30 (p = 0.030) whereas neither centralized ratings nor patient self-ratings achieved statistical significance. Alternatively, patient self-ratings separated the combination treatment from buspirone (p = 0.030) whereas neither clinician rating method achieved significance. A "dual" scoring concordance range reduced the placebo response rate and increased the drug effect between the combination treatment and placebo. These findings reveal scoring variability between each of the three ratings methods and challenge the reliability of any single method to accurately assess symptom severity scores, particularly at baseline. The use of "dual" scoring criteria may help to confirm symptom severity scores and improve ratings precision, particularly prior to enrolling subjects into CNS trials.

An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery.

We used in vitro neurogenesis-based human neural stem cell (hNSCs) assays and rodent in vivo behavioral assays to identify potential novel antidepressants. A combination of buspirone and melatonin displayed antidepressant activity in these assays whereas neither buspirone nor melatonin alone showed any antidepressant-like profile. After evaluating numerous combination ratios, we determined that low dose buspirone 15 mg combined with melatonin-SR 3 mg yielded optimal antidepressant efficacy in our pre-clinical platform. The low dose of buspirone suggested that antidepressant efficacy might be achieved with only minimal adverse event liability. Based on these data, we conducted an exploratory 6-week, multi-center, double-blind, randomized, placebo- and comparator-controlled study of the combination of buspirone and melatonin in subjects with acute Major Depressive Disorder (MDD). The combination treatment revealed a significant antidepressant response in subjects with MDD on several measures (Clinical Global Impression of Severity and Improvement, Inventory of Depressive Symptomatology) compared to either placebo or buspirone 15 mg monotherapy. These preliminary findings have clinical implications and suggest that a platform of pre-clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy.