Fosmanogepix for the Treatment of Invasive Mold Diseases Caused by Aspergillus Species and Rare Molds: A Phase 2, Open-Label Study (AEGIS)

Abstract

Background

Fosmanogepix (FMGX) inhibits glycosylphosphatidylinositol anchored cell wall transfer protein 1, essential for anchoring mannoproteins to fungal cell wall, critical for host invasion. This Phase 2 study evaluated efficacy and safety of FMGX treatment in invasive mold diseases (IMDs) by Aspergillus spp. and rare molds in adults with limited treatment options.

Methods

Participants (≥18 years) received FMGX 1000 mg intravenously (IV; 3-hour infusion) twice on Day 1 followed by 600 mg IV or 800 mg oral (optional from Day 4) once a day for ≤42 days. Key endpoints were all-cause mortality (Day 42) and Data Review Committee (DRC)-assessed global response (end of study treatment), adjudicated as success (complete or partial response) or failure (stable disease or progression of disease or death).

Results

Of 21 participants enrolled (safety population), 20 were included in the modified Intent-to-Treat population (mean age: 61.9 years; females: 2 [10%]). Day-42 all-cause mortality was 25% (80% confidence interval [CI]: 12.7%—41.5%). DRC-assessed global response success rate was 40% (80% CI: 24.9%—56.7%). 258 adverse events (AEs) were reported (n = 21). 15 participants experienced 36 FMGX-related AEs, 2 had 3 serious AEs. Three participants (14.3%) discontinued study treatment due to FMGX-related AEs. Nine deaths (43%) were reported. One death was assessed as possibly related and unrelated to FMGX by the investigator and Data and Safety Monitoring Board, respectively.

Conclusions

Safety profile was acceptable in high-risk patients with limited treatment options, supporting development of FMGX for treating IMDs caused by Aspergillus and rare molds.

Clinical Trials Registration. NCT04240886; EudraCT number: 2019-001386-33.

Fosmanogepix 1000 mg intravenous (IV) (loading dose) and 600 mg IV or 800 mg oral (maintenance dose) resulted in 25% all-cause mortality at Day 42 and demonstrated acceptable safety profile in adults with invasive mold diseases and limited treatment options.

Graphical Abstract

Graphical Abstract.

Fosmanogepix for the Treatment of Invasive Mold Diseases Caused by Aspergillus Species and Rare Molds: A Phase 2, Open-Label Study (AEGIS). This graphical abstract is also available at Tidbit: https://tidbitapp.io/institutional-portal/clinical-infectious-diseases/tidbits/fosmanogepix-for-the-treatment-of-invasive-mold-diseases-caused-by-aspergillus-species-and-rare-molds-a-phase-2-open-label-study-aegis/update

Invasive mold diseases (IMDs) often occur in immunosuppressed patients [1, 2], causing substantial healthcare resource utilization and deaths [1]. Estimated mortality rates range from ∼30–50% (susceptible) to ∼60–95% (cryptic and azole-resistant) for Aspergillus spp [3, 4]. and 30–90% for rare mold infections [5]. Currently recommended treatment for invasive aspergillosis (IA) and other mold infections includes triazoles, polyenes, and echinocandins [1, 6, 7]. Many rare molds display inherent resistance to available antifungals [5]. Drug-drug interactions (DDI), pharmacokinetic (PK) variability, short-and long-term toxicities have been observed with azoles [2, 8]. Amphotericin B (AMB) formulations are associated with nephrotoxicity and hypokalemia [6]. No randomized controlled trials have demonstrated efficacy of echinocandin monotherapy for primary IMD treatment [2, 6, 9].

Fosmanogepix (FMGX), an N-phosphonooxymethylene prodrug of manogepix (MGX) [5], is the first of the “gepix” class of antifungals, which inhibits fungal glycosylphosphatidylinositol (GPI)-anchored wall transfer protein 1 (Gwt1), an inositol acyltransferase essential for trafficking and anchoring mannoproteins to the fungal cell membrane and cell wall, critical for host cell invasion and infection [5, 10, 11]. MGX is inactive against the closest mammalian Gwt1 ortholog, phosphatidylinositol glycan anchor biosynthesis class W (PIGW), indicating fungal specificity [5, 11].

MGX has broad in vitro activity against azole- and echinocandin-resistant fungi, species including Candida (except C. krusei and C. kefyr), Cryptococcus, Aspergillus, Scedosporium, Fusarium, and some Mucorales strains [12–15]. Improved survival rates were observed in mouse models of pulmonary aspergillosis, scedosporiosis, and disseminated fusariosis [16], with reduced fungal burden in lung [17], kidney, and brain [5, 18]. FMGX showed acceptable safety profile in healthy volunteers [10], patients with acute myeloid leukemia (AML) and neutropenia [19], and in two Phase 2, multicenter studies with high treatment success rates for candidemia [20] and candidemia/invasive candidiasis caused by Candida auris [21]. In a preliminary DDI assessment, FMGX was neither a strong inhibitor nor inducer of cytochrome P450 enzymes (NCT02957929 [22]; data not published). Additionally, both intravenous (IV) and oral formulations achieved target area under the concentration-time curve (AUCs) anticipated for efficacy against yeasts and molds [10].

This Phase 2 study was conducted to evaluate efficacy and safety of FMGX treatment in IMDs caused by Aspergillus spp. and rare molds in adults with limited treatment options [23].

METHODS

Study Design and Participants

This Phase 2, open-label, multicenter, non-comparative study (NCT04240886; EudraCT number: 2019-001386-33) evaluated FMGX efficacy and safety for the treatment of IMDs caused by Aspergillus spp. and rare molds (eg, Scedosporium spp., Lomentospora prolificans, Fusarium spp., and Mucorales fungi) in adults with limited treatment options. Initially, 2 cohorts were planned: Cohort A (participants with IMDs) and Cohort B (participants with IMDs and lower respiratory tract severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or influenza A/B infection), both receiving same FMGX IV/oral treatment. However, on study termination in April 2022 to prioritize a randomized comparative Phase 3 study in the same indication, no participants had been enrolled in Cohort B.

This study (04 January 2020 to 09 May 2022) was conducted at 8 centers in 4 countries (Belgium, Germany, Israel, and United States) per protocol, Declaration of Helsinki, International Council for Harmonization guidelines on Good Clinical Practice (ICH GCP), Directive 2001/20/EC, and other applicable laws and regulations. Participants/legally authorized representatives provided written informed consent before performing any study-specific procedures.

Patients ≥18 years with proven or probable IMDs caused by Aspergillus spp. and other rare molds with limited treatment options due to documented/anticipated resistance, contraindication, intolerance, or no clinical response to standard of care (SOC) antifungal therapy (per relevant regional/country treatment guidelines) were included. Proven or probable IMD diagnosis was defined per the 2020 Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) criteria [24]. Patients with refractory hematologic malignancy, chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis, hepatic dysfunction (total bilirubin >3 × upper limit of normal [ULN]; alanine or aspartate transaminase ≥5 × ULN; cirrhosis or severe hepatic impairment), or severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.173 m²) were excluded. Except as prophylaxis, mold-active azole or polyene antifungal therapy administration (oral, IV, or inhaled) was limited to ≤120 hours immediately before initial FMGX dosing.

Treatments

Study duration was 84 days (post-screening period ≤5 days), including FMGX treatment up to Day 42 (end of study treatment [EOST]), a follow-up visit at Day 70 (28 days post EOST), and a follow-up phone call to assess survival status at Day 84 (42 days post EOST). Treatment included FMGX 1000 mg IV twice daily (BID; loading dose) on Day 1, FMGX 600 mg IV once daily (QD) on Days 2 and 3 (maintenance dose) with an optional switch to 800 mg oral QD (at investigator's discretion) from Day 4 through EOST (Figure 1). All FMGX IV doses were administered via 3-hour infusions. Participants requiring treatment for >42 days could switch to other licensed antifungal therapy per investigator's discretion. For some participants, maintenance QD doses were split and administered BID to improve tolerance (mainly gastrointestinal [GI]). Fungal pathogen identification is described in Supplementary Section 1.

Figure 1.

Study design. ^aPer DRC assessment, 1 participant was excluded from the mITT population due to not meeting the eligibility criteria. ^bFor the 12 participants where the fungal pathogen could not be identified, evidence for probable IMD was based on other diagnostic measures meeting the protocol adapted EORTC/MSGERC criteria, eg, galactomannan antigen (serum, plasma, or BAL) ELISA or Aspergillus PCR. Abbreviations: BAL, bronchoalveolar lavage; BID, twice daily; D, day; DNA, deoxyribonucleic acid; DRC, Data Review Committee; EORTC/MSGERC, European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium; EOST, end of study treatment; ET, early termination; FMGX, fosmanogepix; IMD, invasive mold disease; IV, intravenous; mITT, modified intent-to-treat; PK, pharmacokinetics; QD, once daily.

A Data Review Committee (DRC) comprising infectious disease experts adjudicated the diagnosis of IMDs at enrollment, and provided systematic assessment for clinical, mycological, radiological, and global responses at EOST/early termination (ET) visit. An independent Data and Safety Monitoring Board (DSMB) comprising members with pertinent expertise monitored safety at regular intervals throughout the study.

Assessments

Efficacy

Primary and Key Secondary Endpoint

All-cause mortality through Day 42 (primary efficacy endpoint) and DRC-assessed global response at EOST/ET (secondary efficacy endpoint) were assessed. Global response was categorized into success (complete response [CR] and/or partial response [PR]) and failure (stable disease [SD], progression of disease [PD], and/or death), based on prespecified criteria [25]. Although SD was categorized as failure, absence of PD in high-risk patients with limited treatment options may provide evidence of treatment efficacy [25]. Global response was therefore categorized as success, failure, and SD.

Other Efficacy Endpoints

DRC assessed clinical, radiological, and mycological responses at EOST/ET. Clinical and radiological responses were categorized based on resolution (CR), major improvement (PR), minor/no improvement (SD), or deterioration (failure) of attributable symptoms, signs, and/or bronchoscopic findings at baseline (clinical response) and radiological findings attributed to IMDs versus baseline (radiological response) [25]. Mycological response was categorized based on absence of molds in the clinical specimen (eradication), complete clinical and imaging response without invasive procedure to obtain a clinical specimen (presumed eradication), any evidence (culture, microscopy, or histopathology) indicating IMD presence (persistence), or inadequate data available for the above categorizations (indeterminate) [25].

PK and Safety

Other Secondary Endpoints

Safety was assessed by the frequency of adverse events (AEs), monitored from Day 1 (baseline) to Day 70 (follow-up visit). FMGX and MGX PK were assessed (plasma samples collected: predose and 3 hours post start of infusion on Days 1, 2, 3, 7, and 14; predose on Days 28 and 42; at any time at EOST, follow-up, and ET [if applicable] visits). For participants who switched to oral dosing, samples were collected predose and at 3 hours postdose on the first day of oral dosing, Days 7 and 14, and at any time on Days 28 and 42 and EOST, follow-up, and ET (if applicable) visits. If the participant switched back to IV dosing, PK samples were collected predose and at 3 hours post start of infusion on the day of switching and per the schedule of sample collection for IV dosing thereafter. PK analysis was conducted using a non-linear mixed-effects population modeling approach. Parameters assessed were maximum plasma concentration (C_max); time to reach C_max (T_max); minimum plasma concentration (C_min), AUC for MGX from 0 to 24 hours (AUC_0-24).

Exploratory Endpoints

All-cause mortality through Day 84 and change from baseline in serum galactomannan (predose on Days 1, 2, and 3, Days 7, 14, 28, and 42, at EOST) and serum 1,3-β-D-glucan levels (predose on Day 1, Days 14, 28, and 42, at EOST, at the follow-up visit) were assessed.

Sample Size and Analysis Sets

Sample size determination was based on the primary efficacy endpoint (Day-42 all-cause mortality) in the modified intent-to-treat (mITT) population. Assuming an all-cause mortality of 20% for FMGX and 45% for conventional AMB deoxycholate from historical controls [26] (used instead of a placebo arm to determine sample size), 24 participants in the mITT population were required to provide >90% power to detect a difference (1-sided significance level of 0.1). Findings from Herbrecht et al (2002) suggested that AMB deoxycholate survival was ∼65% [26]. Compared to the primary population in Herbrecht et al, participants in the current study were refractory to antifungal therapy and were likely to be sicker. Therefore, an adjusted survival of 55% (ie, mortality rate: 45%) was considered for the AMB historical control. FMGX survival rate and 1-sided lower confidence interval (CI) was assessed in relation to this adjusted value of 55%. Assuming 60% of dosed participants were eligible for inclusion in the mITT population, dosing of ∼40 participants would allow statistical testing of proof-of-concept.

Safety population (referred to as the intent-to-treat [ITT] population hereafter) included all participants who received ≥1 dose of FMGX. The mITT population included all participants in the ITT population who also had a DRC-confirmed diagnosis of proven or probable IMD. PK population included all participants who received any amount of FMGX and had evaluable PK data.

Efficacy endpoints and safety data were summarized descriptively, and a 1-sided exact binomial test (0.1 level of significance) was used for hypothesis testing (all-cause mortality at Day 42 < 45% [based on historical control data] [26]). PK parameters were estimated by applying population PK analysis using validated software (NONMEM v7.4 and Perl-speaks-NONMEM [PsN] v4.9.0, ICON plc) and summarized descriptively by collection timepoint.

RESULTS

Of 25 patients screened, 21 were enrolled and included in the ITT and PK population. Of these, one did not meet the DRC-assessed diagnostic criteria of proven or probable IMD [24]. The mITT population included 20 participants (participant disposition; Supplementary Table 2).

Baseline and Demographic Characteristics

Eighteen males and 2 females were included in the mITT population (n = 20) and mean age (years [standard deviation]) was 61.9 (11.8). Median FMGX treatment duration was 39 days. Per DRC assessment, 16 (80%) and 4 (20%) participants had probable IMD and proven IMD, respectively, at baseline (Table 1). Among 21 participants (ITT population), hematological malignancies were most common including AML, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) (n = 20 [95.2%]).

Table 1.

Baseline and Demographic Characteristics (mITT Population)

Baseline Characteristics	FMGX Cohort N = 20
Age (y), mean (standard deviation)	61.9 (11.8)
Gender, n (%)
Male	18 (90)
Female	2 (10)
Race, n (%)
White	19 (95)
Other	1 (5)
Severity of disease assessed by Karnofsky, n (%)
≤30	1 (5)
>30	19 (95)
Diagnosis of IMD per DRC, n (%)
Probable	16 (80)
Proven	4 (20)
Site of IMD, n (%)
Othera	3 (15)
Pulmonary	16 (80)
Sinuses	1 (5)
Fungal pathogen isolates tested by JMI Labs, n b	7
Aspergillus fumigatus	2
Aspergillus flavus	1
Fusarium solani	1
Lomentospora prolificans	1
Mucor circinelloides	1
Candida albicans	1
Total duration of FMGX treatment, median (range)	39 (4, 43)

Abbreviations: DRC, Data Review Committee; FMGX, fosmanogepix; IMD, invasive mold disease; mITT, modified intent-to-treat; yrs, years.

^aOther sites included finger (cutaneous), leg (cutaneous), and positive blood culture of Lomentospora prolificans.

^bA total of 7 isolates (from 6 participants) were tested by a reference microbiology laboratory (Jones Microbiology Institute [JMI] Labs). Low MGX minimum effective concentrations (MEC_range: 0.008–0.03 μg/mL) were observed for all molds except Mucor circinelloides (4 μg/mL).

Efficacy (mITT Population)

Primary and Key Secondary Endpoint

All-cause mortality through Day 42 (primary efficacy endpoint) was 25% (80% CI: 12.7%, 41.5%), which is <45% predefined mortality rate (Table 2). DRC-assessed treatment success (secondary efficacy endpoint) was 40% (80% CI: 24.9%, 56.7%) with CR and PR achieved in 4 (20%) participants each. SD was reported in 2 (10%) participants (Table 2). Investigator-assessed treatment success was 45% (80% CI: 31.0%, 64.2%) with CR achieved in 4 (20%) and PR in 5 (25%) participants (Supplementary Table 3).

Table 2.

Efficacy Endpoints (mITT Population)

Efficacy Endpoints	FMGX Cohort N = 20
Primary: Day 42 All-Cause Mortality, n (%); 80% CI	5 (25); 12.7–41.5
Secondary: DRC assessed global response at EOST/ET
Treatment success, n (%); 80% CI	8 (40); 24.9–56.7
Complete response, n (%)	4 (20)
Partial response, n (%)	4 (20)
Stable disease, n (%)	2 (10%)
Treatment failure, n (%)	10 (50)
Progression of disease, n (%)	6 (30)
Death, n (%)	4 (20)
Other: DRC assessed clinical, radiological, and mycologicala assessments at EOST/ET
Clinical response
Clinical success, n (%)	10 (50)
Complete response, n (%)	8 (40)
Partial response, n (%)	2 (10)
Stable disease, n (%)	3 (15)
Radiological response
Radiological success, n (%)	10 (50)
Complete response, n (%)	4 (20)
Partial response, n (%)	6 (30)
Stable disease, n (%)	2 (10)
Mycological response, n (%)	8 (40)
Eradication, n (%)	1 (5)
Presumed eradication, n (%)	7 (35)
Exploratory: Day 84 all-cause mortality, n (%); 80% CI	8 (40); 24.9–56.7

Abbreviations: CI, confidence interval; DRC, Data Review Committee; EOST, end of study treatment; ET, early termination; FMGX, fosmanogepix; mITT, modified intent-to-treat.

^aMycological response was defined as eradication and presumed eradication.

Other Efficacy Endpoints

Clinical, radiological, and mycological success rates were 50%, 50%, and 40%, respectively, per DRC assessment (Table 2) and 55%, 50%, and 45%, respectively, per investigator assessment (Supplementary Table 3).

PK (PK Population) and Safety (ITT Population)

Other Secondary Endpoint: Population Modelling Based PK

MGX PK parameters were predicted from empirical Bayes estimates. Geometric mean MGX C_max, C_min, and AUC_0-24 on Day 1 (following FMGX IV 1000 mg BID) versus Day 14 (following FMGX IV 1000 mg BID [Day 1] and 600 mg QD [Days 2-14]) were: 9.13 versus 9.57 µg/mL, 4.35 versus 5.53 µg/mL, and 116 versus 161 µg·hr/mL, respectively. Mean T_max was 3 hours on both Days 1 and 14. For participants who switched to 800 mg oral FMGX (Days 4–14), geometric mean MGX C_max, C_min, and AUC_0-24 on Day 14 were 10.5 µg/mL, 6.66 µg/mL, and 189 µg·hr/mL. Mean T_max was 4.37 hours (Supplementary Table 4).

Other Secondary Endpoint: Safety

All 21 participants experienced ≥1 treatment-emergent adverse event (TEAE), with a total of 258 all-causality TEAEs reported. Thirteen (61.9%) experienced serious AEs (SAEs), 6 (28.6%) experienced Grade 5 TEAEs and 11 (52.4%) experienced Grade 3 or 4 TEAEs. Seven (33.3%) participants discontinued FMGX treatment due to AEs (most common: nausea [n = 4] and decreased appetite [n = 2]) (Tables 3 and 4).

Table 3.

Summary of Overall Safety (ITT Population)

Safety Parameters	FMGX Cohort N = 21
Overall safety summary, n (%)
Number of TEAEs	258
Participants with TEAEs	21 (100)
Serious TEAEs	13 (61.9)
Grade 3 or 4 TEAEs	11 (52.4)
Grade 5 TEAEs	6 (28.6)
Discontinuations from study due to TEAEs	0
Discontinuation of FMGX due to TEAEsa	7 (33.3)
Total deaths	9 (42.9)
Through EOSTb	4
EOST through follow-up visit	2
Post follow-up visitc	3

Abbreviations: AE, adverse event; DSMB, Data and Safety Monitoring Board; FMGX, fosmanogepix; ITT, intent-to-treat; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SOC, system organ cass; TEAEs, treatment emergent adverse events.

^aParticipants with an AE record indicating that action taken was study drug (FMGX) withdrawn but the AE did not cause participant discontinuation from the study.

^bOne death assessed as possibly related and unrelated to FMGX by the investigator and DSMB, respectively.

^cSurvival status post follow-up visit was assessed by telephone and causes of death were not recorded for the 3 deaths that occurred after the follow-up visit AEs were coded using MedDRA v25.1.

Table 4.

Summary of Serious TEAEs by SOC and PT (ITT Population)

Serious TEAEs by SOC and PT, n (%)	FMGX Cohort N = 21
Participants with serious TEAEs	13 (61.9)a
Infections and infestations	7 (33.3)
Sepsis	2 (9.5)
Catheter site infection	1 (4.8)
Device related sepsis	1 (4.8)
Endocarditis	1 (4.8)
Fungal infection	1 (4.8)
Pneumonia	1 (4.8)
Septic shock	1 (4.8)
Stenotrophomonas bacteraemia	1 (4.8)
Blood and lymphatic system disorders	3 (14.3)
Febrile neutropenia	3 (14.3)
Thrombocytopenia	1 (4.8)
Cardiac disorders	3 (14.3)
Cardiac arrest	2 (9.5)
Ventricular tachycardia	1 (4.8)
Gastrointestinal disorders	2 (9.5)
Diarrhea	2 (9.5)
Abdominal pain	1 (4.8)
Vomiting	1 (4.8)
Renal and urinary disorders	2 (9.5)
Acute kidney injury	1 (4.8)
Renal impairment	1 (4.8)
Respiratory, thoracic, and mediastinal disorders	2 (9.5)
Respiratory failure	2 (9.5)
General disorders and administration site conditions	1 (4.8)
Sudden death	1 (4.8)
Metabolism and nutrition disorders	1 (4.8)
Decreased appetite	1 (4.8)
Musculoskeletal and connective tissue disorders	1 (4.8)
Back pain	1 (4.8)
Nervous system disorders	1 (4.8)
Peripheral neuropathy	1 (4.8)
Vascular disorders	1 (4.8)
Hypotension	1 (4.8)

Abbreviations: AE, adverse event; DSMB, Data and Safety Monitoring Board; FMGX, fosmanogepix; ITT, intent-to-treat; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SOC, system organ class; TEAEs, treatment emergent adverse events.

^aParticipants were only counted once per treatment per event; totals for the number of participants at a higher level are not necessarily the sum of those at the lower levels since a participant may report 2 or more different adverse events within the higher-level category. AEs were coded using MedDRA v25.1.

Of 21 participants, 15 (71.4%) experienced 36 FMGX-related TEAEs. Of these 15, 2 (9.5%) participants experienced 3 FMGX-related SAEs, 1 (4.8%) experienced a Grade 5 TEAE and 3 (14.3%) experienced Grade 3 or 4 FMGX-related TEAEs. Three (14.3%) participants discontinued FMGX-treatment due to FMGX-related AEs (nausea, vomiting, and decreased appetite).

Of the 2 participants who experienced FMGX-related SAEs, 1 experienced diarrhea and decreased appetite and another experienced unwitnessed sudden death on Day 14, assessed as possibly related to FMGX by the investigator. Autopsy (excluding brain) indicated diffuse alveolar damage, invasive pulmonary aspergillosis with recent pulmonary hemorrhage, no myocardial fungal involvement, no signs of acute myocardial infarction, nor significant coronary disease. Preclinical or clinical cardiopulmonary toxicity signals were absent. Since brain examination was not performed, an alternative cause due to an acute central nervous system (CNS) event (eg, acute stroke, CNS bleed) unrelated to FMGX could not be ruled out. The DSMB concluded that FMGX-related cardiac AEs were unlikely to occur and found no evidence that this death was related to FMGX-treatment.

Total 9 deaths were reported in the study (Table 3). FMGX-related and overall TEAEs are summarized in Supplementary Tables 5 and 6, respectively.

To improve FMGX tolerability, QD dosing was split and administered BID in 6 of 21 participants (1 IV and 5 oral). Modifications were made per investigator's decision, largely due to GI AEs in 5 participants (nausea and vomiting [n = 2]; nausea, diarrhea, and vomiting [n = 1 each]). In 3 of these 5 participants, dose modifications alleviated/resolved ≥1 AEs. For 1 participant, modifications were based on the participant's decision (no AE recorded). No clinically significant abnormalities were observed in hematology, chemistry, ECG, vital signs, physical and neurological examinations, or other laboratory parameters.

Exploratory Endpoints

All-cause mortality through Day 84 was 40% (80% CI: 24.9%, 56.7%) (Table 2). No clear trends were observed in galactomannan or 1,3-β-D-Glucan levels.

DISCUSSION

IMDs, including infections by Aspergillus spp. and rare molds, occur frequently in patients with underlying hematological malignancies [27]. Treatment options remain limited due to poor tolerance and exposure infection sites, intrinsic resistance [2, 5, 6, 8], and increasing resistance to mold active-azoles, a first-line treatment against various IMDs [27], emphasizing the need for new antifungals. Current Phase 2, open-label, single arm study evaluated FMGX efficacy and safety for the treatment of IMDs caused by Aspergillus spp. and rare molds in adults with limited treatment options.

All-cause mortality at Day 42 (primary efficacy endpoint) was 25.0%. This study used a 1-sided exact binomial test (alpha = .1 level) to test the hypothesis that mortality rate at Day 42 < 45% (provided upper limit of CI <45%; based on historical AMB control data) [26]. The upper bound of 80% CI (12.7%, 41.5%) was below the pre-specified 45% target, indicating that FMGX all-cause mortality was lower than the mortality rate historically associated with AMB [28]. This is important because participants in the current study were severely ill versus historical controls. Considering that treatment with azoles was not an option in the current population with limited treatment options, AMB is a relevant comparator.

In a case-control analysis, patients with proven/probable mucormycosis receiving primary isavuconazole treatment (n = 21) were compared with controls receiving primary AMB treatment (n = 33). Day 42 all-cause mortality was 33% in isavuconazole cases versus 39% in AMB-matched controls [29]. In another study assessing mortality due to voriconazole-resistant A. fumigatus in patients with hematological malignancies, Day 42 all-cause mortality was 42.3% (11/26 cases) in the voriconazole-resistant group versus 28.2% in the voriconazole-susceptible group (29/103 cases) [30]. Day 42 all-cause mortality in the current study was 25%.

DRC-assessed treatment success was 40% (secondary efficacy endpoint; CR and PR in 20% participants each) and 10% of participants had SD. Although SD was categorized as treatment failure (per prespecified criteria) [25], absence of PD in high-risk patients with limited treatment options may represent evidence of efficacy in clinical practice [31]. Clinical, radiological, and mycological responses were 50%, 50%, and 40%, respectively. Investigator- and DRC-assessed responses were generally consistent.

Consistent with previous evaluations [10, 19], most frequently reported FMGX-related TEAEs were GI-related (nausea [52.4%], vomiting [33.3%], and diarrhea [23.8%]). Treatment discontinuations in participants with FMGX-related TEAEs were due to GI AEs (nausea, vomiting, and decreased appetite), none of which were severe. GI-related AEs were also most commonly reported in SECURE [2] and VITAL [29] trials of isavuconazole for IMD treatment. Dose modifications (800 mg QD to 400 mg BID) due to FMGX-related GI AEs were reported in 5 participants, of which BID dosing resulted in improvement/resolution of ≥1 of these AEs in 3 participants. Assuming linear FMGX PK, similar exposures for 400 mg BID and 800 mg QD are expected as AUC_0-24 with and without oral switch to 800 mg (Day 14) were similar ie, 189 and 161 µg·hr/mL, respectively, despite a severely ill population being treated.

Of 9 total deaths, 3 occurred post follow-up (cause of death not recorded). For 6 deaths occurring through follow-up, 5 were considered FMGX-unrelated by the investigator. This mortality rate is expected in the severely ill population enrolled with nearly all patients having underlying malignancies and life-threatening IMD. One unwitnessed sudden death was considered possibly FMGX-related by the investigator; however, DSMB determined it as unrelated to FMGX-treatment.

In conclusion, this open-label, non-comparative, prospective study describes the first clinical use of FMGX for treatment of invasive pulmonary aspergillosis and other IMDs caused by rare molds. FMGX mortality rate was lower versus historical controls, with an acceptable safety profile in high-risk patients. This study was mainly limited by the small number of participants (n = 20) and single-arm design. Other limitations associated with clinical trials for rare fungal diseases include heterogenicity of underlying disease and causative pathogens, no existing SOC treatment for many IMDs [31]. Results of this study in patients with limited treatment options are clinically relevant and support continued FMGX development for treating IMDs caused by Aspergillus and hard-to-treat rare molds.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. M. R. H. contributed to the conception or design; the acquisition, analysis, or interpretation of data; writing and reviewing. M. T. contributed to the conduct of the study and interpretation of data; writing and reviewing. O. A. C. contributed to writing and reviewing. G. R. T. III contributed to writing and reviewing. M. A. S. contributed to writing and reviewing. J. A. M. was the principal investigator at UZ Leuven—Pharmacy, Belgium; contributed to writing and reviewing. S. S. D. was the principal investigator at City of Hope National Medical Center, USA; contributed to writing and reviewing. G. R. was the principal investigator at Sheba Medical Center, Israel; contributed to writing and reviewing. S. H. contributed to the conduct of the study; writing and reviewing. M. A. contributed to the statistical analysis; the acquisition, analysis, or interpretation of data; writing and reviewing. A. J. contributed to the pharmacokinetic analysis; interpretation of data; writing and reviewing. R. P. contributed to interpretation of data; writing and reviewing. All authors approved the final version.

Acknowledgments. The authors thank all investigators, staff, and patients for participating in study-related activities and procedures. The authors acknowledge Kanchan Bhati (M. Pharm) and Kripa Madnani (PhD, CMPP™), both employees of Pfizer Inc, for providing medical writing assistance under the guidance of the authors.

Data availability. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Financial support. The study was funded by Amplyx Pharmaceuticals, Inc, an affiliate of Pfizer Inc. Pfizer provided medical writing support. In 2023, Basilea Pharmaceutica International Ltd, Allschwil acquired the rights to fosmanogepix.