FORWARD-IM

To evaluate the efficacy of fosmanogepix for the treatment of adult patients with IMIs caused by Aspergillus spp. (in patients with LTO), Fusarium spp., Scedosporium spp., Lomentospora prolificans, Mucorales fungi, or other multi-drug resistant molds based on Day 42 all-cause mortality.

• To evaluate the efficacy of fosmanogepix for the treatment of adult patients with IMIs caused by Aspergillus spp. (in patients with LTO), Fusarium spp., Scedosporium spp., Lomentospora prolificans, Mucorales fungi, or other multi-drug resistant molds.
• To evaluate the safety and tolerability of IV and oral fosmanogepix.
• To evaluate the PK of fosmanogepix (prodrug) and manogepix (active moiety).

1. Patients aged ≥18 years (or the minimum country-specific age of consent if >18) at
   Screening who have provided/ their legally authorized representative has provided the signed informed consent indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate in the study. If the patient is unable to consent for himself/herself, a legally authorized representative must provide informed consent on their behalf.
2. Patients with a diagnosis of proven or probable IMI defined in accordance with the Revision and Update of the Consensus Definitions of IFD from the EORTC/MSGERC as adapted for this study (Appendix 11) will enroll into one of two cohorts:
   • Cohort A: patients with proven or probable IMI who require primary treatment. This cohort will enroll patients who have received no more than 96 hours (within the last 7 days prior to randomization) of potantially effective therapy for the current IMI (see Table 5 for ptentially effective therapy by subcohort)
     Patients will be enrolled in four distinctive cohorts of fungal pathogen groups:
     • Aspergillus spp. (with limited treatment options as defined by the criteria below)
     • Fusarium spp.
     • Lomentospora prolificans
     • Mucorales fungi
   • Patients with infection due to Aspergillus species may be enrolled if they havelimited treatment options, defined as the inability to utilize a triazole for first-line treatment, due to one or more of the following criteria:
     • a.  Resistance of the isolates to triazoles, based on
       • i. In vitro susceptibility testing using EUCAST methodology with azole resistance defined as resistance against isavuconazole, posaconazole orvoriconazole using the following MIC criteria (Guinea 2020)
         • Isavuconazole: MIC > 2 mg/L for A. fumigatus, A. terreus and A. flavus and MIC > 0.25 mg/L for A. nidulans
         • Posaconazole: MIC > 0.25 mg/L for A. fumigatus and A. terreus
         • Voriconazole: MIC > 1 mg/L for A. fumigatus, and A. nidulans
       • ii. Azole resistance based on molecular identification of resistance mutations in the Cyp51A gene including TR34/L98H, TR46/Y121F/T289A or single point mutations (e.g. G54R/W, P216S, G448S, G432S, M220K/I/R, Y121F, F219S or TR120/F46Y/M172V/E427K)
     • b. Development of breakthrough invasive aspergillosis while on prophylaxis with systemic isavuconazole, itraconazole, posaconazole or voriconazole for at least 7 days
     • c. Documented previous history of azole intolerance to voriconazole, posaconazole and isavuconazole
     • d. Inability to manage drug-drug interactions due to CYP450 3A4 inhibition by systemic isavuconazole, itraconazole, posaconazole or voriconazole:
       • i. Presence or history of clinical side effects due to drug-drug interactions presumed to be caused by azole-mediated CYP450 3A4/5 inhibition
       • ii. Presence or history of fluctuating blood drug levels of concomitant
         medications (e.g. sirolimus, tacrolimus) presumed to be caused by to azolemediated CYP450 3A4/5 inhibition
       • iii. Requirement of concomitant administration of a sensitive substrate to CYP450 3A4/5 (FDA 2024) that exhibit a narrow therapeutic window, if this drug has led to drug-drug interactions presumed to be caused by azolemediated CYP450 3A4/5 inhibition or if there is no prior experience of coadministration with isavuconazole, itraconazole, posaconazole or voriconazole.
         Sensitive substrates of CYP 450 3A4 with a narrow thrapeutic window include the following drugs:
         • Alfentanil
         • Cyclosporine
         • Everolimus
         • Ibrutinib
         • Lomitapide
         • Sirolimus
         • Tacrolimus
         • Venetoclax
           Inclusion of patients with other sensitive substrates of CYP450 A4/5 may be possible after discussion with and if approved by the Medical Monitor. Co-administration of drugs that are metabolized by CYP450 A4/5 should be approached with caution and the need for increased frequency of therapeutic drug monitoring (where applicable) considered, as per institutional practice at the study site.
       • If diagnosis of proven or probable IMI is not achieved initially, patients with possible IMI at time of randomization may be enrolled but must be willing or be in process of an ongoing diagnostic work up which is anticipated to result in a mycological diagnosis of proven or probable IMI (additional mycological samples collected within the 7 days after the first administration of study treatment). This post-randomization fungal species identification may lead to an update in the fungal pathogen group (different than the one used at patient enrollment). If proven or probable IMI is not confirmed, patients with possible IMI may continue in the study but will not be considered for the analysis of the primary study objective and will be analyzed separately.
   • Cohort B: patients who require salvage therapy. This cohort will enroll patients with IMIs caused by Aspergillus spp., Fusarium spp., Lomentospora prolificans, Mucorales fungi, or other multi-drug-resistant molds including Scedosporium spp. who have received treatment with a standard-of-care antifungal therapy for up to 30 days and developed intolerance (including inability to manage drug-drug interactions), toxicity, lack of clinical response (after at least 8 days of standard-of-care antifungal therapy, see Section 6.1.2 for details), and/or have a fungal isolate resistant to standard-of-care antifungal therapy.
3. Patient’s condition allows for appropriate infection source control measures, including:
   •  a. Removal of pre-existing catheters and devices that are considered a potential source of the IMI.
   • b. Surgical debridement, e.g., for IMIs affecting the sinus or for invasive mold soft tissue or bone and joint infections.

1.      Refractory hematologic malignancy with no potential to respond to additional chemotherapy, or uncontrolled malignancy not responding to current treatment.

2.      Chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis.

3.      Patients on mechanical ventilation at Screening.

4.      Invasive fungal disease caused by more than one fungal pathogen are not permitted in Cohort A but are permitted in Cohort B.

5.      Patients with a Karnofsky Performance Status < 30 at Screening.

6.      Requirement, or anticipated requirement, for dialysis.

7.      Patients with known human immunodeficiency virus infection who have CD4+ count < 200 mm3 and/or viral load > 400 copies/mL, or who have had an active opportunistic infection within 6 months prior to Screening.

8.      Ongoing medical history of neurological disorders (unless related to the IMI)

9.      Patients receiving palliative care only.

10.  Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the Investigator’s judgment, make the patient inappropriate for the study or interfere with the ability to conduct study assessments.

11.  Current use of any prohibited concomitant medication(s) or those unwilling/unable to use a permitted concomitant medication(s).

12.  Treatment with any investigational drug in any clinical trial within the 30 days prior to the first administration of study drug, except for treatment strategy trials with approved compounds, prospective registries or diagnostic/biomarker studies. Note: local regulations or other factors may require more than 30 days. An investigational drug is defined as a drug which is not approved in any indication in any country.

13.  Prior enrollment in this or any previous study of fosmanogepix.

14.  Moderate or severe hepatic impairment, active viral hepatitis B or C, ALT or AST ≥ 5 × ULN or total bilirubin > 3 × ULN unless this is due to isolated hyperbilirubinemia or documented Gilbert`s syndrome.

15.  Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the Investigator, and Sponsor delegate employees directly involved in the conduct of the study and their family members.

16.  Patient who is pregnant or lactating.

17.  Known hypersensitivity to fosmanogepix, manogepix, or any of the excipients.

Cohort A: primary antifungal treatment for IMI. Patients who have received ≤ 96 hours of prior mold-active antifungal treatment for the current episode of the IMI within the 7 days prior to randomization will be randomized in a 2:1 ratio to fosmanogepix (IV with optional oral switch) or comparators based on the confirmed or suspected fungal pathogen group, stratified by site and presence or absence of hematologic malignancy at baseline.

In Cohort A, approximately 180 patients will be enrolled in one of five mutually exclusive subcohorts based on the mold causative for the invasive infection:

• Subcohort 1: invasive aspergillosis with limited treatment options (n~48 patients in total, in order to achieve 30 randomized to fosmanogepix and 15 to comparator in the mITT population)
• Subcohort 2: invasive fusariosis (n~33 patients in total, to achieve 20 randomized to fosmanogepix and 10 to comparator in the mITT population) 
• Subcohort 3: invasive lomentosporiosis (n~33 patients in total, to achieve 20 randomized to fosmanogepix and 10 to comparator in the mITT population)
• Subcohort 4: invasive mucormycosis (n~33 patients in total, to achieve 20 randomized to fosmanogepix and 10 to comparator in the mITT population)
• Subcohort 5: invasive scedosporiosis (n~33 patients in total, to achieve 20 randomized to fosmanogepix and 10 to comparator in the mITT population)

As the primary endpoint analysis will be assessed in the modified Intent-to-Treat (mITT) population of patients with proven or probable IMI in accordance with the Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the EORTC/MSGERC (Donnelly 2020), and because the mITT population will be dependent on the assessment by the independent Adjudication Committee (AC), the analysis population status of a patient will not be immediately available. Therefore, subcohorts may require over-enrollment by approximately 10 to 20% to ensure the required number of patients in the mITT population are available for each subcohort.

Individual subcohorts may also be closed prematurely, e.g., due to slow patient accrual of patients with proven or probable IMI in these rare mold categories.

In the fosmanogepix group, patients who require switching to an alternative therapy, for lack of efficacy, toxicity, or concerns related to drug-drug interactions should be considered treatment failures, should have their end of study treatment (EOST) visit, and may be switched to BAT as determined by the Investigator. These patients should be followed until Day 84 or Day 180 (depending on the required treatment duration).

In the BAT group, the investigator must define a treatment strategy prior to randomization. This treatment strategy may involve initial combination therapy with a subsequent switch to monotherapy or initial intravenous therapy (e.g. with amphotericin B) with subsequent oral maintenance therapy (e.g. with an azole).

In the BAT group, patients who require treatment escalation (including dosage increases >50%, unless guided by therapeutic drug monitoring) or switching to an alternative treatment strategy (including switching from monotherapy to combination therapy), for lack of efficacy, toxicity or concerns related to drug-drug interactions should be considered treatment failures, should have their EOST visit, and may be switched to an alternative BAT strategy or may switch to fosmanogepix treatment, as determined by the study Investigator. These patients should be followed until Day 84 or Day 180 (depending on the required treatment duration).

Patients in the BAT group who change in the context of treatment de-escalation should not be considered as treatment failures. Patients randomized with possible invasive fungal disease (IFD) whose treatment strategy is changed based on post-randomization fungal species identification may also change their treatment strategy without being considered a failure.

Cohort B: Salvage treatment in patients (n~40) who have received initial treatment with standard-of-care antifungal therapy for up to 30 days and developed intolerance (including inability to manage drug-drug interactions), toxicity, lack of clinical response (after at least 8 days of potential effective antifungal treatment, see Section 6.1.2 for details), and/or have a fungal isolate resistant to standard-of-care antifungal therapy. All patients enrolled in Cohort B will receive fosmanogepix.

The target duration of study treatment in this study is 84 days (12 weeks), which can be extended up to 180 days. There will be a Follow-up (FU) period of 6 weeks after EOST. The total duration of participation in the study is approximately up to a maximum of 8 months (inclusive of the screening period).

Patients who are responding to fosmanogepix and require antifungal treatment for longer than 180 days but have no adequate alternative treatment options may be considered for a post-study/expanded access program.

The major assessment time points will be at Day 42 (survival) and EOST (Overall Response). Other assessment time points will include Day 84.