Phase 3 Study on the Efficacy and Safety of Fosmanogepix in Adult Patients with Invasive Mold Infections by Aspergillus, Fusarium, and Multidrug-Resistant Molds

The primary objective of this study is to evaluate the **efficacy** of fosmanogepix in treating adult patients with **invasive mold infections** (IMIs) caused by Aspergillus spp., Fusarium spp., Lomentospora prolificans, Mucorales fungi, or other multidrug-resistant molds. This is clinically relevant as these infections often occur in patients with limited treatment options, and effective management is crucial for improving patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of fosmanogepix specifically for patients with IMIs caused by the aforementioned pathogens, particularly in those with limited treatment options.
• Assessing the **safety** and **tolerability** of both intravenous (IV) and oral formulations of fosmanogepix.
• Evaluating the **pharmacokinetics** (PK) of fosmanogepix as a prodrug and its active moiety, manogepix.

The clinical trial involves a total of **116 participants** diagnosed with **invasive mold infections** (IMIs) caused by Aspergillus spp., Fusarium spp., Lomentospora prolificans, Mucorales fungi, or other multidrug-resistant molds. The study population includes both male and female adults, with an age range that encompasses young adults to older adults. Participants were selected based on a diagnosis of proven or probable IMI, as defined by the adapted criteria from the EORTC/MSGERC, and their condition must allow for appropriate infection source control measures. The trial includes a vulnerable population, indicating that special considerations are in place for their participation. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection process ensures that participants have limited treatment options, highlighting the need for evaluating the efficacy of fosmanogepix in this specific patient group.

The clinical trial is designed to evaluate the **efficacy** and safety of **fosmanogepix** in adult patients with invasive mold infections caused by Aspergillus spp., Fusarium spp., Lomentospora prolificans, Mucorales fungi, or other multidrug-resistant molds. This is a Phase 3, open-label, two-cohort study. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is approximately 8 months, with the recruitment phase expected to start on September 6, 2025, and the trial concluding by February 1, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the diagnosis of proven or probable invasive mold infections. The primary endpoint is the all-cause mortality rate at Day 42, with secondary endpoints including treatment success rates and incidence of adverse events. Follow-up visits are scheduled at Day 42, Day 84, and at the end of study treatment (EOST) to assess clinical, mycological, and radiological responses. The end-of-study visit will occur approximately 6 weeks after EOST to monitor long-term outcomes and adverse events.

The expected length of participant involvement is up to 8 months, including the follow-up period. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation for the safety of the participant. The trial will utilize both intravenous and oral administration of the investigational product, with plasma concentration assessments conducted at specified intervals to evaluate pharmacokinetics.

**Fosmanogepix** is an experimental antifungal medication being evaluated in this clinical trial. It is available in two pharmaceutical forms: a **solution for infusion** and a **tablet**. The solution for infusion is administered via **intravenous use**, while the tablet is taken **orally**. The maximum treatment period for both forms is 180 days for the solution and 177 days for the tablet. The dosage for the solution and tablet forms is measured in **milligrams**; however, specific dosing information is not provided. Fosmanogepix is classified as a chemical antifungal and is designated as an orphan drug for this study.

**Voriconazole** is used as a comparator treatment in this study. It is administered as a **PHF00230MIG** form via **intravenous administration**. The maximum daily dose is 12 mg/kg, with a total maximum dose of 1444 mg/kg over a treatment period of 180 days. Voriconazole is a chemical antifungal agent.

**Anidulafungin** is another comparator antifungal agent in the trial, administered in a **PHF00230MIG** form through **intravenous administration**. The maximum daily dose is 200 mg, with a total maximum dose of 18.1 g over 180 days. Anidulafungin is also a chemical antifungal.

**Amphotericin B** is included as a comparator treatment, provided in a **PHF00170MIG** form for **intravenous administration**. The maximum daily dose is 5 mg/kg, with a total maximum dose of 900 mg/kg over the 180-day treatment period. Amphotericin B is a chemical antifungal agent.

**Micafungin** is administered as a comparator in a **PHF00230MIG** form via **intravenous administration**. The maximum daily dose is 150 mg, with a total maximum dose of 27 g over 180 days. Micafungin is a chemical antifungal.

**Caspofungin Acetate** is used as a comparator treatment, administered in a **PHF00230MIG** form through **intravenous administration**. The maximum daily dose is 70 mg, with a total maximum dose of 9.02 g over 180 days. Caspofungin Acetate is a chemical antifungal.

**Isavuconazole** is included as a comparator, provided in a **PHF00006MIG** form for **intravenous administration**. The maximum daily dose is 600 mg, with a total maximum dose of 36.8 g over the 180-day treatment period. Isavuconazole is an antifungal agent.

**Posaconazole** is administered as a comparator in a **PHF00094MIG** form via **intravenous administration**. The maximum daily dose is 600 mg, with a total maximum dose of 54.3 g over 180 days. Posaconazole is a chemical antifungal.

**Terbinafine Hydrochloride** is used as a comparator treatment, administered in a **PHF00245MIG** form through **oral administration**. The maximum daily dose is 250 mg, with a total maximum dose of 45 g over 180 days. Terbinafine Hydrochloride is a chemical antifungal.

**Rezafungin Acetate** is included as a comparator, provided in an unspecified form for **intravenous administration**. The maximum daily dose is 400 mg, with a total maximum dose of 5.4 g over the 180-day treatment period. Rezafungin Acetate is an antifungal agent.

The efficacy of **fosmanogepix** in treating invasive mold infections will be assessed through a series of primary and secondary endpoints. The primary endpoint is the all-cause mortality rate at Day 42. Secondary endpoints include the proportion of patients achieving overall treatment success, clinical response, mycological response, and radiological response at Day 42, Day 84, and the End of Study Treatment (EOST). Additionally, the all-cause mortality rate at Day 84 will be evaluated.

Further assessments will include the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), treatment-related adverse events, adverse events of special interest, and adverse events leading to discontinuation. Clinically significant laboratory abnormalities, abnormal neurological examination findings, and 12-lead electrocardiogram (ECG) assessments will also be monitored up to six weeks after EOST.

Pharmacokinetic parameters will be evaluated by measuring plasma concentrations of **fosmanogepix** and its active moiety, manogepix, following both intravenous and oral administration. For intravenous administration, plasma samples will be collected pre-dose and at 3, 6, and 9 hours post-start of the 3-hour infusion on Day 3, and at 24 hours prior to Day 4 dosing. For oral administration, plasma samples will be collected on Days 7, 14, 28, and 42, with additional post-dose samples at 72 hours (±1 day) and 192 hours (±2 days) after the last dose.