An interventional efficacy and safety Phase 3 double-blind 2-arm study to investigate IV followed by oral fosmanogepix compared with IV caspofungin followed by oral fluconazole in adult participants with candidemia and/or invasive candidiasis.

The primary objective of this study is to evaluate the **efficacy** of intravenous (IV) followed by oral administration of fosmanogepix in the treatment of adult patients with **candidemia** and/or **invasive candidiasis**. This is compared to a standard-of-care regimen involving IV caspofungin followed by oral fluconazole. The clinical relevance of this objective lies in determining whether fosmanogepix can provide a more effective treatment option for these serious fungal infections, potentially improving patient outcomes and offering an alternative to existing therapies.

Secondary objectives include:

• Evaluating the efficacy of fosmanogepix compared to caspofungin/fluconazole based on independent assessment of overall response, clinical and mycological response at different timepoints.
• Assessing the time to first negative blood culture for patients with baseline candidemia.
• Evaluating the safety and tolerability of IV followed by oral fosmanogepix in the treatment of adult patients with candidemia and/or invasive candidiasis, compared to a standard of care regimen of IV caspofungin followed by oral fluconazole.
• Examining the pharmacokinetics (PK) of fosmanogepix (prodrug) and manogepix (active moiety).

The clinical trial involves a total of **317 participants** diagnosed with **candidemia** and/or **invasive candidiasis**. The study population includes both male and female subjects aged 18 years and older, with the age range extending to include older adults. Participants were selected based on their diagnosis within 96 hours prior to randomization, confirmed by culture, Gram stain, or a rapid diagnostic test, and presenting clinical criteria such as fever, hypothermia, hypotension, tachypnea, tachycardia, or local signs of infection. The trial population includes a vulnerable group, indicating that special considerations are in place for their participation. Participants' general health status allows for necessary infection source control measures, such as the removal of pre-existing intravascular catheters and devices. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of intravenous (IV) followed by oral **fosmanogepix** compared to a standard-of-care regimen of IV **caspofungin** followed by oral **fluconazole** in adult participants with **candidemia** and/or **invasive candidiasis**. The trial is structured into two arms, with participants randomly assigned to receive either the investigational treatment or the comparator regimen. The study is expected to commence recruitment on November 7, 2024, and conclude by January 22, 2028, with an estimated duration of participant involvement of up to 42 days, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age and diagnosis of candidemia or invasive candidiasis within 96 hours prior to randomization. Following randomization, participants will receive either the investigational or comparator treatment, with follow-up visits scheduled to monitor treatment response and safety. The primary endpoint is the proportion of patients with an overall response of treatment success at the end of study treatment (EOST), as determined by an independent Adjudication Committee. Secondary endpoints include the time to first negative blood culture and the incidence of treatment-emergent adverse events.

The study includes several follow-up visits, with assessments conducted at day 14, end of IV treatment, EOST, and six weeks post-EOST to evaluate clinical and mycological responses. Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the efficacy and safety of fosmanogepix in comparison to the established treatment regimen, contributing valuable insights into the management of candidemia and invasive candidiasis.

**Fosmanogepix** is an experimental medication used in this clinical trial, available in two pharmaceutical forms: **solution for infusion** and **tablet**. The active substance, **fosmanogepix**, is a chemical compound with the sponsor product code BAL2243. The intravenous form is administered via **intravenous use**, while the tablet form is administered **orally**. The maximum treatment period for the intravenous form is 42 days, and for the tablet form, it is 36 days. Both forms are designated as orphan drugs, indicating their use in treating rare conditions. The dosing schedule and participant compliance are monitored throughout the trial.

**Caspofungin** is used as a comparator treatment in this study. It is provided as a **powder for concentrate for solution for infusion** and is administered via **intravenous use**. The maximum daily dose is 70 mg, with a total maximum dose of 2940 mg over a treatment period of 42 days. Caspofungin is a chemical antifungal agent, and its administration is closely monitored to ensure participant compliance.

**Fluconazole** is another comparator treatment, available in the form of **hard capsules** for **oral use**. The active substance, **fluconazole**, is a chemical antifungal agent. The maximum daily dose is 800 mg, with a total maximum dose of 14800 mg over a 36-day treatment period. The formulation and manufacturing process of the capsules are identical to the commercial Diflucan® 200 mg capsule, except for the unprinted capsule shells. Participant compliance with the dosing schedule is monitored throughout the study.

**Sodium Chloride** is used as a placebo in this trial, provided as a **solution for infusion**. It is administered as a **solution for injection**, with a maximum daily dose of 250 ml and a total maximum dose of 10500 ml over a 42-day treatment period. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased results.

Additional placebos are used for the oral administration of **fosmanogepix** and **fluconazole**. These placebos are designed to match the appearance and administration route of the active medications, ensuring the study remains double-blind. The placebos do not contain any active substances and are used to assess the efficacy and safety of the experimental treatments compared to standard-of-care therapy.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients with an overall response of treatment success at the end of study treatment (EOST), as determined by an independent Adjudication Committee (AC). This endpoint is aligned with the FDA's secondary endpoint criteria.

Secondary endpoints include several measures: the proportion of patients with an overall response of treatment at Day 14, at the end of intravenous treatment (EOIV), and at follow-up (FU) 6 weeks after EOST. Additionally, clinical response success will be evaluated at these same timepoints. Mycological response, defined as eradication or presumed eradication, will also be assessed at Day 14, EOIV, EOST, and FU 6 weeks after EOST. The time to first negative blood culture in patients treated with fosmanogepix compared to those receiving caspofungin/fluconazole will be measured. Furthermore, the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), treatment-related adverse events, adverse events of special interest (AESI), and adverse events leading to discontinuation will be recorded. Clinical laboratory tests, neurological assessments, and 12-lead ECGs will be conducted to support these evaluations. Pharmacokinetic (PK) analyses will include descriptive summaries of plasma concentrations over time.