FAST-IC

To evaluate the efficacy of IV followed by oral fosmanogepix in the treatment of adult patients with candidemia and/or invasive candidiasis, by comparison to a standard-of-care regimen of IV caspofungin followed by oral fluconazole.

To evaluate the efficacy of fosmanogepix compared to caspofungin/fluconazole based on independent AC-assessed overall response, clinical and mycological response at different timepoints.

To evaluate the time to first negative blood culture for patients with baseline candidemia.

To evaluate the safety and tolerability of IV followed by oral fosmanogepix in the
treatment of adult patients with candidemia and/or invasive candidiasis, by comparison to a standard-of-care regimen of IV caspofungin followed by oral fluconazole.

To examine the PK of fosmanogepix (prodrug) and manogepix (active moiety).

Exploratory:

To examine the use of health care resources utilization by patients in this study.

To assess the association between positive and negative predictive values of BDG at baseline and EOST for overall response or failure at EOST.

1. Patients ≥ 18 years (or the minimum country-specific age of consent if > 18) at Screening who have provided signed informed consent indicating that they understand the purpos.

2. Diagnosis of candidemia and/or invasive candidiasis within ≤ 96 hours (4 days)
before randomization, defined as follows:

Meets one or more of the following criteria indicating presence of Candida in blood
or from a specimen obtained from a normally sterile site or newly placed drain
(< 24hrs):
a) One or more cultures positive for yeast or Candida spp. sampled within 96 hours
prior to randomization
b) Positive Gram stain (or other method of direct microscopy) for yeast from blood
or specimen from a normally sterile site sampled within 96 hours prior to
randomization
c) Positive result for Candida using a Sponsor-approved rapid diagnostic test from a
blood specimen obtained within 96 hours prior to randomization.

Plus

Meets one or more of the clinical criteria judged attributable to candidemia / invasive candidiasis occurring at any time from ≤ 12 hours prior to the qualifying positive index culture being taken (above) through to randomization:
d) Fever (> 38 °C / 100.4 °F measured orally, > 38.5 °C / 101.3 °F measured
tympanically, > 37.5 °C / 99.5 °F measured by axillary method, or > 39 °C / 102.2 °F measured rectally),
e) Hypothermia (< 36 °C / 96.8 °F oral, or equivalent),
f) Hypotension (SBP < 90 mmHg or decrease of > 30mmHg),
g) Tachypnea (respiratory rate > 20 breaths per minute),
h) Tachycardia (heart rate > 100 beats per minute with a normovolemic or
hypervolemic status),
i) Local signs associated with organ/site infected with Candida (e.g., purulent drainage, swelling, heat, erythema), and/or radiologic findings suggesting invasive candidiasis.

3. Patient’s condition allows for appropriate infection source control measures,
including removal of pre-existing intravascular catheters and devices, if necessary.

1. Existing infection
(a) Infection known to be due to Candida krusei, in blood or any other normally sterile site.
(b) Inappropriate fungal infection source control (e.g., presence of an indwelling vascular catheter or devices that cannot be removed, an abscess that cannot be drained and is likely to be the source of infection, etc.)
(c) Diagnosis of certain deep-seated Candida infections:
- hardware associated septic arthritis (septic arthritis in a native joint is allowed), osteomyelitis, endocarditis, myocarditis, hepatosplenic candidiasis,
CNS infection, endophthalmitis, or
- a site of infection that would require antifungal therapy to exceed the maximal
duration of study drug treatment (i.e., 6 weeks [42 days]).
Note: Candida spp. isolated from urine, or other sites that may be colonized
(e.g., bronchoalveolar lavage, sputum), or from sites that are not normally sterile,
do not constitute invasive candidiasis.

2. Life expectancy of < 72 hours in the opinion of the investigator.

3. Requirement, or expected requirement, for hemodialysis.

4. Ongoing medical history of neurological disorders including the following conditions presenting with a CTCAE Grade ≥ 2:
(a) cerebellar coordination and balance disturbances, such as ataxia, abnormal
coordination or gait disorders
(b) delirium or hallucinations
(c) dyskinesia and movement disorders such as hypokinesia, dyskinesia or
psychomotor hyperactivity
(d) seizure or convulsions
(e) tremor

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

6. 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.

7. Current use of any prohibited concomitant medications or those unwilling/unable to use a permitted concomitant medication. (defined in study protocol section 6.8)

8. Received > 2 days (> 48 hours) equivalent of prior systemic antifungal treatment at
approved dose and frequency to treat the current episode of candidemia (e.g., > two
doses of a once daily antifungal agent or > four doses of a twice daily antifungal
agent), within the 96 hours prior to randomization.
Exceptions:
‐ Receipt of antifungal therapy to which any Candida spp. isolated in culture is not
susceptible.
‐ Patients who develop candidemia or invasive candidiasis while on prophylaxis
with an azole or amphotericin B are permitted for inclusion if they did not receive
> 2 days (>48 hours) of systemic antifungal treatment to treat the current episode
of candidemia or invasive candidiasis.

9. Previous administration with an investigational drug or investigational vaccine within 30 days or five half-lives preceding the first dose of study drug used in this study (whichever is longer). 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 the country.

10. Prior participation in this or any previous study of fosmanogepix.

11. Hepatic Impairment – any of the following:
(a) Moderate or severe hepatic impairment (Child-Pugh Score > 6 points) in patients with a history of chronic cirrhosis.
(b) Active viral hepatitis B by presence of HBsAg or Hepatitis C defined by anti-HCV and HCV-RNA.
Exceptions:
‐ Patients with past or resolved (defined as having a positive anti-HBc and a negative HBsAg test) hepatitis B virus infection are eligible.
‐ Patients positive for anti-HCV are eligible only if polymerase chain reaction
(PCR) is negative for HCV-RNA.
(c) ALT or AST ≥ 5 × ULN.
(d) Total bilirubin > 3 × ULN, unless isolated hyperbilirubinemia or due to
documented Gilbert’s syndrome.

12. Female patient is pregnant or lactating.

13. Known hypersensitivity to fosmanogepix, manogepix, caspofungin, any
echinocandin, fluconazole or to any of their excipients.

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

Eligible patients will be randomized in a 2:1 ratio to either the fosmanogepix or the

caspofungin IV/oral fluconazole arm, stratified by site and the presence or absence of

baseline neutropenia (defined as ANC < 500 cells/μL). Stratification by baseline

neutropenia will be based on the local laboratory results.

Blinded study drug will be administered for 14 days after clearance of Candida from the bloodstream (14-day time clock starts from the first collection of the two negative blood cultures taken at least 12 hours apart on two consecutive assessment days with no intermittent or subsequent positive blood cultures) for those with candidemia only, or until resolution of the relevant features of Candida infection at other invasive sites, in accordance with standard practice guidelines or local protocols, but may be continued for a maximum of 42 days. The maximum duration of treatment with blinded study drug is 42 days. There will be a follow-up period of 6 weeks after EOST. The total duration of participation in the study is up to a maximum 12.5 weeks (inclusive of the screening period).