Conditions: Invasive Fungal Infections
Keywords: APX001 APX001A fosmanogepix manogepix aspergillus aspergillosis covid covid19 mold mould pulmonary aspergillosis pulmonary aspergillus galactomannan Karius SARS-CoV-2 fusarium mucorales mucor rhizopus scedosporium fungal disease invasive fungal disease EORTC
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
This is a Phase 2, multicenter study to evaluate APX001 for the treatment of invasive fungal infections caused by Aspergillus spp. or rare molds (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: fosmanogepix
Intervention descriptions: intervention 1: IV and oral fosmanogepix

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL
A Phase 2, Open-Label Study to Evaluate the Safety and Efficacy of 
APX001 in the Treatment of Patients with Invasive Mold Infections 
Caused by Aspergillus Species or Rare Molds
Investigational Product: APX001
Protocol Number: APX001-202
EudraCT Number: 2019-001386-33
Sponsor:
Amplyx Pharmaceuticals, Inc.
12730 High Bluff Drive, Suite 160
San Diego, CA 92130
United States
Telephone: +1-858-345-1755
Fax: +1-858-345-1346
Version Number: 3.0
Date: 29 September 2020
Confidentiality Statement
The information in this document is confidential and is not to be disclosed without the written 
consent of Amplyx Pharmaceuticals, Inc. except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for 
Amplyx Pharmaceuticals, Inc. You are allowed to disclose the contents of this document only to 
your Institutional Review Board or Independent Ethics Committee and study personnel directly 
involved with conducting this protocol. Persons to whom the information is disclosed must be 
informed that the information is confidential and proprietary to Amplyx Pharmaceuticals, Inc. and 
that it may not be further disclosed to third parties.


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SIGNATURE PAGE
A Phase 2, Open-Label Study to Evaluate the Safety and Efficacy of APX001 in the 
Treatment of Patients with Invasive Mold Infections Caused by Aspergillus Species or Rare 
Molds
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study.
Signature
Date
 MD
Amplyx Pharmaceutical, Inc. 
PPD
PPD


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INVESTIGATOR AGREEMENT
By signing below I agree that:
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Amplyx Pharmaceuticals, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to 
Amplyx Pharmaceuticals, Inc. and that it may not be further disclosed to third parties. I understand 
that the study may be terminated or enrollment suspended at any time by Amplyx Pharmaceuticals, 
Inc., with or without cause, or by me if it becomes necessary to protect the best interests of the 
study patients.
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices.
______________________________________________
____________________
Investigator’s Signature
Date
______________________________________________
Investigator’s Printed Name


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SYNOPSIS
TITLE: A Phase 2, Open-Label Study to Evaluate the Safety and Efficacy of APX001 in the 
Treatment of Patients with Invasive Mold Infections Caused by Aspergillus Species or Rare Molds
PROTOCOL NUMBER: APX001-202
INVESTIGATIONAL PRODUCT: APX001
PHASE: 2
INDICATION: Treatment of patients with invasive mold infections (IMIs) caused by Aspergillus
species (spp.) or rare molds
OBJECTIVES:
The primary objective of this proof-of-concept study is to evaluate the safety and efficacy of 
APX001 for the treatment of adult patients aged 18 years and above with IMIs caused by 
Aspergillus spp. or rare molds (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi), 
who have limited antifungal treatment options. 
The secondary objectives of this study are to:

Evaluate global response at End of Study Treatment (EOST)

Evaluate safety parameters of APX001

Evaluate pharmacokinetic (PK) parameters of APX001
BACKGROUND:
APX001, a first-in-class small molecule investigational drug candidate, is the water-soluble 
methyl phosphate prodrug of the active moiety APX001A. APX001 is rapidly converted in vivo
to APX001A. APX001A has a novel mechanism of antifungal action, with broad spectrum activity 
against major fungal pathogens including Candida spp. and Aspergillus spp.
APX001A inhibits the fungal glycosylphosphatidylinositol (GPI)-anchored wall transfer protein 1 
(GWT1) enzyme, a highly conserved inositol acylase that catalyzes an early step in the 
GPI-anchored biosynthesis pathway. This inhibition has pleiotropic effects on the fungal cell due 
to inhibition of cell wall mannoprotein localization, which compromises cell wall integrity, 
biofilm formation, germ tube formation, and fungal growth. APX001A does not inhibit 
phosphatidylinositol glycan anchor biosynthesis class W (PIGW) protein, the closest mammalian 
ortholog of the fungal GWT1 protein consistent with the potential for a significant target-based 
therapeutic window. 
APX001A has demonstrated broad in vitro antifungal activity against Candida spp., 
Cryptococcus spp., Aspergillus spp., Scedosporium spp., Fusarium spp., and Mucorales fungi, 
including activity against azole- and echinocandin-resistant strains. APX001A has demonstrated 
synergy with echinocandins (Aspergillus)
and azoles (Candida). 
In 5-fluorouracil 
immunosuppressed mice with IMIs (Aspergillus fumigatus, Scedosporium prolificans, and 


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Fusarium solani), APX001 demonstrated statistically significantly improved survival rates and 
reduced pulmonary fungal colony counts. In cyclophosphamide and cortisone acetate 
immunosuppressed mice with IMIs (A. fumigatus, Scedosporium apiospermum, F. solani, and 
Rhizopus spp.), APX001 demonstrated statistically significantly improved survival rates and 
reduced 
fungal 
burden. 
Pharmacokinetic-pharmacodynamic 
(PK-PD) 
studies 
in 
immunosuppressed mice with invasive infections caused by A. fumigatus have shown that the area 
under the concentration-time curve (AUC) divided by the minimal effective concentration (MEC) 
ratio is the driver of efficacy. The dose regimen employed in this study provides a steady state
AUC 200 µghr/mL, which is associated with efficacy (colony count and survival benefit) in 
immunocompromised mice with invasive pulmonary aspergillosis (IPA). Additionally, formal 
PK-PD studies demonstrated that the dose regimen has favorable probability of target attainment 
(PTA) for the majority of isolates anticipated to be encountered in this study. 
In Phase 1 clinical studies of APX001, the safety, tolerability, and PK of single and multiple 
ascending doses administered intravenously (IV) and orally (PO) have been studied. To date, 
a total of 197 healthy volunteers and 21 patients with acute myeloid leukemia (AML) have 
received APX001 across 5 Phase 1 studies (APX001-101, APX001-102, APX001-103, 
APX001-105, APX001-106). The duration of the multiple-dose regimens in these studies were 7, 
14, and 42 days (6 weeks).
Phase 1 studies in healthy volunteers: The highest doses administered in 2 dose escalation 
studies, APX001-101 and APX001-102, were 600 mg IV daily and 1000 mg PO daily for 14 days, 
respectively. The 6-week dose regimen administered in study APX001-105 is closely matching 
the dose and duration that will be employed in this protocol. In these 3 Phase 1 studies, all doses 
of APX001 were safe and well tolerated. The majority of the treatment-emergent adverse events 
(TEAEs) were mild, transitory, and resolved without intervention. There were no severe or serious 
adverse events (SAEs) reported and no dose-limiting toxicities were observed. In all 3 Phase 1
studies, no laboratory test results nor results from other safety evaluations (physical examination, 
electrocardiogram [ECG], vitals) met the criteria for a TEAE nor did any result meet the a priori 
rules that prevented dose escalation. 
In an additional dose escalation study, APX001-106, cohorts of healthy volunteers were 
administered 750 to 900 mg IV daily for 6 days, preceded by various loading doses. Some of the 
900 mg dose regimens that employed high loading doses were not well tolerated. Consequently, 
at this time the 900 mg dose regimen will not be employed in this study. 
APX001 and APX001A PK parameters for both single and multiple APX001 IV and PO doses in 
all 4 Phase 1 studies in healthy volunteers were linear and dose proportional. In the cohort 
embedded within the PO dose Phase 1 study APX001-102, APX001 demonstrated a favorable
(ie, APX001 was not a strong inhibitor or strong inducer of cytochrome P450 [CYP] enzymes)
drug-drug interaction (DDI) profile. The relative bioavailability of the PO APX001 formulation is 
>90% in both the presence or absence of food, demonstrating that no food effect exists. In addition, 
the target AUCs anticipated for efficacy against both yeasts and molds have been achieved with 
both IV and PO dose formulations. 
Further details of all the Phase 1 studies can be found in the Investigator’s Brochure (IB).


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Phase 1 studies in patients: Study APX001-103 was conducted in patients with newly diagnosed 
AML undergoing induction chemotherapy. The objective of this study was to evaluate the safety, 
tolerability, and PK of IV and PO doses of APX001 in a patient population in which the 
investigational medicinal product will be studied. There were no treatment-related SAEs reported 
during the study and none of the TEAEs reported as related to APX001 resulted in drug 
withdrawal/discontinuation. With the exception of 1 Grade 3 TEAE (hypertension), all TEAEs 
reported as related to APX001 were of the Common Terminology Criteria for Adverse Events
Grades 1 and 2. 
All clinically significant abnormal clinical laboratory findings observed in this study, vital signs, 
ECG, and physical examination findings, can be attributed to the underlying condition of AML 
and the aggressive induction chemotherapy. Overall, the safety results from this study indicate 
daily doses of IV or PO APX001 given for 14 days were safe and well tolerated. No evidence of 
significant or additional risks of APX001 in this patient population was observed and no new 
safety concerns were identified. 
Plasma concentrations and calculated exposures of APX001 and APX001A in study APX001-103 
were lower than expected based on PK data from prior Phase 1 studies in healthy volunteers 
(APX001-101 and APX001-102). Potential factors that might contribute to this observation were 
thoroughly investigated and are described in the IB. These experiments confirmed that the plasma 
concentrations of APX001 and/or APX001A are dependent on hematocrit values. The lowered 
exposures observed in the APX001-103 PK results are most likely due to a dilution effect. 
When plasma concentrations are adjusted to account for this effect, PK parameters in 
APX001-103 are similar to those observed in prior healthy volunteer studies. 
Further details of all the Phase 1 studies can be found in the IB. 
In summary, APX001 has a novel mechanism of action with broad spectrum activity against 
Candida spp. (yeast) and Aspergillus spp. (mold), including activity against polyene and 
azole-resistant strains of Aspergillus spp. APX001 has demonstrated efficacy in a number of 
animal models of IMIs, including Aspergillus spp., Fusarium spp., Scedosporium spp., 
and Mucorales fungi. To date, APX001 in both IV and PO formulations has been safe and well 
tolerated with a favorable DDI profile. APX001 has the potential to be used as a first-line agent 
for the treatment of IMIs.
POPULATION:
This study will enroll male and female patients aged 18 years and above with a confirmed 
diagnosis of invasive aspergillosis or invasive rare mold infection. Patients will have limited or no 
treatment options due to documented/anticipated resistance, contraindication, intolerance, or lack 
of clinical response to standard of care (SOC) antifungal therapy, as advocated by the relevant 
regional/country treatment guidelines. The study will enroll 
 cohorts, Cohort A 
  Up to 
40 patients will be enrolled in Cohort A, and these patients will have an IMI which was diagnosed 
according to the EORTC/MSGERC criteria. 
 
 
Inclusion Criteria:
Patients must meet all of the following criteria to be eligible for study entry:
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1. Males or females, 18 years or older.
2. Patients with IMI caused by Aspergillus spp. Patients who present with IMI due to other 
filamentous fungi (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi such as 
Mucor spp. or Rhizopus spp.) may also be enrolled.
o
Cohort A:  Diagnosis of proven or probable IMI will be defined in accordance with the 
Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the 
EORTC/MSGERC .
o
3. Have limited or no treatment options due to documented or anticipated resistance, 
contraindication, intolerance, or lack of clinical response to SOC antifungal therapy, 
as advocated by the relevant regional/country treatment guidelines. 
4. Patients where the Investigator considers that there is a potential advantage of using APX001 
over current SOC (eg, broad spectrum of activity, activity against resistant mold pathogens, 
IV and PO formulations, favorable DDI profile, favorable hepatic and renal safety profile, 
wide tissue distribution including brain), and/or where the SOC antifungal therapy carries 
significant risk of toxicity or treatment failure (eg, emergence of IMI during antifungal 
prophylaxis, DDI risk, safety/toxicity risk, site of infection not accessible by SOC).
5. Female patients of nonchildbearing potential must be 1 of the following:
o
Surgically sterile (hysterectomy, bilateral tubal ligation, bilateral salpingectomy, and/or 
bilateral oophorectomy). 
o
Postmenopausal (amenorrhea for >12 months without an alternative medical cause). 
6. Females of childbearing potential (ie, not postmenopausal or surgically sterilized) must have 
a negative urine or serum pregnancy test result within 96 hours prior to Baseline (ie, predose 
on Day 1). Participating females of childbearing potential with male partners, and males with 
female partner(s) of childbearing potential, must agree to use 2 forms of contraception, 1 of 
which must be highly effective and the other an acceptable barrier method (male or female 
condom), throughout the duration of the study and for 90 days following the last study drug 
administration. Highly effective methods of contraception include the following:
o
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (PO, intravaginal, or transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (PO, injectable, or implantable), 
intrauterine device, or intrauterine hormone-releasing system.
o
Bilateral tubal occlusion or vasectomized partner.
Note: A vasectomized partner is a highly effective method of contraception, provided that 
the male partner is the sole sexual partner of the study patient who is a female of 
childbearing potential and that the vasectomized partner has received medical assessment 
of surgical success. 
o
Sexual abstinence.
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Note: True abstinence, when in line with the preferred and usual lifestyle of the patient, 
is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug treatment. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception.
7. Male patients must agree to abstain from sperm donation and use condoms with spermicide 
during sexual intercourse between Screening and at least 90 days after administration of the 
last dose of study drug. Male patients must ensure nonpregnant female partner(s) of 
childbearing potential comply with the contraception requirements in Inclusion Criterion 6.
8. Patients must be willing to participate in the study, to give written informed consent, and to 
comply with the study restrictions; where permitted by local regulations, written informed 
consent from a legal authorized representative will be obtained for patients who are unable to 
give consent.
9.
 
Exclusion Criteria:
Patients who meet any of the following criteria will not be eligible for the study:
1. Refractory hematologic malignancy with no potential to respond to additional chemotherapy.
2. Chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis.
3. Treatment with systemic (PO, IV, or inhaled) antifungal therapy with a mold-active azole or 
polyene for ∀120 hours immediately before initial dosing.
Note: An exception is antifungal prophylaxis, for which there is no restriction on duration, 
but must be stopped upon commencement of treatment with APX001.
Additionally, patients with invasive fungal infection caused by a mold with documented 
resistance to or lack of coverage by the prior SOC in question, as well as patients with 
polyene-induced renal toxicity or those who have received empirical treatment with 
echinocandins, may have received >120 hours prior treatment and remain eligible for the 
study. These patients must be discussed with the Medical Monitor prior to enrollment, and 
prior treatment in this case should not exceed >168 hours. 
4. Evidence of significant hepatic dysfunction, defined as any of the following:
o
Total bilirubin >3 ∃the upper limit of normal (ULN) unless isolated hyperbilirubinemia 
or due to documented Gilbert’s disease.
o
Alanine transaminase or aspartate transaminase ∀5 ∃ULN.
o
Severe or moderate hepatic impairment (Child-Pugh Score >6 points) at any time during 
2 weeks prior to dosing. The Child-Pugh score of > 6 is applicable only to patients with 
hepatic dysfunction and cirrhosis.  
5. Ongoing medical history of neurological disorders including abnormal movements or seizures.
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Note: A current CNS mold infection as well as a stable history of peripheral neuropathy will 
not be considered exclusionary
6. Patient receiving palliative care only.
7. Known hypersensitivity or other serious reaction to APX001 or any ingredient of APX001.
8. Patient is lactating and/or pregnant or intending to be pregnant during the duration of the study.
9. Investigational drug administered within 30 days or 5 terminal half-lives prior to study drug 
dosing (whichever is longer).
Note: Participation in research protocols for approved agents for the treatment of an 
underlying condition is permitted.
10. Prior participation in this study or any previous study of APX001.
11. Concomitant use of medication that is a strong inducer (ie, rifampin, carbamazepine, 
phenytoin, rifabutin, efavirenz, nevirapine, phenobarbital, modafinil, St. John’s Wort, 
enzalutamide) of CYP enzymes.
12. Any other condition or laboratory abnormality that, in the opinion of the Investigator or the 
Sponsor, would put the patient at unacceptable risk for participation in the study or may 
interfere with the assessments included in the study.
13. Patients on mechanical ventilation
14. Cohort A only: Suspected or confirmed COVID-19 or Influenza A/B infection.
15. Patients with severe renal impairment as determined by estimated glomerular filtration rate 
(eGFR) <30 mL/min /1.173 m2 calculated by CKD-EPI, including patients on dialysis.
16. Patients with a Karnofsky Performance Status ≤30 at screening
STUDY DESIGN AND DURATION:
This is a Phase 2, multicenter, open-label, non-comparative study to evaluate the safety and 
efficacy of APX001 for the treatment of IMIs caused by Aspergillus spp. or rare molds 
(eg, Scedosporium spp., Fusarium spp., and Mucorales fungi). Patients 18 years of age or older 
will undergo Screening procedures for up to 5 days, following which eligible patients will 
participate in the study drug Treatment Period for up to 6 weeks, with a Follow-Up Visit 4 weeks 
after EOST, and a Follow-Up Phone Call 12 weeks after Day 1 (Day 84). The total duration of a 
patient’s participation in the study will be approximately 12 weeks, inclusive of the follow-up 
telephone call required on Day 84. Patients who require treatment for longer than 6 weeks can be 
switched to other licensed antifungal therapy (OLAT) at the discretion of the Investigator and in 
consultation with the Medical Monitor if the situation allows. 
This study will be conducted at up to 40 global sites. 


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A schematic representing the study’s design is included below:
BID = twice daily; EOST = End of Study Treatment; IV = intravenous(ly); PO = oral(ly); QD = once daily. 
This study will consist of 
 parallel cohorts.  Cohort A will enroll up to 40 patients, 
  Each cohort has a single treatment arm consisting of 
a loading dose of 1000 mg APX001, administered over 3 hours by IV infusion twice daily (BID) 
within the first 24 hours after initiation of the first infusion. On Days 2 and 3, 600 mg APX001 
will be administered over 3 hours by IV infusion once daily (QD). From Day 4 through EOST, 
the IV dose remains 600 mg APX001 administered over 3 hours by IV infusion QD, or patients 
may be switched to PO administration of 800 mg APX001 QD. Antiemetics (preferably a 5-HT3
antagonist such as ondansetron or granisetron) should be administered in patients who develop 
nausea and/or vomiting associated with APX001 administration (both IV and oral), and oral 
APX001 may be given with food. Additionally, prophylactic antiemetics, (preferably a 5-HT3
antagonist such as ondansetron or granisetron) may be administered prior to dosing (both IV and 
oral) in patients considered at higher risk of gastrointestinal intolerance. The decision to switch 
from IV to PO APX001 will be based on the Investigator’s discretion and can be done on any day 
from Day 4 onwards. Patients will remain hospitalized for at least 2 days following the initial 
switch from IV to PO so that their tolerance to the oral medication may be evaluated and treated 
as necessary, and patients may be switched between IV and PO as needed. Oral APX001 may be 
given as an outpatient. 
Administration of APX001 should not continue for longer than 6 weeks (inclusive of the loading 
dose [Day 1]). If an Investigator documents an improvement or resolution in clinical signs and 
symptoms prior to 6 weeks, eg, if follow-up imaging (as applicable) shows improvement; or a 
mycological response (if amenable to repeat sampling) is observed, the Investigator may choose 
to discontinue dosing. Patients will be requested to return for an EOST and a Follow-Up Visit and 
to agree to a Follow-Up Phone Call. 
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Dosing is described below: 
Load Dosing
Day 1 (Baseline)
Maintenance Dosing 
Days 2-42 [1]
Total Enrolled (n)
IV BID
IV QD [1]
PO QD [1,2]
1000 mg
600 mg
800 mg
50
1.
On Days 2 and 3, APX001 will be administered over 3 hours by IV infusion QD. From Day 4 through EOST, 
the IV dose remains 600 mg APX001 administered over 3 hours by IV infusion QD, or patients may be 
switched to PO administration of 800 mg APX001 QD. 
2.
Patients may switch between IV and PO as needed.  Oral APX001 may be given as an outpatient. 
BID = twice daily; EOST = End of Study Treatment; IV = intravenous(ly); PO = oral(ly); QD = once daily.
Blood samples (serum and plasma) and other diagnostic specimens (eg, bronchoalveolar lavage 
[BAL]) will be collected at Screening for pathogen DNA analysis utilizing next-generation 
sequencing (optional) and/or polymerase chain reaction (PCR) analysis. Urine samples will be 
collected at Screening for the aspergillosis urine test. 
Plasma samples for PK (APX001 [prodrug] and APX001A [active moiety]) will be collected 
predose and 3 hours post start of infusion on Days 1 (Baseline), 2, 3, 7, and 14; predose on Days 28 
and 42; and at any time in clinic at EOST, the Follow-Up Visit, and the Early Termination (E/T) 
Visit (if applicable). Additionally, for patients who switch to PO dosing, samples should be 
collected predose and at 3 hours postdose on the initial day of PO dosing, Day 7, and Day 14 and 
at any time in clinic on Days 28 and 42, at EOST, at the Follow-Up Visit, and at the E/T Visit 
(if applicable). If the patient switches back to IV dosing, PK samples should be collected predose 
and at 3 hours post start of infusion on that day as well. 
Serum samples for analysis of 
 will be collected at Screening; predose on Days 1 
(Baseline), 2, and 3; on Days 7, 14, 28, and 42; at EOST; and at the E/T Visit (if applicable).
Serum samples for analysis of
will be collected at Screening; predose on Day 1 
(Baseline); on Days 14, 28, and 42; at EOST; at the Follow-Up Visit; and at the E/T Visit 
(if applicable). 
Assessment of clinical signs and symptoms will be conducted at Screening; at all visits from Day 1 
(Baseline) through EOST; at the Follow-Up Visit; and at the E/T Visit (if applicable).
Radiological assessments (including computed tomography scans of the chest, sinuses, and/or 
abdomen) will be performed during Screening (SOC scans within 3 days of Screening will be 
accepted as long as the scans can be provided to the central reader). Computed tomography scans 
of the chest, sinuses, and/or abdomen will be repeated on Day 14 and at EOST, and if clinically 
indicated on Days 7, 21, 28, 35, and 42; at the Follow-Up Visit; and at the E/T Visit (if applicable). 
Samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, sinus aspirate, tracheal 
aspirate) will be collected and processed for culture and susceptibility by the local laboratory at 
Screening, and as clinically indicated at any visit from Day 1 (Baseline) through EOST, at the 
Follow-Up Visit, and at the E/T Visit (if applicable). Screening samples for fungal cultures to 
determine eligibility may have been collected as SOC 120 hours prior to initial dosing. All fungal 
isolates cultured at the local laboratory will be sent to the central mycology reference laboratory 
for confirmation of identification and susceptibility testing. 
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Bronchoalveolar lavage samples will be collected per SOC for culture at the local laboratory and 
 testing at the central laboratory as clinically indicated at any visit from Screening 
throughout the study. 
The safety and tolerability of APX001 will be evaluated through physical examination findings, 
clinical signs and symptoms, vital signs, changes in clinical laboratory tests, 12-lead ECGs, 
any other exploration, and monitoring of adverse events and concomitant medications or 
procedures.
DOSAGE FORMS AND ROUTE OF ADMINISTRATION:
On Day 1 (Baseline), a 1000 mg APX001 loading dose will be administered over 3 hours by IV 
infusion BID within the first 24 hours after initiation of the first infusion.
On Days 2 and 3, a 600 mg APX001 maintenance dose will be administered over 3 hours by IV 
infusion QD.
From Day 4 through EOST, APX001 will be administered as either:
!
600 mg APX001 over 3 hours by IV infusion QD
!
800 mg APX001 PO QD 
Note: Study drug will not be administered for longer than 6 weeks (inclusive of the loading dose 
[Day 1]). If an Investigator documents an improvement or resolution in clinical signs and 
symptoms prior to 6 weeks, eg, if follow up imaging (as applicable) shows improvement; or a 
mycological response (if amenable to repeat sampling) is observed, the Investigator may choose 
to discontinue dosing. Patients will be requested to return for an EOST and Follow-Up Visit and 
to agree to a Follow-Up Phone Call. Patients who still require treatment after EOST should 
continue on OLAT. 
RATIONALE FOR DOSE AND SCHEDULE SELECTION: 
In a PK-PD IPA study, immunocompromised mice were infected with 6 strains of A. fumigatus, 
inclusive of wild type, azole-resistant, and echinocandin-resistant strains. Groups of animals were 
dosed with APX001 at different dose fractionations. The AUC from time 0 to 24 hours 
(AUC(0-24))/MEC ratio was determined to be the PK-PD index that best correlated with antifungal 
efficacy as assessed by fungal burden (conidial equivalents [CEs] measured by real time 
quantitative PCR) in lung homogenates. The stasis and 1-logarithm drop endpoints were defined 
as the quantity of A. fumigatus in CEs just prior to APX001 administration compared to CEs at 
the endpoint of assessment at 96 hours. The median total drug AUC/MEC which achieved stasis 
and 1-logarithm kill endpoints for each A. fumigatus strain were 2801.6 and 5258.2.
The clinical isolates surveillance data from 2017, 2018 and 2019 of APX001A antifungal activity
against Aspergillus spp. shows that the majority (96%) of Aspergillus isolates have MEC values 
of 0.008 to 0.03 μg/mL. The MEC in 90% of patients (MEC90) for Aspergillus isolates likely to 
be found in the clinical patient population under study is 0.03 μg/mL.
One dose regimen of APX001 will be evaluated in this study. In Phase 1 studies in healthy 
volunteers, the dose regimen in this study was safe and well tolerated. While the study allows a 
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switch to PO dosing as early as Day 4, the following table describes the estimated total drug 
AUC(0-24) and PTA for stasis in CE at the MEC90 with the companion PO switch at Day 7.
Load IV BID
(Day 1 [Baseline])
IV 
Maintenance QD 
(Days 2-7)
PO 
Maintenance QD 
(Days 8-42)
AUC(0-24)
(Days 7/14/42)
PTAs at MEC90
(stasis [Day 14])
1000 mg
600 mg
800 mg
195/224/224
∀90%
AUC(0-24) = area under the concentration-time curve from time 0 to 24 hours; BID = twice daily; 
IV = intravenous(ly); MEC90 = minimal effective concentration in 90% of patients; PO = oral(ly); 
PTA = probability of target attainment; QD = once daily.
The dose regimen employed in this study provides a steady state AUC ∀200 μg·hr/mL, which is 
associated with efficacy (colony count and survival benefit) in immunocompromised mice with 
IPA. Additionally, formal PK-PD studies demonstrated that the dose regimen has favorable PTA 
for the majority of isolates anticipated to be encountered in this study. 
Formal PK-PD for invasive rare mold infections (eg, Fusarium spp., Scedosporium spp., 
Mucorales fungi) have not yet been conducted. However, immunocompromised animal models of 
rare mold infections demonstrate colony count and survival benefit at AUCs provided by the dose 
regimen employed in this study. 
EFFICACY ENDPOINTS: 
Primary:
!
All-cause mortality through Day 42.
Note: All-cause mortality will represent the percentage of patients who die after the first dose 
of study drug through Day 42 from any cause.
Secondary:
!
Global response at EOST
 
SAFETY VARIABLES:
Safety assessments will include physical examinations, vital signs, clinical laboratory evaluations, 
12-lead ECGs, any other exploration, and adverse events.
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WITHDRAWAL CRITERIA:
Study drug dosing must be discontinued for any of the following reasons:

The patient withdraws consent or requests discontinuation from the study for any reason

Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol

Occurrence of drug-induced liver injury (DILI)

Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the patient

Pregnancy

Requirement of prohibited concomitant medication (eg, systemic antifungal therapy)

Patient failure to comply with protocol requirements or study-related procedures

Termination of the study by the Sponsor or the regulatory authority
If a patient must be discontinued from study drug administration for any of the above criteria, 
the patient will still be encouraged to continue visits and assessments necessary for appropriate 
safety follow-up.
If a patient withdraws prematurely from the study due to any of the above criteria or for any other 
reason, study staff should make every effort to contact the Sponsor prior to discontinuation, 
if possible, and to complete the full panel of assessments scheduled for the E/T Visit. The reason 
for patient withdrawal must be documented in the electronic Case Report Form. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records.
Withdrawn patients will not be replaced. 
The study may be discontinued for any of the following reasons: 5 or more patients in the study 
(cumulative) experience the same Grade 2 (or higher) related adverse event (laboratory or clinical) 
which is coded in the same high-level group term per the Medical Dictionary for Regulatory 
Activities coding, throughout the duration of the study; a recommendation from the Data and 
Safety Monitoring Board (DSMB) based on other safety signals; lack of study drug availability; 
inability to enroll the study; or decision by a regulatory authority or the Sponsor. 
DATA REVIEW COMMITTEE:
A DRC comprised of infectious disease experts will adjudicate the diagnosis of IMI at enrollment. 
This committee will also provide systematic assessment for clinical, mycological, radiological, 
and global responses at EOST and at the E/T Visit (if applicable). 
Global responses will be classified as complete or partial response (categorized as treatment 
success), stable response, progression of disease, or death (categorized as treatment failure) 
according to prespecified criteria. Guidelines for the DRC are described in the DRC Charter.


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DATA AND SAFETY MONITORING BOARD: 
A DSMB comprised of members with pertinent expertise will be responsible for the periodic 
review of cumulative data from the study as set forth in the DSMB Charter, or more frequently at 
the request of the DSMB. The DSMB will advise the Sponsor on the continuing safety of patients 
and those yet to be recruited to the study, as well as the continuing validity and scientific merit of 
the study. The DSMB may recommend to the Sponsor that dosing in the study be suspended if, in 
the opinion of the DSMB, further dosing in the study would pose an inappropriate safety risk. 
Guidelines for what constitutes inappropriate safety risks are described in the DSMB Charter.
ANALYSIS POPULATIONS:
Intent-to-Treat Population/Safety Population:
The Intent-to-Treat (ITT)/Safety Population will include all patients who have received at least 
1 dose of study drug. 
Modified Intent-to-Treat Population:
The modified Intent-to-Treat (mITT) Population will include all patients in the ITT Population 
who satisfy the following criteria:
!
Receive at least 1 dose of study drug
!
Cohort A: Have a diagnosis of proven or probable IMI confirmed by the DRC
!
The mITT Population will be the primary population used for the efficacy analysis. 
Per-Protocol Population:
The Per-Protocol Population will include all patients in the mITT Population who satisfy the 
following criteria:
!
Meet the protocol’s key inclusion criteria and exclusion criteria
!
Have no major protocol violations
Pharmacokinetic Population:
The PK Population will include all patients who receive any amount of study drug and have 
evaluable PK data. The PK Population will be used for the PK analysis.  
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STATISTICAL ANALYSES:
Each Cohort will be analyzed and presented separately.  There will be no pooling of data across 
the Cohorts. 
The primary population for efficacy analysis will be the mITT Population.
The efficacy endpoints will be summarized descriptively, and all-cause mortality through Day 42
will be summarized. 
Cohort A only: The 1-sided exact binomial test at the alpha = 0.1 level of significance will be used 
to test the hypothesis that the all-cause mortality at Day 42 is less than 45% (based on historical 
control data). 
The percentage of patients with global response will be summarized.
All safety analyses will be performed on the Safety Population. Safety data will be subject to 
clinical review and summarized by appropriate descriptive statistics. A DSMB will be assigned to 
monitor safety on an ongoing basis throughout the study.
The PK analysis of plasma concentration data will be performed using validated software in order 
to derive the population mean (and variance) values of specific PK parameters. 
Plasma concentrations will be summarized descriptively by time point of collection. 
Summary statistics in the tabulation will include the number of observations, mean, standard 
deviation, percent coefficient of variation, median, minimum, and maximum. Pharmacokinetic 
parameters will be estimated using population PK analysis methods, which will be described in a 
separate data analysis plan. Results of the PK analysis will be reported separately.
SAMPLE SIZE DETERMINATION:
Approximately 50 patients will be dosed in this open-label, parallel-group, proof-of-concept study.
Cohort A: 
Patients with proven or probable IMI are eligible for inclusion in the mITT Population, which is 
the primary efficacy population (DRC confirmation required of proven or probable IMI). 
The sample size calculation is based on the mITT Population from the first dose of APX001 
through EOST (up to 6 weeks) for the all-cause mortality primary endpoint. A total of 24 patients 
in the mITT Population are needed, providing >90% power to detect the difference at a 1-sided 
significance level of 0.1, assuming an all-cause mortality of 20% for APX001 and 45% for 
adjusted amphotericin B-treated all-cause mortality from the historical control. Assuming 60% of 
dosed patients will be eligible to be included in the mITT Population, a dosing of approximately
40 patients allows for statistical testing of proof-of-concept for an estimate of 24 patients in the 
mITT Population.
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SITES: Up to 40 global sites
SPONSOR:
Amplyx Pharmaceuticals, Inc.
12730 High Bluff Drive, Suite 160
San Diego, CA 92130
United States
Telephone: +1-858-345-1755
Fax: +1-858-345-1346
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TABLE OF CONTENTS
1
INTRODUCTION AND BACKGROUND INFORMATION......................................... 25
1.1
Rationale ...................................................................................................................... 27
1.2
Risk/Benefit ................................................................................................................. 28
1.2.1
Potential Risks.................................................................................................. 28
1.2.2
Potential Benefits ............................................................................................. 28
1.2.3
Assessment of Potential Risks and Benefits .................................................... 29
2
STUDY OBJECTIVES ....................................................................................................... 29
2.1
Primary Objective ........................................................................................................ 29
2.2
Secondary Objectives................................................................................................... 29
3
STUDY DESCRIPTION..................................................................................................... 29
3.1
Summary of Study Design ........................................................................................... 29
3.2
Study Indication ........................................................................................................... 32
4
SELECTION AND WITHDRAWAL OF PATIENTS .................................................... 32
4.1
Inclusion Criteria.......................................................................................................... 32
4.2
Exclusion Criteria......................................................................................................... 34
4.3
Withdrawal Criteria...................................................................................................... 35
4.4
Discontinuation Rules.................................................................................................. 36
4.4.1
Study Discontinuation Rules............................................................................ 36
4.4.2
Patient Discontinuation Rules.......................................................................... 36
4.5
Premature Study Termination ...................................................................................... 37
5
STUDY TREATMENTS..................................................................................................... 37
5.1
Treatment Groups......................................................................................................... 37
5.2
Rationale for Dosing .................................................................................................... 37
5.3
Randomization and Blinding ....................................................................................... 38
5.4
Breaking the Blind ....................................................................................................... 38
5.5
Drug Supplies............................................................................................................... 38
5.5.1
Formulation and Packaging.............................................................................. 38
5.5.2
Study Drug Preparation and Dispensing.......................................................... 39
5.5.3
Study Drug Administration.............................................................................. 39
5.5.4
Treatment Compliance..................................................................................... 40
5.5.5
Storage and Accountability.............................................................................. 40


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5.6
Prior and Concomitant Medications and/or Procedures............................................... 40
5.6.1
Excluded Medications and/or Procedures........................................................ 40
5.6.1.1
APX001 as a Victim Substrate for Cytochrome P450 Drug-drug 
Interactions ........................................................................................ 40
5.6.1.2
APX001A as a Perpetrator of Cytochrome P450 Drug-drug 
Interactions ........................................................................................ 41
5.6.2
Restricted Medications and/or Procedures....................................................... 41
5.6.3
Documentation of Prior and Concomitant Medication Use............................. 41
6
STUDY PROCEDURES ..................................................................................................... 42
6.1
Informed Consent......................................................................................................... 42
6.2
Screening Visit (Day -5 to Day -1) .............................................................................. 42
6.3
Treatment Period (Day 1 up to Day 42)....................................................................... 43
6.3.1
Day 1 (Baseline)............................................................................................... 43
6.3.2
Day 2................................................................................................................ 43
6.3.3
Day 3................................................................................................................ 44
6.3.4
Day 7 (&1 Day)................................................................................................. 44
6.3.5
Day 14 (&1 Day)............................................................................................... 45
6.3.6
Day 21 (&2 Days)............................................................................................. 46
6.3.7
Day 28 (&2 Days)............................................................................................. 46
6.3.8
Day 35 (&2 Days)............................................................................................. 47
6.3.9
Day 42 (&2 Days)............................................................................................. 47
6.4
End of Study Treatment (+2 Days).............................................................................. 48
6.5
Follow-Up Visit (4 Weeks After End of Study Treatment [&3 Days])........................ 49
6.6
Follow-Up Phone Call (Day 84 [&3 Days])................................................................. 49
6.7
Early Termination Visit and Withdrawal Procedures .................................................. 50
7
EFFICACY ASSESSMENTS............................................................................................. 50
7.1
Primary Efficacy Endpoint........................................................................................... 50
7.2
Secondary Efficacy Endpoint....................................................................................... 51
7.4
Clinical Signs and Symptoms Assessment .................................................................. 51
7.5
Microbiological Assessments....................................................................................... 51
7.5.1
Pathogen DNA ................................................................................................. 51
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7.5.2
Aspergillosis Urine Test................................................................................... 51
7.5.3
Serum Biomarkers............................................................................................ 51
7.5.4
Bronchoalveolar Lavage .................................................................................. 52
7.5.5
Fungal Culture.................................................................................................. 52
7.6
Pharmacokinetic Assessments ..................................................................................... 52
8
SAFETY ASSESSMENTS.................................................................................................. 52
8.1
Adverse Events............................................................................................................. 52
8.1.1
Adverse (Drug) Reaction ................................................................................. 53
8.1.2
Unexpected Adverse Drug Reaction................................................................ 53
8.1.3
Assessment of Adverse Events by the Investigator ......................................... 54
8.2
Serious Adverse Events................................................................................................ 55
8.3
Serious Adverse Event Reporting −Procedures for Investigators............................... 56
8.4
Pregnancy Reporting.................................................................................................... 57
8.5
Expedited Reporting..................................................................................................... 57
8.6
Special Situation Reports............................................................................................. 58
8.7
Clinical Laboratory Evaluations .................................................................................. 59
8.8
Vital Signs.................................................................................................................... 59
8.9
Electrocardiograms ...................................................................................................... 59
8.10 Physical Examinations ................................................................................................. 59
8.11 Computed Tomography ............................................................................................... 60
9
STATISTICS........................................................................................................................ 60
9.1
Analysis Populations.................................................................................................... 60
9.2
Statistical Methods....................................................................................................... 61
9.2.1
Analysis of Efficacy......................................................................................... 61
9.2.2
Analysis of Safety ............................................................................................ 61
9.2.2.1
Pharmacokinetic Analysis ................................................................. 62
9.2.3
Interim Analysis............................................................................................... 62
9.2.4
Data Review Committee .................................................................................. 62
9.2.5
Data and Safety Monitoring Board .................................................................. 62
9.2.6
Sample Size Determination.............................................................................. 62
10 DATA MANAGEMENT AND RECORD KEEPING ..................................................... 63
10.1 Data Management ........................................................................................................ 63


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10.1.1 Data Handling .................................................................................................. 63
10.1.2 Computer Systems ........................................................................................... 63
10.1.3 Data Entry ........................................................................................................ 63
10.1.4 Medical Information Coding............................................................................ 63
10.1.5 Data Validation ................................................................................................ 64
10.2 Record Keeping............................................................................................................ 64
11 INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL............................ 64
11.1 Ethical Conduct of the Study ....................................................................................... 64
11.2 Institutional Review Board/Independent Ethics Committee........................................ 64
11.3 Informed Consent......................................................................................................... 65
11.4 Subject Card................................................................................................................. 65
11.5 Study Monitoring Requirements.................................................................................. 65
11.6 Disclosure of Data........................................................................................................ 66
11.7 Retention of Records.................................................................................................... 66
11.8 Publication Policy ........................................................................................................ 66
11.9 Financial Disclosure..................................................................................................... 66
11.10 Insurance and Indemnity.............................................................................................. 66
11.11 Legal Aspects............................................................................................................... 67
12 STUDY ADMINISTRATIVE INFORMATION.............................................................. 67
12.1 Protocol Amendments.................................................................................................. 67
12.2 Address List ................................................................................................................. 67
12.2.1 Sponsor............................................................................................................. 67
12.2.2 Contract Research Organization ...................................................................... 67
12.2.3 Drug Safety ...................................................................................................... 67
12.2.4 Biological Specimens....................................................................................... 68
12.2.5 Mycology Reference Laboratory ..................................................................... 68
12.2.6 Pharmacokinetic Laboratory............................................................................ 68
13 REFERENCES .................................................................................................................... 69
APPENDIX A:    SCHEDULE OF PROCEDURES ............................................................... 71
APPENDIX B:    CLINICAL SAFETY LABORATORY ANALYTES................................ 74
APPENDIX C:    FUNGAL AND OTHER LABORATORY ANALYTES .......................... 75


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APPENDIX D:    REVISION AND UPDATE OF THE CONSENSUS DEFINITIONS OF 
PROVEN INVASIVE FUNGAL DISEASE FROM THE 
EORTC/MSGERC ....................................................................................... 76
APPENDIX E:    REVISION AND UPDATE OF THE CONSENSUS DEFINITIONS OF 
PROBABLE INVASIVE FUNGAL DISEASE FROM THE 
EORTC/MSGERC ....................................................................................... 77
APPENDIX F:    
 DIAGNOSTIC CRITERIA FOR INVASIVE 
ASPERGILLOSIS........................................................................................ 79
APPENDIX G:    RESPONSE CRITERIA .............................................................................. 80
APPENDIX H:    DRUG-INDUCED LIVER INJURY CRITERIA...................................... 82
LIST OF TABLES
Table 1.
Patient Enrollment by Dosing Arm............................................................................. 31
Table 2.
Estimated Area Under the Curve and Probability of Target Attainment for the 
APX001 Dose Regimen.............................................................................................. 38
LIST OF FIGURES
Figure 1.
Study Schematic.......................................................................................................... 30
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation
Definition
AML
Acute myeloid leukemia
AUC
Area under the concentration-time curve
AUC(0-24)
Area under the concentration-time curve from 0 to 24 hours
BAL
Bronchoalveolar lavage
BID
Twice daily
CBC
Complete blood count
CE
Conidial equivalent
CFR
Code of Federal Regulations
CRA
Clinical research associate
CT
Computed tomography
CTA
Clinical trial authorization
CTCAE
Common Terminology Criteria for Adverse Events
CVC
Central venous catheter
CYP
Cytochrome P450
DDI
Drug-drug interaction
DRC
Data Review Committee
DSMB
Data and Safety Monitoring Board
E/T
Early Termination
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EIU
Exposure In Utero
EORTC
European Organization for Research and Treatment of Cancer
EOST
End of Study Treatment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GPI
Glycosylphosphatidylinositol
GWT1
Glycosylphosphatidylinositol-anchored wall transfer protein 1
IA
Invasive Aspergillosis
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee


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Abbreviation
Definition
IMI
Invasive mold infection
IMP
Investigational medicinal product
INR
International normalized ratio
IPA
Invasive pulmonary aspergillosis
IRB
Institutional Review Board
ITT
Intent-to-Treat
IV
Intravenous(ly)
LAR
Legal authorized representative
MEC
Minimal effective concentration
MEC90
Minimal effective concentration in 90% of patients
mITT
Modified Intent-to-Treat
MSG
Mycosis Study Group
MycoMEIA
Aspergillosis urine test
OLAT
Other licensed antifungal therapy
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PIGW
Phosphatidylinositol glycan anchor biosynthesis class W
PK
Pharmacokinetic(s)
PO
Oral(ly)
PT
Prothrombin time
PTA
Probability of target attainment
QD
Once daily
qPCR
Quantitative polymerase chain reaction
SAE
Serious adverse event
SOC
Standard of care
spp.
Species
SUSAR
Suspected Unexpected Serious Adverse Reactions
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


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1
INTRODUCTION AND BACKGROUND INFORMATION 
APX001, a first-in-class small molecule investigational drug candidate, is the water-soluble methyl 
phosphate prodrug of the active moiety APX001A. APX001 is rapidly converted in vivo to 
APX001A. APX001A has a novel mechanism of antifungal action, with broad spectrum activity 
against major fungal pathogens including Candida species (spp.) and Aspergillus spp.1,2,3,4,5
APX001A inhibits the fungal glycosylphosphatidylinositol (GPI)-anchored wall transfer protein 1 
(GWT1) enzyme, a highly conserved inositol acylase that catalyzes an early step in the 
GPI-anchored biosynthesis pathway. This inhibition has pleiotropic effects on the fungal cell due 
to inhibition of cell wall mannoprotein localization, which compromises cell wall integrity, biofilm 
formation, germ tube formation, and fungal growth. APX001A does not inhibit 
phosphatidylinositol glycan anchor biosynthesis class W (PIGW) protein, the closest mammalian 
ortholog of the fungal GWT1 protein consistent with the potential for a significant target-based 
therapeutic window.6,7
APX001A has demonstrated broad in vitro
antifungal activity against Candida spp., 
Cryptococcus spp., Aspergillus spp., Scedosporium spp., Fusarium spp., and Mucorales fungi, 
including activity against azole- and echinocandin-resistant strains. APX001A has demonstrated 
synergy with echinocandins (Aspergillus)8
and azoles (Candida).9
In 5-fluorouracil 
immunosuppressed mice with invasive mold infections (IMIs)
(Aspergillus fumigatus, 
Scedosporium prolificans, and Fusarium solani), APX001 demonstrated statistically significantly
improved survival rates and reduced pulmonary fungal colony counts.8 In cyclophosphamide and 
cortisone acetate immunosuppressed mice with IMIs (A. fumigatus, Scedosporium apiospermum,
F. solani, and Rhizopus spp.), APX001 demonstrated statistically significantly improved survival 
rates and reduced fungal burden.4 Pharmacokinetic-pharmacodynamic (PK-PD) studies in 
immunosuppressed mice with invasive infections caused by A. fumigatus have shown that the area 
under the concentration-time curve (AUC) divided by the minimal effective concentration (MEC) 
ratio is the driver of efficacy.10,11 The dose regimen employed in this study provides a steady state
AUC 200 µghr/mL, which is associated with efficacy (colony count and survival benefit) in 
immunocompromised mice with invasive pulmonary aspergillosis (IPA). Additionally, formal 
PK-PD studies demonstrated that the dose regimen has favorable probability of target attainment 
(PTA) for the majority of isolates anticipated to be encountered in this study.
In Phase 1 clinical studies of APX001, the safety, tolerability, and PK of single and multiple 
ascending doses administered intravenously (IV) and orally (PO) have been studied. To date, a 
total of 197 healthy volunteers and 21 patients with acute myeloid leukemia (AML) have received 
APX001 across 5 Phase 1 studies (APX001-101, APX001-102, APX001-103, APX001-105, 
APX001-106). The duration of the multiple-dose regimens in these studies were 7, 14, and 42 days 
(6 weeks).
Phase 1 studies in healthy volunteers:
The highest doses administered in 2 dose escalation studies, APX001-101 and APX001-102, were 
600 mg IV daily and 1000 mg PO daily for 14 days, respectively. The 6-week dose regimen 
administered in study APX001-105 is closely matching the dose and duration that will be 
employed in this protocol. In these 3 Phase 1 studies, all doses of APX001 were safe and well 


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tolerated. The majority of the treatment-emergent adverse events (TEAEs) were mild, transitory,
and resolved without intervention. There were no severe or serious adverse events (SAEs) reported 
and no dose-limiting toxicities were observed. In all 3 Phase 1 studies, no laboratory test results 
nor results from other safety evaluations (physical examination, electrocardiogram [ECG], vitals) 
met the criteria for a TEAE nor did any result meet the a priori rules that prevented dose escalation. 
In an additional dose escalation study, APX001-106, cohorts of healthy volunteers were 
administered 750 to 900 mg IV daily for 6 days, preceded by various loading doses. Some of the 
900 mg dose regimens that employed high loading doses were not well tolerated. Consequently, 
at this time the 900 mg dose regimen will not be employed in this study. 
APX001 and APX001A PK parameters for both single and multiple APX001 IV and PO doses in 
all 4 Phase 1 studies in healthy volunteers were linear and dose proportional. In the cohort 
embedded within the PO dose Phase 1 study APX001-102, APX001 demonstrated a favorable
(ie APX001 was not a strong inhibitor or strong inducer of cytochrome P450 [CYP] enzymes)
drug-drug interaction (DDI) profile. The relative bioavailability of the PO APX001 formulation is 
>90% in both the presence or absence of food, demonstrating that no food effect exists. In addition, 
the target AUCs anticipated for efficacy against both yeasts and molds have been achieved with 
both IV and PO dose formulations. 
Further details of all the Phase 1 studies can be found in the Investigator’s Brochure (IB). 
Phase 1 studies in patients: 
Study APX001-103 was conducted in patients with newly diagnosed AML undergoing induction 
chemotherapy. The objective of this study was to evaluate the safety, tolerability, and PK of IV 
and PO doses of APX001 in a patient population in which the investigational medicinal product
(IMP) will be studied. There were no treatment-related SAEs reported during the study and none 
of the TEAEs reported as related to APX001 resulted in drug withdrawal/discontinuation. With 
the exception of 1 Grade 3 TEAE (hypertension), all TEAEs reported as related to APX001 were 
of the Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 and 2. 
All clinically significant abnormal clinical laboratory findings observed in this study, vital signs, 
ECG, and physical examination findings, can be attributed to the underlying condition of AML 
and the aggressive induction chemotherapy. Overall, the safety results from this study indicate 
daily doses of IV or PO APX001 given for 14 days were safe and well tolerated. No evidence of 
significant or additional risks of APX001 in this patient population was observed and no new safety 
concerns were identified. 
Plasma concentrations and calculated exposures of APX001 and APX001A in study APX001-103 
were lower than expected based on PK data from prior Phase 1 studies in healthy volunteers 
(APX001-101 and APX001-102). Potential factors that might contribute to this observation were 
thoroughly investigated and are described in the IB. These experiments confirmed that the plasma 
concentrations of APX001 and/or APX001A are dependent on hematocrit values. The lowered 
exposures observed in the APX001-103 PK results are most likely due to a dilution effect. When 
plasma concentrations are adjusted to account for this effect, PK parameters in APX001-103 are 
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Further details of all the Phase 1 studies can be found in the IB. 
In summary, APX001 has a novel mechanism of action with broad spectrum activity against 
Candida spp. (yeast) and Aspergillus spp. (mold), including activity against polyene and 
azole-resistant strains of Aspergillus spp. APX001 has demonstrated efficacy in a number of 
animal models of IMIs, including Aspergillus spp., Fusarium spp., Scedosporium spp., and 
Mucorales fungi. To date, APX001 in both IV and PO formulations has been safe and well 
tolerated with a favorable DDI profile. APX001 has the potential to be used as a first-line agent 
for the treatment of IMIs.
1.1
Rationale
The need for improved treatment of invasive fungal diseases remains high, particularly with the 
growing number of immunocompromised patients, such as AML patients, non-Hodgkin’s 
lymphoma patients, and solid organ transplant recipients, who are at particular risk for developing 
these infections and in whom treatment can be complex. Species of Candida and Aspergillus are 
well recognized as the 2 major causes of fungal diseases in these patients, although other emerging 
fungi, such as rare molds (eg, Fusarium spp., Scedosporium spp., and Mucorales fungi), are 
contributing to the need to find new and better strategies for managing these infections. Existing 
antifungal agents can be difficult to use, are often poorly tolerated, have DDIs, may not be 
available as IV and PO formulations, or have become increasingly ineffective due to the rise of 
drug resistant fungal strains.
Patients enrolled in this study will have limited or no antifungal treatment options due to 
documented/anticipated resistance, contraindication, intolerance, or lack of clinical response to 
standard of care (SOC) antifungal therapy. Under this setting, APX001 may have potential 
advantages over SOC antifungal therapy and thus supports its preliminary investigation for the 
treatment of IMIs. 
Invasive aspergillosis is a well-described complication of severe influenza pneumonia.  
Severe influenza in critically ill patients is complicated by IPA in 7-23% of cases and associated 
with a case fatality rate of more than 50%.  Since December 2019 coronavirus disease 2019 
(COVID-19) has rapidly spread around the globe, becoming a pandemic threat.  Patients infected 
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience major lung 
damage due to viral replication and the ensuing cytokine storm and complex inflammatory 
processes. The severe damage to lung tissue can lead to secondary infections.  Most recently, cases 
of invasive pulmonary aspergillosis in patients with COVID-19 pneumonia with ARDS have been 
reported.  Given this, it is important to consider the evaluation of APX001 in the management of 
these patients.  As such, a separate Cohort has been incorporated into the protocol.  


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1.2
Risk/Benefit
1.2.1
Potential Risks
Patients participating in this study will receive a drug in clinical development that has not yet been 
approved by regulatory authorities. It is unknown if patients with invasive infections caused by 
Aspergillus spp. or rare molds will benefit from treatment with APX001. Based on 
histopathological findings in minipigs administered APX001 orally for 15 weeks, there is a 
potential that patients receiving treatment with APX001 may be at risk for liver toxicity; male 
patients may also be at risk for irreversible testicular toxicity (impaired fertility).   Based on the 
findings in Phase 1 and 2 studies, there is a potential that patients receiving treatment with APX001 
may develop headache, dizziness, fatigue, nausea, and vomiting. For more information on the 
APX001 safety profile please refer to the IB.  
1.2.2
Potential Benefits
APX001 may have potential benefits compared to the current SOC for treatment of invasive 
infections caused by Aspergillus spp. or rare molds. Furthermore, APX001 has a differentiated 
safety profile, is available as IV and PO formulation, and may have fewer DDIs than the SOC 
treatments. 
Patients with azole-resistant mold infections, including azole-resistant A. fumigatus and some rare 
molds (eg, Fusarium spp., Scedosporium spp., Mucorales fungi) typically receive IV treatment 
with a polyene. Polyenes have been associated with risk of nephrotoxicity, electrolyte imbalance, 
and infusion reactions which can be limiting in patient care.12 APX001 has broad-spectrum 
antifungal activity with coverage against azole-resistant molds, and has the potential to be safer 
and easier to use compared to polyene. 
APX001 may provide an advantage over a polyene for the treatment of “breakthrough” infections 
in patients receiving prophylaxis with mold active triazoles. APX001 has the potential to provide 
antifungal coverage for A. fumigatus and rare molds, without the potential for polyene-induced 
toxicities. With wide tissue penetration, APX001 may provide a benefit for the treatment of 
patients with invasive fungal infections in the eye and central nervous system. 
APX001 may provide a benefit to patients with invasive fungal infections who are unable to 
receive treatment with a mold-active azole due to intolerance, toxicity, or clinically significant 
drug interactions. APX001 has the potential to provide broad-spectrum antifungal coverage,
without the risk of hepatic or other azole-associated toxicities, and is expected to be less likely to 
induce clinically significant drug interactions. 
Thus, APX001 is an investigational drug therapy that may fill an unmet need with a unique 
mechanism of action and no suspected cross-resistance to other mold active antifungals seen in 
animal models or surveillance to date. 
Additionally, in those patients with a COVID-19 pneumonia who develop invasive aspergillosis, 
APX001 may provide a potential treatment for the secondary IPA infection.  


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1.2.3
Assessment of Potential Risks and Benefits
APX001 is a broad-spectrum antifungal agent, available in both IV and PO formulations, with 
wide-tissue distribution, including the eye and central nervous system. APX001 has a
differentiated safety and DDI profile compared to SOC antifungal therapy. Patients with limited 
treatment options will be included in this investigational study if they have an invasive infection 
with Aspergillus or a rare mold, and there is a potential advantage of receiving treatment with 
APX001 compared to the current SOC. 
Patients participating in this clinical study will receive more intense health monitoring as detailed 
in the schedule of procedures. 
2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this proof-of-concept study is to evaluate the safety and efficacy of 
APX001 for the treatment of adult patients aged 18 years and above with IMIs caused by 
Aspergillus spp. or rare molds (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi), 
who have limited antifungal treatment options.
2.2
Secondary Objectives
The secondary objectives of this study are to:

Evaluate global response at End of Study Treatment (EOST)

Evaluate safety parameters of APX001

Evaluate PK parameters of APX001
3
STUDY DESCRIPTION
3.1
Summary of Study Design
This is a Phase 2, multicenter, open-label, parallel-group, non-comparative study to evaluate the 
safety and efficacy of APX001 for the treatment of IMIs caused by Aspergillus spp. or rare molds
(eg, Scedosporium spp., Fusarium spp., and Mucorales fungi). Patients 18 years of age or older 
will undergo Screening procedures for up to 5 days, following which eligible patients will 
participate in the study drug Treatment Period for up to 6 weeks, with a Follow-Up Visit 4 weeks 
after EOST, and a Follow-Up Phone Call 12 weeks after Day 1 (Day 84). The total duration of a 
patient’s participation in the study will be approximately 12 weeks, inclusive of the follow-up 
telephone call required on Day 84. Patients who require treatment for longer than 6 weeks can be 
switched to other licensed antifungal therapy (OLAT) at the discretion of the Investigator and in 
consultation with the Medical Monitor if the situation allows.
This study will be conducted at up to 40 global sites. 
A complete schedule of procedures for the study is found in APPENDIX A.


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Figure 1 presents a schematic for the study. 
Figure 1.
Study Schematic
BID = twice daily; EOST = End of Study Treatment; IV = intravenous(ly); PO = oral(ly); QD = once daily. 
This study will consist of 
 parallel cohorts.  Cohort A will enroll up to 40 patients, 
  Each cohort has a single treatment arm consisting of 
a loading dose of 1000 mg APX001, administered over 3 hours by IV infusion twice daily (BID)
within the first 24 hours after initiation of the first infusion. On Days 2 and 3, 600 mg APX001 
will be administered over 3 hours by IV infusion once daily (QD). From Day 4 through EOST, the 
IV dose remains 600 mg APX001 administered over 3 hours by IV infusion QD, or patients may 
be switched to PO administration of 800 mg APX001 QD. Antiemetics (preferably a 5-HT3
antagonist such as ondansetron or granisetron) should be administered in patients who develop 
nausea and/or vomiting associated with APX001 administration (both IV and oral), and oral 
APX001 may be given with food. Additionally, prophylactic antiemetics, (preferably a 5-HT3
antagonist such as ondansetron or granisetron) may be administered prior to dosing (both IV and 
oral) in patients considered at higher risk of gastrointestinal intolerance. The decision to switch 
from IV to PO APX001 will be based on the Investigator’s discretion and can be done on any day 
from Day 4 onwards. Patients will remain hospitalized for at least 2 days following the initial 
switch from IV to PO so that their tolerance to the oral medication may be evaluated and treated 
as necessary.  Patients may be switched between IV and PO as needed.  Oral APX001 may be 
given as an outpatient. 
Administration of APX001 should not continue for longer than 6 weeks (inclusive of the loading 
dose [Day 1]). If an Investigator documents an improvement or resolution in clinical signs and 
symptoms prior to 6 weeks, eg, if follow-up imaging (as applicable) shows improvement; or a 
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mycological response (if amenable to repeat sampling) is observed, the Investigator may choose 
to discontinue dosing. Patients will be requested to return for an EOST and Follow-Up Visit and 
to agree to a Follow-Up Phone Call. 
Table 1 describes dosing for the study. 
Table 1.
Patient Enrollment by Dosing Arm
Load Dosing
Day 1 (Baseline)
Maintenance Dosing
Days 2-42 [1]
Total Enrolled (n)
IV BID
IV QD [1]
PO QD [1,2]
1000 mg
600 mg
800 mg
50
1.
On Days 2 and 3, APX001 will be administered over 3 hours by IV infusion QD. From Day 4 through EOST, 
the IV dose remains 600 mg APX001 administered over 3 hours by IV infusion QD, or patients may be 
switched to PO administration of 800 mg APX001 QD. 
2.
Patients may switch back and forth between IV and PO as needed.  Oral APX001 may be given as an outpatient. 
BID = twice daily; EOST = End of Study Treatment; IV = intravenous(ly); PO = oral(ly); QD = once daily. 
Blood samples (serum and plasma) and other diagnostic specimens (eg, bronchoalveolar lavage 
[BAL]) will be collected at Screening for pathogen DNA analysis utilizing next-generation 
sequencing (optional) and/or polymerase chain reaction (PCR) analysis. Urine samples will be 
collected at Screening for the aspergillosis urine test (MycoMEIA). 
Plasma samples for PK (APX001 [prodrug] and APX001A [active moiety]) will be collected 
predose and 3 hours post start of infusion on Days 1 (Baseline), 2, 3, 7, and 14; predose on Days 28
and 42; and at any time in clinic at EOST, the Follow-Up Visit; and the Early Termination (E/T) 
Visit (if applicable). Additionally, for patients who switch to PO dosing, samples should be 
collected predose and at 3 hours postdose on the initial day of PO dosing, Day 7, and Day 14 and 
at any time in clinic on Days 28 and 42, at EOST, at the Follow-Up Visit, and at the E/T Visit
(if applicable). If the patient switches back to IV dosing, PK samples should be collected predose 
and at 3 hours post start of infusion on that day as well. 
Serum samples for analysis of 
 will be collected at Screening; predose on Days 1
(Baseline), 2, and 3; on Days 7, 14, 28, and 42; at EOST; and at the E/T Visit (if applicable).
Serum samples for analysis of 
 will be collected at Screening; predose on Day 1
(Baseline); on Days 14, 28, and 42; at EOST; at the Follow-Up Visit; and at the E/T Visit 
(if applicable). 
Assessment of clinical signs and symptoms will be conducted at Screening; at all visits from Day 1
(Baseline) through EOST; at the Follow-Up Visit; and at the E/T Visit (if applicable).
Radiological assessments (including computed tomography [CT] scans of the chest, sinuses, 
and/or abdomen) will be performed during Screening (SOC scans within 3 days of Screening will 
be accepted as long as the scans can be provided to the central reader). Computed tomography 
scans of the chest, sinuses, and/or abdomen will be repeated on Day 14 and at EOST, and if 
clinically indicated on Days 7, 21, 28, 35, and 42; at the Follow-Up Visit; and at the E/T Visit 
(if applicable).
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Samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, sinus aspirate, tracheal 
aspirate) will be collected and processed for culture and susceptibility by the local laboratory at 
Screening, and as clinically indicated at any visit from Day 1 (Baseline) through EOST, at the 
Follow-Up Visit, and at the E/T Visit (if applicable). Screening samples for fungal cultures to 
determine eligibility may have been collected as SOC within 120 hours prior to initial dosing. 
All fungal isolates cultured at the local laboratory will be sent to the central mycology reference 
laboratory for confirmation of identification and susceptibility testing.
Bronchoalveolar lavage samples will be collected per SOC for culture at the local laboratory and 
testing at the central laboratory as clinically indicated at any visit from Screening 
throughout the study. 
The safety and tolerability of APX001 will be evaluated through physical examination findings, 
clinical signs and symptoms, vital signs, changes in clinical laboratory tests, 12-lead ECGs, any 
other exploration, and monitoring of adverse events and concomitant medications or procedures.
3.2
Study Indication
APX001 is indicated for the treatment of patients with IMIs caused by Aspergillus spp. or rare 
molds. 
4
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1
Inclusion Criteria
This study will enroll male and female patients aged 18 years and above with a confirmed diagnosis 
of invasive aspergillosis or invasive rare mold infection. Patients will have limited or no treatment 
options due to documented/anticipated resistance, contraindication, intolerance, or lack of clinical 
response to SOC antifungal therapy, as advocated by the relevant regional/country treatment 
guidelines. The study will enroll 
cohorts, Cohort A 
  Up to 40 patients will be enrolled 
in Cohort A, and these patients will have an IMI which was diagnosed according to the 
EORTC/MSGERC criteria. 
 
 
Patients must meet all of the following criteria to be eligible for study entry:
1. Males or females, 18 years or older.
2. Patients with IMI caused by Aspergillus spp. Patients who present with IMI due to other 
filamentous fungi (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi such as 
Mucor spp. or Rhizopus spp.) may also be enrolled.
o
Cohort A:  Diagnosis of proven or probable IMI will be defined in accordance with the 
Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the 
EORTC/MSGERC (Donnelly et al., 2019)13 (see APPENDIX D and APPENDIX E).
o
 
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3. Have limited or no treatment options due to documented or anticipated resistance, 
contraindication, intolerance, or lack of clinical response to SOC antifungal therapy, 
as advocated by the relevant regional/country treatment guidelines. 
4. Patients where the Investigator considers that there is a potential advantage of using APX001 
over current SOC (eg, broad spectrum of activity, activity against resistant mold pathogens, 
IV and PO formulations, favorable DDI profile, favorable hepatic and renal safety profile, wide 
tissue distribution including brain), and/or where SOC antifungal therapy carries significant 
risk of toxicity or treatment failure (eg, emergence of IMI during antifungal prophylaxis, DDI 
risk, safety/toxicity risk, site of infection not accessible by SOC).
5. Female patients of nonchildbearing potential must be 1 of the following:
o
Surgically sterile (hysterectomy, bilateral tubal ligation, bilateral salpingectomy, and/or 
bilateral oophorectomy). 
o
Postmenopausal (amenorrhea for >12 months without an alternative medical cause). 
6. Females of childbearing potential (ie, not postmenopausal or surgically sterilized) must have a 
negative urine or serum pregnancy test result within 96 hours prior to Baseline (ie, predose on 
Day 1). Participating females of childbearing potential with male partners, and males with 
female partner(s) of childbearing potential, must agree to use 2 forms of contraception, 1 of 
which must be highly effective and the other an acceptable barrier method (male or female 
condom), throughout the duration of the study and for 90 days following the last study drug 
administration. Highly effective methods of contraception include the following:
o
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (PO, intravaginal, or transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (PO, injectable, or implantable), 
intrauterine device, or intrauterine hormone-releasing system.
o
Bilateral tubal occlusion or vasectomized partner.
Note: A vasectomized partner is a highly effective method of contraception, provided that 
the male partner is the sole sexual partner of the study patient who is a female of 
childbearing potential and that the vasectomized partner has received medical assessment 
of surgical success. 
o
Sexual abstinence.
Note: True abstinence, when in line with the preferred and usual lifestyle of the patient, is 
considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug treatment. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and
withdrawal are not acceptable methods of contraception.
7. Male patients must agree to abstain from sperm donation and use condoms with spermicide 
during sexual intercourse between Screening and at least 90 days after administration of the 
last dose of study drug. Male patients must ensure nonpregnant female partner(s) of 
childbearing potential comply with the contraception requirements in Inclusion Criterion 6. 


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8. Patients must be willing to participate in the study, to give written informed consent, and to 
comply with the study restrictions; where permitted by local regulations, written informed 
consent from a legal authorized representative (LAR) will be obtained for patients who are 
unable to give consent.
9.
 
 
4.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible for the study:
1. Refractory hematologic malignancy with no potential to respond to additional chemotherapy.
2. Chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis.
3. Treatment with systemic (PO, IV, or inhaled) antifungal therapy with a mold-active azole or 
polyene for ∀120 hours immediately before initial dosing.
Note: An exception is antifungal prophylaxis, for which there is no restriction on duration but 
must be stopped upon commencement of treatment with APX001.
Additionally, patients with invasive fungal infection caused by a mold with documented 
resistance to or lack of coverage by the prior SOC in question, as well as patients with 
polyene-induced renal toxicity or those who have received empirical treatment with 
echinocandins may have received >120 hours prior treatment and remain eligible for the study. 
These patients must be discussed with the Medical Monitor prior to enrollment, and prior 
treatment in this case should not exceed >168 hours.
4. Evidence of significant hepatic dysfunction, defined as any of the following:
o
Total bilirubin >3 ∃the upper limit of normal (ULN) unless isolated hyperbilirubinemia or 
due to documented Gilbert’s disease.
o
Alanine transaminase or aspartate transaminase ∀5 ∃ULN.
o
Severe or moderate hepatic impairment (Child-Pugh Score >6 points) at any time during 
2 weeks prior to dosing. The Child-Pugh score of > 6 is applicable only to patients with 
hepatic dysfunction and cirrhosis.  
5. Ongoing medical history of neurological disorders including abnormal movements or seizures.
Note:  A current CNS mold infection as well as a stable history of peripheral neuropathy will 
not be considered exclusionary.  
6. Patient receiving palliative care only.
7. Known hypersensitivity or other serious reaction to APX001 or any ingredient of APX001.
8. Patient is lactating and/or pregnant or intending to be pregnant during the duration of the study.
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9. Investigational drug administered within 30 days or 5 terminal half-lives prior to study drug 
dosing (whichever is longer).
Note: Participation in research protocols for approved agents for the treatment of an underlying 
condition is permitted.
10. Prior participation in this study or any previous study of APX001.
11. Concomitant use of medication that is a strong inducer (ie, rifampin, carbamazepine, 
phenytoin, rifabutin, efavirenz, nevirapine, phenobarbital, modafinil, St. John’s Wort, 
enzalutamide) of CYP enzymes.
12. Any other condition or laboratory abnormality that, in the opinion of the Investigator or the 
Sponsor, would put the patient at unacceptable risk for participation in the study or may 
interfere with the assessments included in the study.
13. Patients on mechanical ventilation
14. Cohort A only: Suspected or confirmed COVID-19 or Influenza A/B infection.
15. Patients with severe renal impairment as determined by estimated glomerular filtration rate 
(eGFR) <30 mL/min /1.173 m2 calculated by CKD-EPI, including patients on dialysis
16. Patients with a Karnofsky Performance Status ≤30 at screening
4.3
Withdrawal Criteria
Study drug dosing must be discontinued for any of the following reasons:

The patient withdraws consent or requests discontinuation from the study for any reason

Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol

Occurrence of drug-induced liver injury (DILI) [APPENDIX G]

Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the patient

Pregnancy

Requirement of prohibited concomitant medication (eg, systemic antifungal therapy)

Patient failure to comply with protocol requirements or study-related procedures

Termination of the study by the Sponsor or the regulatory authority
If a patient must be discontinued from study drug administration for any of the above criteria,
the patient will still be encouraged to continue visits and assessments necessary for appropriate 
safety follow-up. 


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If a patient withdraws prematurely from the study due to any of the above criteria or for any other 
reason, study staff should make every effort to contact the Sponsor prior to discontinuation, 
if possible, and to complete the full panel of assessments scheduled for the E/T Visit. The reason 
for patient withdrawal must be documented in the electronic Case Report Form (eCRF).
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records.
Withdrawn patients will not be replaced.
4.4
Discontinuation Rules
4.4.1
Study Discontinuation Rules
At any time, the independent Data and Safety Monitoring Board (DSMB) may temporarily 
suspend enrollment until any significant safety concerns are resolved or terminate the study to 
ensure patient safety, if in the opinion of the DSMB, further dosing would pose an inappropriate 
safety risk. Guidelines for what constitutes inappropriate safety risks are described in the DSMB 
Charter.
Additionally, the study may be discontinued for any of the following reasons: 5 or more patients 
in the study (cumulative) experience the same Grade 2 (or higher) related adverse event 
(laboratory or clinical) which is coded in the same high-level group term per the 
Medical Dictionary for Regulatory Activities coding, throughout the duration of the study; lack of
study drug availability; inability to enroll the study; or decision by a regulatory authority or the 
Sponsor.
4.4.2
Patient Discontinuation Rules
Study treatment for an individual patient may be discontinued for lack of clinical and/or 
microbiological response, any adverse event, SAE, laboratory abnormality, or intercurrent illness
which, in the opinion of the Investigator, indicates that continued dosing in the study is not in the 
best interest of the patient. Whenever feasible, the Investigator should discuss the patient situation 
with the Medical Monitor prior to discontinuation of the patient.
A patient who has discontinued study drug administration will still be encouraged to continue 
visits and assessments necessary for appropriate safety follow-up, and to complete the full panel 
of assessments scheduled for the E/T Visit. The reason for patient withdrawal must be documented 
in the eCRF. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
Withdrawn patients will not be replaced. 


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4.5
Premature Study Termination
The study may be terminated prematurely by the Sponsor or a regulatory authority if there is 
sufficient reasonable cause. Reasonable cause includes reaching a discontinuation rule 
(Section 4.4), evidence of inappropriate risk for study patients, lack of study product availability, 
or reason to conclude that it will not be possible to collect the data necessary to reach the study’s 
objectives and it is therefore not ethical to continue enrollment of more patients. 
In addition, an independent DSMB may terminate the study if, in the opinion of the DSMB, 
further dosing would pose an inappropriate safety risk. Guidelines for what constitutes 
inappropriate safety risks are described in the DSMB Charter. 
The Sponsor will promptly inform the Investigators and the regulatory authority(ies) of the 
termination of the study and the reason(s) for the termination. The Investigators are responsible
for promptly informing patients that they must discontinue study drug. The Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) will also be informed promptly and provided 
the reason(s) for the termination, as specified by the applicable regulatory requirement(s). 
5
STUDY TREATMENTS
5.1
Treatment Groups
Patients in Cohorts A and B will receive the same treatment. Patients will receive a loading dose 
of 1000 mg APX001, administered over 3 hours by IV infusion BID within the first 24 hours after 
initiation of the first infusion. On Days 2 and 3, 600 mg APX001 will be administered over 3 hours 
by IV infusion QD. From Day 4 through EOST, the IV dose remains 600 mg APX001 
administered over 3 hours by IV infusion QD, or patients may be switched to PO administration 
of 800 mg APX001 QD. The decision to switch from IV to PO APX001 will be based on the 
Investigator’s discretion. 
5.2
Rationale for Dosing
In a PK-PD IPA study, immunocompromised mice were infected with 6 strains of A. fumigatus, 
inclusive of wild type, azole-resistant, and echinocandin-resistant strains. Groups of animals were 
dosed with APX001 at different dose fractionations. The AUC from time 0 to 24 hours
(AUC(0-24))/MEC ratio was determined to be the PK-PD index that best correlated with antifungal 
efficacy as assessed by fungal burden (conidial equivalent [CEs] measured by real time 
quantitative PCR [qPCR]) in lung homogenates. The stasis and 1-logarithm drop endpoints were 
defined as the quantity of A. fumigatus in CEs just prior to APX001 administration compared to 
CEs at the endpoint of assessment at 96 hours. The median total drug AUC/MEC which achieved 
stasis and 1-logarithm kill endpoints for each A. fumigatus strain were 2801.6 and 5258.2.14
The clinical isolates surveillance data from 2017,2018, and 2019 of APX001A antifungal activity
against Aspergillus spp. shows that the majority (96%) of Aspergillus isolates have MEC values 
of 0.008 to 0.03 µg/mL. The MEC in 90% of patients (MEC90) for Aspergillus isolates likely to be 
found in the clinical patient population under study is 0.03 µg/mL.


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One dose regimen of APX001 will be evaluated in this study. In Phase 1 studies in healthy 
volunteers, the dose regimen in this study was safe and well tolerated. While the study allows a 
switch to PO dosing as early as Day 4, Table 2 describes the estimated total drug AUC(0-24) and 
PTA for stasis in CE at the MEC90 with the companion PO switch at Day 7.
Table 2.
Estimated Area Under the Curve and Probability of Target Attainment for 
the APX001 Dose Regimen 
Load IV BID
(Day 1 [Baseline])
IV
Maintenance QD
(Days 2-7)
PO
Maintenance QD
(Days 8-42)
AUC(0-24)
(Days 7/14/42)
PTAs at MEC90
(stasis [Day 14])
1000 mg
600 mg
800 mg
195/224/224
90%
AUC(0-24) = area under the concentration-time curve from time 0 to 24 hours; BID = twice daily; 
IV = intravenous(ly); MEC90 = minimal effective concentration in 90% of patients; PO = oral(ly); 
PTA = probability of target attainment; QD = once daily.
The dose regimen employed in this study provides a steady state AUC 200 µg·hr/mL, which is 
associated with efficacy (colony count and survival benefit) in immunocompromised mice with 
IPA. Additionally, formal PK-PD studies demonstrated that the dose regimen has favorable PTA 
for the majority of isolates anticipated to be encountered in this study. 
Formal PK-PD for invasive rare mold infections (eg. Fusarium spp., Scedosporium spp., 
Mucorales fungi) have not yet been conducted. However, immunocompromised animal models of 
rare mold infections demonstrate colony count and survival benefits at AUCs provided by the dose 
regimen employed in this study. 
5.3
Randomization and Blinding
This is an open-label study. 
5.4
Breaking the Blind
This is an open-label study. 
5.5
Drug Supplies
5.5.1
Formulation and Packaging
APX001 injection is an aqueous solution formulated at a concentration of 20 mg/mL. 
The formulation consists of APX001 drug substance, sodium chloride, potassium phosphate 
(dibasic and monobasic), hydrochloric acid, sodium hydroxide, and water for injection. A 20 or 
50 mL sterile glass vial is filled with 17.5 or 35 mL of APX001 injection, respectively, yielding 
350 or 700 mg/vial. APX001 injection will be further diluted and administered as an IV infusion. 
Preparation and dilution instructions will be provided in the Pharmacy Manual.
The formulation of 200 mg tablets consists of APX001 drug substance, microcrystalline cellulose, 
colloidal silicon dioxide, pregelatinized starch, povidone, anhydrous dibasic calcium phosphate, 
talc, and magnesium stearate. All tablets are coated with an aqueous coated film system and 


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purified water. The tablets are stored in high-density polyethylene bottles with a child-resistant 
container.
All APX001 supplies will be labeled according to the requirements of local law and legislation, as 
well as current Good Manufacturing Practice and Good Clinical Practice (GCP) guidelines.
5.5.2
Study Drug Preparation and Dispensing
Study drug will be delivered to the study site by an authorized delegate of the Sponsor. Site staff 
who have been delegated the task of drug dispensing by the Investigator will dispense the 
appropriate treatment. 
Additional details regarding study drug preparation and dispensing will be provided in the 
Pharmacy Manual.
5.5.3
Study Drug Administration
APX001 for IV administration will be delivered via central venous catheter (CVC) or peripheral 
IV line access according to SOC. APX001 for IV administration must not be infused into the same 
CVC or peripheral line access that is being used concurrently for the administration of other 
medications. Volumetric infusion pumps will be used during the administration of APX001 to 
ensure the prescribed volume is delivered to the patient. The infusion rate and total volume 
administered will be recorded on the patient’s IV bag label and in their source documentation. 
A loading dose of 1000 mg APX001 will be administered over 3 hours by IV infusion BID within 
the first 24 hours after initiation of the first infusion. On Days 2 and 3, 600 mg APX001 will be 
administered over 3 hours by IV infusion QD. From Day 4 through EOST, the IV dose remains 
600 mg APX001 administered over 3 hours by IV infusion QD, or patients may be switched to PO 
administration of 800 mg APX001 QD.
Patients who have completed a minimum of 3 days of IV APX001 may be switched from IV to 
PO APX001 if they are able to ingest medication PO and the Investigator deems it is in the patient’s 
best interest to do so. The switch to PO can be done on any day from Day 4 onwards. Patients will 
remain hospitalized for at least 2 days following the initial switch from IV to PO so that their 
tolerance to the oral medication may be evaluated and treated as necessary. Oral APX001 may be 
given with food, and prophylactic antiemetics may be administered.  Patients may be switched 
between IV and PO as needed.  Oral APX001 may be given as an outpatient. 
Study drug will not be administered for longer than 6 weeks (inclusive of the loading dose 
[Day 1]). If an Investigator documents an improvement or resolution in clinical signs and 
symptoms prior to 6 weeks, eg, if follow-up imaging (as applicable) shows improvement; or a 
mycological response (if amenable to repeat sampling) is observed, the Investigator may choose 
to discontinue dosing. Patients will be requested to return for an EOST and Follow-Up Visit and 
to agree to a Follow-Up Phone Call. Patients who still require treatment after EOST should 
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Tablets are to be administered at the same time each day, whole, and taken by mouth with water. 
No splitting or crushing of tablets is allowed. 
Intravenous APX001 will be administered inpatient by clinic staff while PO APX001 may be 
administered by clinic staff while hospitalized, or independently by patients at home. 
The acceptable dosing window for APX001 is 1 hour on Day 1 (Baseline), and 2 hours on Day 2 
through EOST. 
5.5.4
Treatment Compliance
Study drug will be administered at the study site. Compliance with treatment dosing will be 
monitored and recorded by site personnel. If patients are discharged home with study treatment, 
compliance will be documented in a dosing diary. During the Treatment Period, outpatients will 
be asked to bring the dosing diary and study drug bottles with them to every clinic visit. 
5.5.5
Storage and Accountability
APX001 injection will be stored at -20C and tablets will be stored at 2C to 8C in a secured 
location (locked) with access restricted to authorized personnel only. Detailed storage and handling 
instructions are located in the study specific Pharmacy Manual. Storage temperature will be 
monitored and recorded. Further details for storage and accountability of study drug will be 
provided in the Pharmacy Manual.
Upon receipt of study drug, the Investigator or designee will conduct a complete inventory of all 
study drug and ensure no damage occurred during shipment. 
The Investigator will maintain adequate records documenting the receipt, use, loss, or other 
disposition of study drug. Drug accountability logs will identify the study drug code number and 
account for the disposition on a patient-by-patient basis, including specific dates and quantities. 
The drug accountability logs will be signed by the individual who dispenses the study drug and 
copies will be provided to the Sponsor. 
All used and unused supplies will be appropriately inventoried and verified by the clinical research 
associate (CRA).
Any unused study drug will be returned to the Sponsor or destroyed on site per local standard 
operating procedure after monitoring has occurred.
5.6
Prior and Concomitant Medications and/or Procedures
5.6.1
Excluded Medications and/or Procedures
5.6.1.1
APX001 as a Victim Substrate for Cytochrome P450 Drug-drug Interactions
APX001 is metabolized by multiple CYP enzymes and thus any single CYP enzyme that is 
inhibited or induced is unlikely to result in clinically significant changes in the levels of APX001A. 
However, patients who are receiving or will receive strong inducers of multiple CYP enzymes 
(eg, rifampin, carbamazepine, phenytoin, rifabutin) are excluded from participating in the study. 


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Concomitant use of multiple medications that are strong inhibitors of different CYP pathways may 
increase levels of APX001A, which in consequence may potentially affect the safety risk of 
APX001 administration. Caution should be advised when coadministering any medication that is 
a strong inhibitor of any CYP(s), especially if another medication(s) that the patient is taking is 
also a strong inhibitor of CYP(s). 
5.6.1.2
APX001A as a Perpetrator of Cytochrome P450 Drug-drug Interactions
APX001A was shown to be a weak inducer of CYP2B6; a moderate inducer of CYP1A2, 
CYP2C19, and CYP3A4; and a weak inhibitor of CYP2C9 and CYP2D6. The potential clinical 
significance of any APX001A DDIs will depend on the extent of induction or inhibition and 
therapeutic margin of the specific victim substrate(s). 
Coadministration of drugs that are metabolized by the CYP enzymes in this study should be 
approached with caution and the need for increased frequency of drug monitoring 
(where applicable) considered, especially for CYP substrates that have a narrow therapeutic 
window.
Refer to https://drug-interactions.medicine.iu.edu/MainTable.aspx for an exhaustive list of CYP 
enzyme inducers and inhibitors.
5.6.2
Restricted Medications and/or Procedures
Eligible patients are prohibited from receiving treatment with systemic (PO, IV, or inhaled) 
antifungal therapy with a mold-active azole or polyene for 120 hours immediately before initial
dosing. The exception to this rule applies to patients who receive antifungal prophylaxis, for which 
there is no restriction on duration but must be stopped upon commencement of treatment with 
APX001. Additionally, patients with invasive fungal infection caused by a mold with documented 
resistance to or lack of coverage by the prior SOC in question, as well as patients with 
polyene-induced renal toxicity or those who have received empirical treatment with 
echinocandins, may have received >120 hours prior treatment and remain eligible for the study. 
These patients must be discussed with the Medical Monitor prior to enrollment, and prior treatment
in this case should not exceed >168 hours. Once on study, patients may not receive concomitant 
systemic antifungal therapy for the treatment of aspergillosis while they are receiving APX001. 
Patients cannot have received any investigational drug within 30 days or 5 terminal half-lives prior 
to dosing (whichever is longer). Participation in research protocols for approved agents for the 
treatment of an underlying condition is permitted. 
5.6.3
Documentation of Prior and Concomitant Medication Use
All prior medications received by the patient within 14 days prior to study drug administration and 
any concomitant medications used through the Follow-Up Visit will be recorded in the source 
documents and on the appropriate eCRF. The medication name, route of administration, dose, 
frequency, indication, and duration of treatment (start and stop dates) will be recorded. Use of 
chemotherapeutic agents earlier than 14 days prior to study drug administration will also be 
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6
STUDY PROCEDURES
6.1
Informed Consent
Written informed consent will be obtained from all patients (or the patient’s LAR) prior to any 
study-specific procedures being performed. Only those patients who have transient loss of capacity 
(eg, septic shock, sedation) can have an LAR sign consent. These patients, upon return of their 
capacity, will then be consented and allowed to make their own informed medical decisions. 
Patients with permanent loss of capacity will not be eligible for study participation.
6.2
Screening Visit (Day -5 to Day -1)
The following procedures will be performed at the Screening Visit:
!
Obtain informed consent.
!
Record demographic information.
!
Cohort A: Record EORTC/MSGERC classification.
!
Assess disease severity using the Eastern Cooperative Oncology Group Performance Status 
and Karnofsky Performance Status.  Assess P/F ratio (if patient is ventilated).
!
Record medical history.
!
Perform urine or serum pregnancy test on women of childbearing potential only.
!
Perform a complete physical examination including assessment of general appearance, skin, 
eyes, heart, chest, abdomen, and a neurological examination and measure height and weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform 12-lead ECG in triplicate.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including complete 
blood count (CBC)
with differential], coagulation [including prothrombin time
(PT)/international normalized ratio (INR)], and urinalysis).
!
Collect blood samples (serum and plasma) and other diagnostic specimens (eg, BAL) for 
pathogen DNA analysis utilizing next-generation sequencing (optional) and/or PCR analysis, 
analysis of
 and 
!
Collect urine sample for MycoMEIA.
!
Perform CT scan of the chest, sinuses, and/or abdomen.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate).
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
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Record prior and concomitant medications.
!
Assess adverse events.
6.3
Treatment Period (Day 1 up to Day 42)
All patients, including those enrolled on the basis of preliminary mycological evidence as noted in
APPENDIX E, will undergo the stated study procedures below. After inclusion into the study, 
every effort should be made to upgrade the certainty of diagnosis of invasive fungal disease. 
6.3.1
Day 1 (Baseline)
The following procedures will be performed on Day 1 (Baseline):
!
Perform urine or serum pregnancy test on women of childbearing potential only if the 
Screening Visit occurred ∀96 hours prior to Day 1 (Baseline).
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Collect serum samples for analysis of 
 and 
predose.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer a loading dose of 1000 mg APX001 by IV infusion over 3 hours BID within the 
first 24 hours after initiation of the first infusion.
!
Collect plasma PK samples predose and 3 hours post start of infusion.
!
Record concomitant medications.
!
Assess adverse events.
6.3.2
Day 2
The following procedures will be performed on Day 2:
!
Assess clinical signs and symptoms. 
!
Collect serum sample for analysis of 
predose.
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!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD.
!
Collect plasma PK samples predose and 3 hours post start of infusion.
!
Record concomitant medications.
!
Assess adverse events.
!
Review accountability for all returned study drug. 
6.3.3
Day 3
The following procedures will be performed on Day 3:
!
Assess clinical signs and symptoms. 
!
Perform 12-lead ECG in triplicate.
!
Collect serum sample for analysis of 
predose.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD.
!
Collect plasma PK samples predose and 3 hours post start of infusion.
!
Record concomitant medications.
!
Assess adverse events.
!
Review accountability for all returned study drug. 
6.3.4
Day 7 (& Day)
The following procedures will be performed on Day 7 (&1 day):
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform 12-lead ECG in triplicate.
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!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Perform CT scan if clinically indicated.
!
Collect serum sample for analysis of 
.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD or 800 mg APX001 PO QD.
!
Collect plasma PK samples predose and 3 hours post start of infusion or PO dosing.
!
Record concomitant medications.
!
Assess adverse events.
!
Review accountability for all returned study drug. 
6.3.5
Day 14 (± Day)
The following procedures will be performed on Day 14 (&1 day):
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform 12-lead ECG in triplicate.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Perform CT scan.
!
Collect serum samples for analysis of 
 and 
.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD or 800 mg APX001 PO QD.
!
Collect plasma PK samples predose and 3 hours post start of infusion or PO dosing.
!
Record concomitant medications.
!
Assess adverse events.
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!
Review accountability for all returned study drug. 
6.3.6
Day 21 (± Days)
The following procedures will be performed on Day 21 (&2 days):
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight. 
!
Assess clinical signs and symptoms. 
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform CT scan if clinically indicated.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated. 
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD or 800 mg APX001 PO QD.
!
Record concomitant medications. 
!
Assess adverse events. 
!
Review accountability for all returned study drug. 
6.3.7
Day 28 (± Days)
The following procedures will be performed on Day 28 (&2 days):
!
Perform urine or serum pregnancy test on women of childbearing potential only. 
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Perform CT scan if clinically indicated.
!
Collect serum samples for analysis of 
 and 
.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus spirate, tracheal aspirate) as clinically indicated.
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!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD or 800 mg APX001 PO QD.
!
Collect plasma PK samples predose for IV dosing or at any time in clinic for PO dosing.
!
Record concomitant medications.
!
Assess adverse events.
!
Review accountability for all returned study drug. 
6.3.8
Day 35 (± Days)
The following procedures will be performed on Day 35 (&2 days): 
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight. 
!
Assess clinical signs and symptoms. 
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform CT scan if clinically indicated.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated. 
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Administer 600 mg APX001 by IV infusion over 3 hours QD or 800 mg APX001 PO QD. 
!
Record concomitant medications. 
!
Assess adverse events.
!
Review accountability for all returned study drug. 
6.3.9
Day 42 (± Days)
If EOST procedures are performed after Day 39, Day 42 procedures will not be required. 
The following procedures will be performed on Day 42 (&2 days): 
!
Administer 600 mg APX001 by IV infusion over 3 hours QD or 800 mg APX001 PO QD.
!
Record Investigator assessment of global response.
!
Assess survival status. 
!
Perform urine or serum pregnancy test on women of childbearing potential only. 
!
Perform a complete physical examination including assessment of general appearance, skin, 
eyes, heart, chest, abdomen, and a neurological examination and measure weight.
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!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation. 
!
Perform 12-lead ECG in triplicate.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Perform CT scan if clinically indicated.
!
Collect serum samples for analysis of 
 and 
.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated. 
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Collect plasma PK samples predose for IV dosing or at any time in clinic for PO dosing.
!
Record concomitant medications.
!
Assess adverse events.
!
Review accountability for all returned study drug.
6.4
End of Study Treatment (+2 Days)
The EOST should occur as soon as possible following completion of APX001 dosing and within 
2 days of last dose. The following procedures will be performed at EOST (+2 days):
!
Record Investigator assessment of global response.
!
Assess survival status. 
!
Perform urine or serum pregnancy test on women of childbearing potential only. 
!
Perform a complete physical examination including assessment of general appearance, skin, 
eyes, heart, chest, abdomen, and a neurological examination and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform 12-lead ECG in triplicate.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Perform CT scan.
!
Collect serum samples for analysis of 
 and 
.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
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Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Collect plasma PK samples at any time in clinic.
!
Record concomitant medications.
!
Assess adverse events.
!
Review accountability for all returned study drug. 
6.5
Follow-Up Visit (4 Weeks After End of Study Treatment [±3 Days])
The following procedures will be performed at the Follow-Up Visit (4 weeks after EOST
[&3 days]):
!
Perform urine or serum pregnancy test on women of childbearing potential only. 
!
Perform a neurological examination (all patients) and a symptom-directed physical 
examination as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform CT scan if clinically indicated.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Collect serum sample for analysis of 
.
!
Collect plasma PK samples at any time in clinic.
!
Record concomitant medications.
!
Assess adverse events.
6.6
Follow-Up Phone Call (Day 84 [±3 Days])
The Follow-Up Phone Call will occur 12 weeks (&3 days) after Day 1 (Baseline). 
The following procedures will be performed during the Follow-Up Phone Call (Day 84 [&3 days]):
!
Assess survival status. 
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6.7
Early Termination Visit and Withdrawal Procedures
For patients who are withdrawn from the study prior to completion, the following procedures will 
be performed at an E/T Visit: 
!
Perform urine or serum pregnancy test on women of childbearing potential only.
!
Perform a complete physical examination including assessment of general appearance, skin, 
eyes, heart, chest, abdomen, and a neurological examination and measure weight.
!
Assess clinical signs and symptoms.
!
Record vital signs, including temperature, blood pressure, heart rate, respiratory rate, 
and oxygen saturation.
!
Perform 12-lead ECG in triplicate.
!
Perform clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis).
!
Perform CT scan if clinically indicated.
!
Collect serum samples for analysis of 
 and 
.
!
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, 
sinus aspirate, tracheal aspirate) as clinically indicated.
!
Collect BAL samples per SOC for culture and 
 testing as clinically indicated.
!
Collect plasma PK samples at any time in clinic.
!
Record concomitant medications.
!
Assess adverse events.
7
EFFICACY ASSESSMENTS
7.1
Primary Efficacy Endpoint
The primary efficacy parameter is the following: 
!
All-cause mortality through Day 42.
Note: All-cause mortality will represent the percentage of patients who die after the first dose 
of study drug through Day 42 from any cause.
Every attempt must be made to record survival status at Day 42 or anytime thereafter for all dosed
patients, regardless of their status of treatment, as long as the patient has not withdrawn consent 
from participation in the study. An in-person assessment is preferred; however, this assessment 
may also be performed via a telephone call if an in-person visit is not possible. 
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7.2
Secondary Efficacy Endpoint
The secondary efficacy parameter is the following: 
!
Global response at EOST
 
7.4
Clinical Signs and Symptoms Assessment
Assessment of clinical signs and symptoms will include examination of the following body 
systems: general appearance including skin, head, eyes, ears, nose, throat, neck, trunk, lymph 
nodes, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, neurological, 
psychological, lymphatic/hematological, and endocrine/metabolic. 
7.5
Microbiological Assessments
7.5.1
Pathogen DNA
Blood samples and/or other diagnostic specimens (eg, BAL) for pathogen DNA analysis utilizing 
next-generation sequencing (optional) and/or PCR analysis will be collected at Screening.
Polymerase chain reaction analysis will be performed at a central laboratory and potentially at the 
local laboratory. The Sponsor may provide sites with a validated qPCR kit to use for testing locally. 
Optional next-generation sequencing of pathogen DNA will be performed by Karius. 
7.5.2
Aspergillosis Urine Test
A urine sample will be collected at Screening for an MycoMEIA.
7.5.3
Serum Biomarkers
Serum samples for the analysis of
will be collected at Screening; predose on Days 1
(Baseline), 2, and 3; on Days 7, 14, 28, and 42; at EOST; and at the E/T Visit (if applicable). 
Analysis of
 will be reported at the local laboratory as clinically indicated, and an 
aliquot of the sample will be sent to the central laboratory for analysis. 
Serum samples for analysis of 
 will be collected at Screening; predose on Day 1
(Baseline); on Days 14, 28, and 42; at EOST; at the Follow-Up Visit; and at the E/T Visit 
(if applicable). Analysis of 
 will be reported at the local laboratory as clinically 
indicated, and an aliquot of the sample will be sent to the central laboratory for analysis of 
. 
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7.5.4
Bronchoalveolar Lavage
Bronchoalveolar lavage samples will be collected per SOC for culture at the local laboratory and 
 testing at the central laboratory as clinically indicated at any visit from Screening 
throughout the study.
7.5.5
Fungal Culture
Samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, sinus aspirate, tracheal 
aspirate) will be collected and processed for culture and susceptibility by the local laboratory at 
Screening, and as clinically indicated at any visit from Day 1 (Baseline) through EOST, at the 
Follow-Up Visit, and at the E/T Visit (if applicable). Screening samples for fungal cultures to 
determine eligibility may have been collected as SOC within 120 hours prior to initial dosing. 
All fungal isolates cultured at the local laboratory will be sent to the central mycology reference 
laboratory for confirmation of identification and susceptibility testing.
7.6
Pharmacokinetic Assessments
Plasma samples for PK (APX001 [prodrug] and APX001A [active moiety]) will be collected 
predose and 3 hours post start of infusion on Days 1 (Baseline), 2, 3, 7, and 14; predose on Days 28
and 42; and at any time in clinic at EOST, the Follow-Up Visit, and the E/T Visit (if applicable). 
Additionally, for patients who switch to PO dosing, samples should be collected predose and at 
3 hours postdose on the initial day of PO dosing, Day 7, and Day 14 and at any time in clinic on
Days 28 and 42, at EOST, at the Follow-Up Visit, and at the E/T Visit (if applicable). If the patient 
switches back to IV dosing, PK samples should be collected predose and at 3 hours post start of 
infusion on that day as well. 
Optionally, if body fluids are sampled as part of routine patient management (eg, BAL, lumbar 
puncture, paracentesis, vitreal fluid collection, abscess drainage), within approximately 2 hours of 
blood sampling for PK, these samples may be stored for future analysis of APX001 and APX001A 
levels.
8
SAFETY ASSESSMENTS
8.1
Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, whether or not related to the IMP. All adverse events, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded on the appropriate eCRF.
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of initial dosing through the Follow-Up Visit. Patients should be 
instructed to report any adverse event that they experience to the Investigator, whether or not they 
think the event is due to study treatment. Following initial dosing, Investigators should make an 
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assessment for adverse events at each visit and record the event on the appropriate adverse event 
eCRF.
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure itself. 
Any medical condition already present at initial dosing should be recorded as medical history and 
not be reported as an adverse event unless the medical condition or signs or symptoms present at 
Baseline changes in severity, frequency, or seriousness at any time during the study. In this case, 
it should be reported as an adverse event.
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at initial dosing and significantly worsen during the study 
should be reported as adverse events, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, 
or are no longer clinically significant. Abnormal test results that are determined to be an error 
should not be reported as an adverse event. Laboratory abnormalities or other abnormal clinical 
findings (eg, ECG abnormalities) should be reported as an adverse event if any of the following 
are applicable:

If an intervention is required as a result of the abnormality

If action taken with the study drug is required as a result of the abnormality

Based on the clinical judgment of the Investigator
8.1.1
Adverse (Drug) Reaction
All noxious and unintended responses to a study drug related to any dose should be considered an 
adverse drug reaction. “Responses” to a study drug means that a causal relationship between a 
study drug and an adverse event is at least a reasonable possibility, ie, the relationship cannot be 
ruled out.
8.1.2
Unexpected Adverse Drug Reaction
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For APX001 the reference safety 
information is included in the IB currently in force. The reference safety information will be 
reviewed yearly, and the periodicity of the review will be harmonized with the reporting period of 
the Development Safety Update Report.


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8.1.3
Assessment of Adverse Events by the Investigator
The Investigator will assess the severity (intensity) of each adverse event and will also categorize 
each adverse event as to its potential relationship to study drug using the categories of “yes” or 
“no.”
Assessment of Severity:
The severity of all adverse events should be graded according to the CTCAE v5.0. For those 
adverse event terms not listed in the CTCAE, the following grading system should be used:

CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated

CTCAE Grade 2: Moderate; minimal local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living

CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living

CTCAE Grade 4: Life threatening consequences; urgent intervention indicated

CTCAE Grade 5: Death related to the adverse event
Causality Assessment:
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions:
No (not related, unlikely to be related) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc) is suspected.
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc) can be 
identified.
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship.
The following factors should also be considered:

The temporal sequence from study drug administration-
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event.


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
Underlying, concomitant, intercurrent diseases-
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have.

Concomitant drug-
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question.

Known response pattern for this class of study drug-
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect.

Exposure to physical and/or mental stresses-
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event.

The pharmacology and PK of the study drug-
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered.
8.2
Serious Adverse Events
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator
or Sponsor, it results in any of the following outcomes:

Death.

A life-threatening adverse event.
Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of either 
the Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death.

Requires hospitalization or prolongation of existing hospitalizations.
Note: Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from Baseline. However, unexpected complications and/or prolongation 
of hospitalization that occur during elective surgery should be recorded as adverse events and 
assessed for seriousness. Admission to the hospital for social or situational reasons (ie, no place 


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to stay, live too far away to come for hospital visits, respite care) will not be considered 
inpatient hospitalizations. 

A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions.

A congenital anomaly/birth defect.

An important medical event.
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency.
8.3
Serious Adverse Event Reporting −Procedures for Investigators
Initial Reports
All SAEs occurring from the time of initial dosing until the Follow-Up Visit must be reported to
Medpace Clinical Safety within 24 hours of the knowledge of the occurrence (After the Follow-Up 
Visit, any SAE that the Investigator considers related to study drug must be reported to the 
Medpace Clinical Safety or the Sponsor/designee).
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC)
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at 
Medpace-safetynotification@medpace.com or 
call the Medpace SAE 
reporting line
(phone number listed below), and fax/email the completed paper SAE form to Medpace 
(contact information listed in Section 8.6) within 24 hours of awareness. When the EDC system 
becomes available, the SAE information must be entered within 24 hours of the system becoming 
available.
Safety Contact Information: Medpace Clinical Safety
Medpace SAE reporting line – USA:
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3
Fax: +1-866-336-5320 or +1-513-570-5196
Email: Medpace-safetynotification@medpace.com
Medpace SAE reporting line – Europe:
Telephone: +49 89 89 55 718 44
Fax: +49 89 89 55 718 104
Email: medpace-safetynotification@medpace.com


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Follow-Up Reports
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient
dies.
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
8.4
Pregnancy Reporting
If a patient becomes pregnant during the study or within the safety follow-up period defined in the 
protocol, the Investigator is to stop dosing with study drug(s) immediately and the patient should 
be withdrawn from the study. Early termination procedures should be implemented at that time. 
A pregnancy is not considered to be an adverse event or SAE; however, it must be reported to 
Medpace Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will 
then provide the Investigator/site the Exposure In Utero (EIU) form for completion. 
The Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical 
Safety. 
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow-up period defined in the protocol, the Investigator should notify 
Medpace Clinical Safety as described above. 
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. 
Once the outcome of the pregnancy is known, the EIU form should be completed and 
faxed/emailed to Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the Investigator should follow the procedures for reporting 
an SAE.
8.5
Expedited Reporting
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSAR) that are fatal or life-threatening as soon as possible to the
Food and Drug Administration (FDA), applicable competent authorities in all the Member States 
concerned, and to the Central Ethics Committee, and in any case no later than 7 days after 
knowledge by the Sponsor/designee of such a case. Relevant follow-up information will 
subsequently be communicated within an additional 8 days. 
All other SUSARs will be reported to the FDA, applicable competent authorities concerned, and to 
the Central Ethics Committee concerned as soon as possible but within a maximum of 15 days of 
first knowledge by the Sponsor/designee. 


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The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation. 
The Sponsor/designee will also inform all Investigators as required per local regulation.
The requirements above refer to the requirements relating to APX001.
8.6
Special Situation Reports
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints.

Overdose: Refers to the administration of a quantity of a study drug given per administration 
or cumulatively (accidentally or intentionally), which is above the maximum recommended 
dose according to the protocol. Clinical judgment should always be applied. In cases of a 
discrepancy in the drug accountability, overdose will be established only when it is clear that 
the patient has taken additional dose(s) or the Investigator has reason to suspect that the patient
has taken additional dose(s). 

Misuse: Refers to situations where the study drug is intentionally and inappropriately used not 
in a way that is not in accordance with the protocol instructions or local prescribing information 
and may be accompanied by harmful physical and/or psychological effects. 

Abuse: Is defined as persistent or sporadic, intentional excessive use of a study drug, which is 
accompanied by harmful physical or psychological effects.

Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a study drug by a healthcare professional, patient, or consumer, respectively. 
The administration or consumption of the unassigned treatment and administration of an 
expired product are always reportable as medication errors, cases of patients missing doses of 
study drug are not considered reportable as medication error.

Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
or performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction. 
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All adverse events associated with these Special Situation 
reports should be reported as adverse events or SAEs as well as recorded on the adverse event 
eCRF and/or the SAE report form. Details of the symptoms and signs, clinical management, 
and outcome should be provided, when available.
Safety Contact Information: Medpace Clinical Safety
Medpace SAE reporting line – USA:
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3
Fax: +1-866-336-5320 or +1-513-570-5196
Email: medpace-safetynotification@medpace.com


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Medpace SAE reporting line – Europe:
Telephone: +49 89 89 55 718 44
Fax: +49 89 89 55 718 104
Email: medpace-safetynotification@medpace.com
8.7
Clinical Laboratory Evaluations
Screening laboratory assessments to determine eligibility will be performed at the local laboratory 
and may have been collected as SOC within the previous 24 hours. Laboratory assessments 
collected after Screening will be sent to the central laboratory for analysis. 
Clinical laboratory assessments (serum chemistry, hematology [including CBC with differential], 
coagulation [including PT/INR], and urinalysis) will occur at Screening; predose on Days 1
(Baseline), 7, 14, 28, and 42; at EOST; and at the E/T Visit (if applicable). 
A urine or serum pregnancy test will be performed at Screening; on Days 1 (Baseline)
(if the Screening Visit occurred 96 hours prior to Day 1 [Baseline]), 28, and 42; at EOST; at the 
Follow-Up Visit; and at the E/T Visit (if applicable) for all women of childbearing potential. 
If clinically indicated and at the discretion of the Investigator, or if a suspected adverse event is 
identified, clinical laboratory assessments may be conducted at any time during the study and 
compared to Baseline. See APPENDIX E for a complete list of clinical laboratory analytes.
8.8
Vital Signs
Vital signs will include temperature, blood pressure, heart rate, respiratory rate, and oxygen 
saturation and will be collected at Screening; predose on Days 1 (Baseline), 7, 14, 21, 28, 35,
and 42; at EOST; at the Follow-Up Visit; and at the E/T Visit (if applicable). Patients should be 
supine for at least 5 minutes prior to measurement of vital signs. 
8.9
Electrocardiograms
A 12-lead ECG will be obtained in triplicate at Screening, Days 3, 7, 14 and 42, EOST, and the 
E/T Visit (if applicable). Patients should be supine for at least 5 minutes prior to the collection of 
12-lead ECGs. 
8.10
Physical Examinations
A complete physical examination will be conducted at Screening, Day 42, EOST, and the E/T Visit 
(if applicable). A complete physical examination will include an assessment of general appearance, 
skin, eyes, heart, chest, abdomen, and a neurological examination. Components of the neurological 
examination include cranial nerve, sensory, and motor examination; reflex and gait testing;
and coordination assessment. Height will be measured at Screening and weight will be measured 
at Screening; on Days 1 (Baseline), 7, 14, 21, 28, 35, and 42; at EOST; at the Follow-Up Visit;
and at the E/T Visit (if applicable). 


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A neurological examination (all patients) and a symptom-directed physical examination will be 
conducted as clinically indicated (ie, new signs or symptoms and follow-up on earlier findings) on 
Days 1 (Baseline), 7, 14, 21, 28, 35, and at the Follow-Up Visit. 
8.11
Computed Tomography
Computed tomography scans of the chest, sinuses, and/or abdomen will be performed during
Screening (SOC scans within 3 days of Screening will be accepted as long as the scans can be 
provided to the central reader). Repeat CT scans will be performed on Day 14 and at EOST, and 
if clinically indicated on Days 7, 21, 28, 35, and 42; at the Follow-Up Visit; and at the E/T Visit 
(if applicable). 
The same CT scanner and imaging protocol used at Screening should be used for subsequent 
CT scans, if possible. Additional CT scans may be performed during treatment and follow-up if 
clinically indicated. 
9
STATISTICS
9.1
Analysis Populations
Each Cohort will be analyzed and presented separately.  There will be no pooling of data across 
the Cohorts.  Each Cohort will have respective ITT, mITT, PP and PK populations.  
Intent-to-Treat Population/Safety Population:
The Intent-to-Treat (ITT)/Safety Population will include all patients who have received at least 
1 dose of study drug.
Modified Intent-to-Treat Population:
The modified Intent-to-Treat (mITT) Population will include all patients in the ITT Population 
who satisfy the following criteria:
!
Receive at least 1 dose of study drug
!
Cohort A:  Have a diagnosis of proven or probable IMI confirmed by the DRC
The mITT Population will be the primary population used for the efficacy analysis. 
Per-Protocol Population:
The Per-Protocol Population will include all patients in the mITT Population who satisfy the 
following criteria:
!
Meet the protocol’s key inclusion criteria and exclusion criteria
!
Have no major protocol violations
C
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Pharmacokinetic Population:
The PK Population will include all patients who receive any amount of study drug and have
evaluable PK data. The PK Population will be used for the PK analysis. 
9.2
Statistical Methods
Summary statistics will be presented. For continuous variables, the number of observations (n), 
mean, standard deviation, median, minimum, and maximum will be provided. For categorical 
variables, the frequency and percentage in each category will be displayed.  Each Cohort will be 
analyzed and presented separately.  There will be no pooling of data across the Cohorts.  
9.2.1
Analysis of Efficacy
The primary population for efficacy analysis will be the mITT Population.
The efficacy endpoints will be summarized descriptively, and all-cause mortality through Day 42
will be summarized. For Cohort A, the 1-sided exact binomial test at the alpha = 0.1 level of 
significance will be used to test the hypothesis that the all-cause mortality at Day 42 is less than 
45% (based on historical control data). 
The percentage of patients with global response will be summarized. 
 
 
 
9.2.2
Analysis of Safety
All safety analyses will be performed on the Safety Population. Safety data will be subject to 
clinical review and summarized by appropriate descriptive statistics. A DSMB will be assigned to 
monitor safety on an ongoing basis throughout the study.
Analyses will be based on adverse events, vital signs, clinical laboratory assessments, and ECGs. 
Safety analyses will be descriptive and will be presented in tabular format with the appropriate 
summary statistics.
A TEAE is defined as an adverse event that started on or after the administration of study drug. 
The number and percentage of patients with TEAEs will be tabulated by system organ class, 
preferred term, and by severity and relationship to treatment. Serious adverse events and adverse 
events leading to discontinuation from study drug will be summarized. Listings will also be 
provided for SAEs and adverse events leading to discontinuation of study drug. 
Descriptive statistics will be provided for clinical laboratory, vital sign, and ECG interval data for 
both actual values and changes from Baseline over time. 
Abnormal physical examination findings will be listed.
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9.2.2.1
Pharmacokinetic Analysis
The PK analysis of plasma concentration data will be performed using validated software in order 
to derive the population mean (and variance) values of specific PK parameters. 
Plasma concentrations will be summarized descriptively by
time point of collection. 
Summary statistics in the tabulation will include n, mean, standard deviation, percent coefficient 
of variation, median, minimum, and maximum. Pharmacokinetic parameters will be estimated 
using population PK analysis methods, which will be described in a separate data analysis plan. 
Results of the PK analysis will be reported separately.
9.2.3
Interim Analysis
No interim analysis is planned for the study. 
9.2.4
Data Review Committee
A DRC comprised of infectious disease experts will adjudicate the diagnosis of IMI at enrollment. 
This committee will also provide systematic assessment for clinical, mycological, radiological, 
and global responses at EOST and at the E/T Visit (if applicable). 
Global responses will be classified as complete or partial response (categorized as treatment 
success), stable response, progression of disease, or death (categorized as treatment failure) 
according to prespecified criteria (APPENDIX G). Guidelines for the DRC are described in the 
DRC Charter.
9.2.5
Data and Safety Monitoring Board
A DSMB comprised of members with pertinent expertise will be responsible for the periodic 
review of cumulative data from the study as set forth in the DSMB Charter, or more frequently at 
the request of the DSMB. The DSMB will advise the Sponsor on the continuing safety of patients 
and those yet to be recruited to the study, as well as the continuing validity and scientific merit of 
the study. The DSMB may recommend to the Sponsor that dosing in the study be suspended if, 
in the opinion of the DSMB, further dosing in the study would pose an inappropriate safety risk. 
Guidelines for what constitutes inappropriate safety risks are described in the DSMB Charter.
9.2.6
Sample Size Determination
Approximately 50 patients will be dosed in this open-label, proof-of-concept study. 
Cohort A: 
Patients with proven or probable IMI are eligible for inclusion in the mITT Population, which is 
the primary efficacy population (DRC confirmation required of proven or probable IMI). 
The sample size calculation is based on the mITT Population from the first dose of APX001 
through EOST (up to 6 weeks) for the all-cause mortality primary endpoint. A total of 24 patients 
in the mITT Population are needed, providing >90% power to detect the difference at a 1-sided 
significance level of 0.1, assuming an all-cause mortality of 20% for APX001 and 45% for adjusted 


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amphotericin B-treated all-cause mortality from the historical control. Assuming 60% of dosed 
patients will be eligible to be included in the mITT Population, a dosing of approximately 
40 patients allows for statistical testing of proof-of-concept for an estimate of 24 patients in the 
mITT Population.
 
 
 
10
DATA MANAGEMENT AND RECORD KEEPING
10.1
Data Management
10.1.1
Data Handling
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. 
The CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for.
10.1.2
Computer Systems
Data will be processed using a validated computer system conforming to regulatory requirements.
10.1.3
Data Entry
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential.
10.1.4
Medical Information Coding
For medical information, the following thesauri will be used:
!
Medical Dictionary for Regulatory Activities (latest) for medical history and adverse events
!
World Health Organization Drug Dictionary for prior and concomitant medications
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10.1.5
Data Validation
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will be 
referred to the investigative site for resolution through data queries.
The eCRFs must be reviewed and electronically signed by the Investigator.
10.2
Record Keeping
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study drug, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records. 
11
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
11.1
Ethical Conduct of the Study
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and wellbeing of study subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible.
11.2
Institutional Review Board/Independent Ethics Committee
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of patients. The study will only be conducted at sites where IRB/IEC
approval has been obtained. The protocol, IB, informed consent form (ICF), advertisements 
(if applicable), written information given to the patients, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the Investigator.
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB/IEC prior to participation of patients in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB/IEC.
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor.


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11.3
Informed Consent
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. 
A copy of the signed ICF will be given to the patient.
11.4
Subject Card 
On enrollment in the study, the patient will receive a subject card to be carried at all times. 
The subject card will state that the patient is participating in a clinical research study, type of 
treatment, number of treatment packs received, and contact details in case of an SAE.
11.5
Study Monitoring Requirements
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki and that valid data are entered into the eCRFs.
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, 
the Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. 
Before the enrollment of any patient in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, IB, eCRFs and procedures 
for their completion, informed consent process, and the procedure for reporting SAEs.
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. 
During the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible.
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log.


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11.6
Disclosure of Data
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare.
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited.
11.7
Retention of Records
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met.
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such as 
another Investigator, another institution, or to the Sponsor.  
11.8
Publication Policy
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved.
11.9
Financial Disclosure
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study.
11.10
Insurance and Indemnity
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution.


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11.11
Legal Aspects
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA).
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinion have been received. 
12
STUDY ADMINISTRATIVE INFORMATION
12.1
Protocol Amendments
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days.
12.2
Address List
12.2.1
Sponsor
Amplyx Pharmaceuticals, Inc.
12730 High Bluff Drive, Suite 160
San Diego, CA 92130
Telephone: +1-858-345-1755
Fax: +1-858-345-1346
12.2.2
Contract Research Organization
Medpace, Inc.
5375 Medpace Way
Cincinnati, OH 45227
Telephone: +1-513-579-9911
Fax: +1-513-579-0444
12.2.3
Drug Safety
Medpace, Inc.
5375 Medpace Way
Cincinnati, OH 45227
Telephone: +1-513-579-9911, dial 3
Fax: +1-513-579-0444


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12.2.4
Biological Specimens
Medpace Reference Laboratories
5365 Medpace Way
Cincinnati, OH 45227
Telephone: +1-800-749-1737 or +1-513-366-3270
Fax: +1-800-705-2177 or +1-513-366-3273
12.2.5
Mycology Reference Laboratory
JMI Labs
345 Beaver Kreek Center
Suite A
North Liberty, IA 52317
Telephone: +1-319-665-3370
Email: info@jmilabs.com
12.2.6
Pharmacokinetic Laboratory
PRA Health Sciences – Early Development Services, Bioanalytical Laboratory
Amerikaweg 18
9407 TK Assen
The Netherlands
Telephone: +0031 592 303424
Email: EDSNL-SRO@prahs.com


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13
REFERENCES
1.
Castanheira M, Duncanson FP, Diekema DJ, et al. Activities of E1210 and comparator 
agents tested by CLSI and EUCAST broth microdilution methods against Fusarium and 
Scedosporium species identified using molecular methods. Antimicrob Agents Chemother. 
2012;56(1):352-357.
2.
Pfaller MA, Hata K, Jones RN, et al. In vitro activity of a novel broad-spectrum antifungal, 
E1210, tested against Candida spp. as determined by CLSI broth microdilution method. 
Diagn Microbiol Infect Dis. 2011;71(2):167-170. 
3.
Pfaller MA, Duncanson F, Messer SA, et al. In vitro activity of a novel broad-spectrum 
antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth 
microdilution methods. Antimicrob Agents Chemother. 2011;55(11):5155-5158. 
4.
Gebremariam T, Alkhazraji S, Algarihi A, et al. APX001 is effective in the treatment of 
murine 
invasive 
pulmonary 
aspergillosis. 
Antimicrob 
Agents 
Chemother. 
2019;63(2):e01713-18. 
5.
Huband M, Pfaller MA, Flamm R, et al. In vitro activity of APX001A and comparator 
agents against 1,706 fungal isolates collected during an international surveillance 
programme (2017). Poster presented at: European Congress of Clinical Microbiology & 
Infectious Diseases; April 2019; Amsterdam, Netherlands.
6.
Watanabe NA, Miyazaki M, Horii T, et al. E1210, a new broad-spectrum antifungal, 
suppresses 
Candida 
albicans
hyphal 
growth 
through 
inhibition 
of 
glycosylphosphatidylinositol 
biosynthesis. 
Antimicrob 
Agents 
Chemother. 
2012;56(2):960-971.
7.
McLellan CA, Whitesell L, King OD, et al. Inhibiting GPI anchor biosynthesis in fungi 
stresses the endoplasmic reticulum and enhances immunogenicity. ACS Chem Biol. 
2012;7(9):1520-1528.
8.
Hata K, Horii T, Miyazaki M, et al. Efficacy of oral E1210, a new broad-spectrum 
antifungal with a novel mechanism of action, in murine models of candidiasis, 
aspergillosis, and fusariosis. Antimicrob Agents Chemother. 2011;55(10):4543-4551.
9.
Wiederhold NP, Najvar LK, Fothergill AW, et al. The investigational agent E1210 is 
effective in treatment of experimental invasive candidiasis caused by resistant Candida 
albicans. Antimicrob Agents Chemother. 2015;59(1):690-692.
10.
Zhao M, Lepak AJ, VanScoy B, et al. In vivo pharmacokinetics and pharmacodynamics of 
APX001 against Candida spp. in a neutropenic disseminated candidiasis mouse model. 
Antimicrob Agents Chemother. 2018;62(4):e02542-17.


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11.
Lepak A, Zhao M, Andes D. In vivo pharmacodynamic evaluation of the novel antifungal 
agent APX001 in a murine model of invasive pulmonary aspergillosis against wild-type 
and Cyp51 mutant Aspergillus fumigatus strains. Poster presented at: European Congress 
of Clinical Microbiology & Infectious Diseases; April 2019; Amsterdam, Netherlands.
12.
Deray 
G. 
Amphotericin 
B 
nephrotoxicity. 
J 
Antimicrob 
Chemother. 
2002;49 Suppl 1:37-41.  
13.
De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definition of invasive fungal disease 
from the European Organization for Research and Treatment of Cancer/Invasive Fungal 
Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases 
Mycoses 
Study 
Group 
(EORTC/MSG) 
Consensus 
Group. 
Clin 
Infect 
Dis. 
2008;46(12):1813-1821.   
14.
Zhao M, Lepak AJ, Marchillo K, et al. APX001 pharmacokinetic/pharmacodynamic target 
determination against Aspergillus fumigatus in an in vivo model of invasive pulmonary 
aspergillosis [published online ahead of print 22 January 2019]. Antimicrob Agents 
Chemother. 2019.


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APPENDIX A:    SCHEDULE OF PROCEDURES
Study Day
Screening
Baseline
Treatment Perioda,b
EOSTc,d
Follow-Up
Visite
Follow-Up 
Phone 
Calle
E/T
-5 to -1
1
2
3
7 
(&1)
14 
(&1)
21
(&2)
28 
(&2)
35
(&2)
42 
(&2)c
(+2)
(&3)
84 (&3)
Informed consent
X
Demographics
X
IMI classificationf
X
Disease severity 
assessmentg
X
Medical history
X
Urine or serum pregnancy 
testh
X
Xi
X
X
X
X
X
Prior/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xj
Xk
Xk
Xk
Xk
Xk
Xk
Xj
Xj
Xk
Xj
Clinical signs and 
symptoms assessmentl
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsm
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGn
X
X
X
X
X
X
X
Clinical laboratory 
assessmentso
Xp
X
X
X
X
X
X
X
Pathogen DNA analysis, 
PCR, and MycoMEIA q
X
CT scan of the chest, 
sinuses, and/or abdomenr
Xs
Xt
X
Xt
Xt
Xt
Xt
X
Xt
Xt
Serum 
collection for 
u
X
X
X
X
X
X
X
X
X
X
Fungal culturesv
X
X
X
X
X
X
X
X
X
X
X
X
X
APX001 administrationw,x
X
X
X
X
X
X
X
X
X
Plasma PK sampley
X
X
X
X
X
X
X
X
X
X
Adverse events assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
BALz
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum collection for 
X
X
X
X
X
X
X
X
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Study Day
Screening
Baseline
Treatment Perioda,b
EOSTc,d
Follow-Up
Visite
Follow-Up 
Phone 
Calle
E/T
-5 to -1
1
2
3
7 
(&1)
14 
(&1)
21
(&2)
28 
(&2)
35
(&2)
42 
(&2)c
(+2)
(&3)
84 (&3)
aa
APX001 accountability
X
X
X
X
X
X
X
X
X
X
Investigator assessment of 
global response 
X
X
Survival status assessment
X
X
X
a.
Administration of APX001 should not continue for longer than 6 weeks. If an Investigator documents an improvement or resolution in clinical signs and 
symptoms prior to 6 weeks, eg, if follow-up imaging (as applicable) shows improvement; or a mycological response (if amenable to repeat sampling) is 
observed, the Investigator may choose to discontinue dosing. Patients will be requested to return for an EOST and Follow-Up Visit and to agree to a Follow-
Up Phone Call.
b.
During the Treatment Period, outpatients will be asked to record daily dosing on a diary and bring the diary and study drug bottles with them to every clinic 
visit. 
c.
If EOST procedures are performed after Day 39, Day 42 procedures will not be required. 
d.
The EOST will occur within 2 days of completion of APX001 dosing. 
e.
The Follow-Up Visit will occur 4 weeks (±3 days) post EOST. The Follow-Up Phone Call will occur 12 weeks (&3 days) after Day 1 (Baseline). 
f.
Cohort A: Historical patient EORTC/MSGERC classification of proven or probable IMI may be used for study assessment.
 
 
g.
Assess disease severity using the Eastern Cooperative Oncology Group Performance Status and Karnofsky Performance Status. Assess P/F ratio (if patient is 
ventilated)
h.
For females of childbearing potential only.
i.
If the Screening Visit occurred ∀96 hours prior to Day 1 (Baseline), perform a urine or serum pregnancy test on women of childbearing potential only. 
j.
Conduct a complete physical examination. The physical examination includes an assessment of general appearance, skin, eyes, heart, chest, abdomen, and a 
neurological examination. Measure height only at Screening. Measure weight at each indicated visit.
k.
Conduct a neurological examination (all patients) and a symptom-directed physical examination as clinically indicated (ie, new signs or symptoms and 
follow-up on earlier findings). Measure weight at each indicated visit.
l.
Assessment of clinical signs and symptoms includes examination of the following body systems: general appearance including skin, head, eyes, ears, nose, 
throat, neck, trunk, lymph nodes, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, neurological, psychological,
lymphatic/hematological, and endocrine/metabolic.
m. Vital signs include temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation. Measure vital signs at Screening; at predose on Days 1
(Baseline), 7, 14, 21, 28, 35, and 42; at EOST; at the Follow-up Visit; and at the E/T Visit (if applicable). Patients should be supine for at least 5 minutes prior 
to measurement of vital signs. 
n.
Collect 12-lead ECGs in triplicate at Screening, on Days 3, 7, 14 and 42, at EOST, and at the E/T Visit (if applicable). Patients should be supine for at least 5 
minutes prior to collection of 12-lead ECGs.
o.
Clinical laboratory assessments include serum chemistry, hematology (including CBC with differential), coagulation (including PT/INR), and urinalysis. 
Collect blood and urine specimens at Screening; at predose on Days 1 (Baseline), 7, 14, 28, and 42; at EOST; and at the E/T Visit (if applicable).
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p.
Clinical laboratory assessments performed at Screening to determine eligibility will be performed at the local laboratory and may have been collected as SOC 
within the previous 24 hours. Laboratory assessments collected after Screening will be sent to the central laboratory for analysis. 
q.
Collect blood samples (serum and plasma) and other diagnostic specimens (eg, BAL) for pathogen DNA analysis utilizing next-generation sequencing 
(optional), PCR analysis, and collect urine sample for MycoMEIA.
r.
The same CT scanner and imaging protocol used at Screening should be used for subsequent CT scans, if possible. Additional CT scans may be performed 
during treatment and follow-up if clinically indicated.
s.
Standard of care scans within 3 days of Screening will be accepted as long as the scans can be provided to the central reader. 
t.
Perform CT scan if clinically indicated.
u.
Collect serum samples for analysis of 
 at Screening; predose on Days 1 (Baseline), 2, and 3; on Days 7, 14, 28, and 42; at EOST; and at the 
E/T Visit (if applicable). Analysis of 
 will be reported at the local laboratory and an aliquot of the sample will be sent to the central laboratory 
for analysis.
v.
Collect samples for fungal cultures (eg, from BAL fluid, sputum, bronchial brush, sinus aspirate, tracheal aspirate) at Screening, and collect as clinically 
indicated at any visit from Day 1 (Baseline) through EOST, at the Follow-Up Visit, and at the E/T Visit (if applicable). Screening samples for fungal cultures 
to determine eligibility may have been collected as SOC within 120 hours prior to initial dosing. All fungal isolates should be submitted to the central mycology 
reference laboratory for confirmation of identification and susceptibility testing.
w.
On Day 1 (Baseline), administer a loading dose of 1000 mg APX001 by IV infusion BID within the first 24 hours after initiation of the first infusion. On Days 2 
and 3, administer 600 mg APX001 by IV infusion QD. From Day 4 through EOST, administer 600 mg APX001 by IV infusion QD, or administer 800 mg 
APX001 PO QD. Antiemetics (preferably a 5-HT3 antagonist such as ondansetron or granisetron) should be administered in patients who develop nausea 
and/or vomiting associated with APX001 administration (both IV and oral), and oral APX001 may be given with food. Additionally, prophylactic antiemetics, 
(preferably a 5-HT3 antagonist such as ondansetron or granisetron) may be administered prior to dosing (both IV and oral) in patients considered at higher risk 
of gastrointestinal intolerance. The decision to switch from IV to PO APX001 will be based on the Investigator’s discretion and can be done on any day from
Day 4 onwards. Patients will remain hospitalized for at least 2 days following the initial switch from IV to PO so that their tolerance to the oral medication 
may be evaluated and treated as necessary. Oral APX001 may be given with food, and prophylactic antiemetics may be administered.   Patients may be 
switched between IV and PO as needed. Oral APX001 may be given as an outpatient. All IV infusions will be administered over 3 hours. APX001 will be 
administered for a maximum of 6 weeks (inclusive of the loading dose [Day 1]). 
x.
Intravenous APX001 will be administered inpatient by staff in clinic while PO APX001 will be administered independently by patients at home. The acceptable 
dosing window for APX001 is &1 hour on Day 1 (Baseline), and &2 hours on Day 2 through EOST.
y.
Collect plasma PK samples predose and 3 hours post start of infusion on Days 1 (Baseline), 2, 3, 7 and 14; predose on Days 28 and 42; and at any time in 
clinic at EOST, the Follow-Up Visit, and the E/T Visit (if applicable). Additionally, for patients who switch to PO dosing, samples should be collected predose 
and at 3 hours postdose on the initial day of PO dosing, Day 7, and Day 14 and at any time in clinic on Days 28 and 42, at EOST, at the Follow-Up Visit,
and at the E/T Visit (if applicable). If the patient switches back to IV dosing, PK samples should be collected predose and at 3 hours post start of infusion on 
that day as well. 
z.
Collect BAL samples per SOC for culture at the local laboratory and 
 testing at the central laboratory as clinically indicated. 
aa. Collect serum samples for analysis of 
 at Screening; predose on Day 1 (Baseline); on Days 14, 28, and 42; at EOST; at the Follow-Up Visit; and at 
the E/T Visit (if applicable). Analysis of 
 will be reported at the local laboratory as per local SOC and an aliquot of the sample will be sent to the 
central laboratory for analysis. 
BAL = bronchoalveolar lavage; BID = twice daily; CBC = complete blood count; CT = computed tomography; E/T = Early Termination; ECG = electrocardiogram; 
EORTC = European Organization for Research and Treatment of Cancer; EOST = End of Study Treatment; IMI = invasive mold infection; INR = international 
normalized ratio; IV = intravenous(ly); MSG = Mycosis Study Group; MycoMEIA = Aspergillosis urine test; PCR = polymerase chain reaction; 
PK = pharmacokinetic(s); PO = oral(ly); PT = prothrombin time; QD = once daily; SOC = standard of care.
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APPENDIX B:    CLINICAL SAFETY LABORATORY ANALYTES
Standard Safety Chemistry Panel
Alanine aminotransferase
Albumin
Alkaline phosphatase
Amylase
Aspartate aminotransferase
Bicarbonate
Blood urea nitrogen
Calcium
Chloride
Creatine kinase
Creatinine
Estimated glomerular filtration rate
Gamma-glutamyl transferase
Glucose
Inorganic phosphorus
Lactate dehydrogenase
Lipase
Potassium
Sodium
Bilirubin (total, direct, and indirect)
Total protein
Uric acid
Hematology
Hematocrit
Hemoglobin
Platelets
Red blood cell count
White blood cell count and differential [1]
1.
Manual microscopic review is performed only if white blood cell count and/or differential values 
are out of reference range. 
Coagulation
Prothrombin time
International normalized ratio
Urinalysis
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopy [1]
Nitrite
pH
Protein
Specific gravity
Urobilinogen
1.
Microscopy is performed only as needed based on positive dipstick test results.
Other Tests
Urine or serum pregnancy test [1]
1. Women of childbearing potential only. 


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APPENDIX C:    FUNGAL AND OTHER LABORATORY ANALYTES
Serum Biomarker
Bronchoalveolar Lavage
Fungal culture
Other Fungal Diagnostics
Next-generation sequencing (optional) 
and/or polymerase chain reaction analysis 
of pathogen DNA (blood and/or other 
diagnostic specimens) 
Aspergillosis urine test 
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APPENDIX D:    REVISION AND UPDATE OF THE CONSENSUS 
DEFINITIONS OF PROVEN INVASIVE FUNGAL 
DISEASE FROM THE EORTC/MSGERC 
Analysis and Specimen
Molds1
Microscopic analysis: 
sterile material
Histopathologic, cytopathologic, or direct microscopic examination2 of a specimen 
obtained by needle aspiration or biopsy in which hyphae are seen accompanied by 
evidence of associated tissue damage
Culture
Sterile material
Recovery of a hyaline or pigmented mold by culture of a specimen obtained by a 
sterile procedure from a normally sterile and clinically or radiologically abnormal 
site consistent with an infectious disease process, excluding bronchoalveolar lavage 
fluid, a paranasal or mastoid sinus cavity specimen, and urine
Blood
Blood culture that yields a mold3 (eg, Fusarium species) in the context of a 
compatible infectious disease process
Serology
Not applicable
Tissue Nucleic Acid 
Diagnosis
Amplification of fungal DNA by PCR combined with DNA sequencing when molds 
are seen in formalin-fixed paraffin-embedded tissue
1.
If culture is available, append the identification at the genus or species level from the culture results.
2.
Tissue and cells submitted for histopathologic or cytopathologic studies should be stained using 
Grocott-Gomori methenamine silver stain or periodic acid Schiff stain to facilitate inspection of fungal 
structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should 
be stained with a fluorescent dye (eg, calcofluor or blankophor).
3.
Recovery of Aspergillus species from blood cultures rarely indicates endovascular disease and almost always 
represents contamination.


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APPENDIX E:    REVISION AND UPDATE OF THE CONSENSUS 
DEFINITIONS OF PROBABLE INVASIVE FUNGAL 
DISEASE FROM THE EORTC/MSGERC  
A diagnosis of probable IFD requires at least 1 Host Factor, 1 Clinical Criterion, and Mycological Evidence 
as described below: 
Host Factors

Recent history of neutropenia (<0.5 × 109 neutrophils/L [<500 neutrophils/mm3] for >10 days) temporally 
related to the onset of fungal disease

Hematologic malignancy

Receipt of an allogeneic stem cell transplant

Receipt of a solid organ transplant

Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) 
at a therapeutic dose of 0.3 mg/kg corticosteroids for ≥3 weeks in the past 60 days

Treatment with other recognized T cell immunosuppressants, such as calcineurin inhibitors, 
TNF-α blockers, lymphocyte-specific monoclonal antibodies, or immunosuppressive nucleoside 
analogues during the past 90 days

Treatment with recognized B-cell immunosuppressants, such as Bruton’s tyrosine kinase inhibitors, 
eg, ibrutinib

Inherited severe immunodeficiency (such as chronic granulomatous disease, STAT 3 deficiency, or severe 
combined immunodeficiency)

Acute GVHD Grade III or IV involving the gut, lungs, or liver that is refractory to first line treatment with 
steroids
Clinical Criteria
Pulmonary aspergillosis
The presence of one of the following 4 signs on CT:

Dense, well-circumscribed lesion(s) with or without a halo sign

Air-crescent sign

Cavity

Wedge-shaped and segmental or lobal consolidation
Other pulmonary mold diseases
The presence of one of the following 5 signs on CT:

Dense, well-circumscribed lesion(s) with or without a halo sign

Air-crescent sign

Cavity

Wedge-shaped and segmental or lobal consolidation

Reverse halo sign
Tracheobronchitis

Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis
Sino-nasal diseases

Acute localized pain (including pain radiating to the eye)

Nasal ulcer with black eschar

Extension from the paranasal sinus across bony barriers, including into the orbit
Central nervous system infection
1 of the following 2 signs:

Focal lesions on imaging

Meningeal enhancement on magnetic resonance imaging or CT
BAL = bronchoalveolar lavage; CSF = cerebrospinal fluid; CT = computed tomography; GVHD = graft versus host disease; 
IFD = invasive fungal disease; PCR = polymerase chain reaction; spp. = species; STAT 3 = signal transducer and activator of 
transcription 3; TNF = tumor necrosis factor.


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Mycological Evidence*
!
Any mold (Aspergillus, Fusarium, Scedosporium species., or Mucorales) recovered by culture from 
sputum, BAL, bronchial brush, or aspirate
!
Microscopical detection of fungal elements in sputum, BAL, bronchial brush, or aspirate indicating a mold
Tracheobronchitis
!
Aspergillus recovered by culture of BAL or bronchial brush
!
Microscopical detection of fungal elements in BAL or bronchial brush indicating a mold
Sino-nasal diseases
!
Mold recovered by culture of sinus aspirate samples
!
Microscopical detection of fungal elements in sinus aspirate samples indicating a mold
Aspergillosis only
 antigen
Antigen detected in plasma, serum, BAL, or CSF 
Any 1 of the following:
!
Single serum or plasma: ∀1.0
!
BAL fluid: ∀1.0
!
Single serum or plasma: ∀0.7 and BAL fluid ∀0.8*
!
CSF: ∀1.0
Aspergillus PCR*
Any 1 of the following:
!
Plasma, serum, or whole blood: 2 or more consecutive PCR tests positive
!
BAL fluid: 2 or more duplicate PCR tests positive
!
At least 1 PCR test positive in plasma, serum, or whole blood and 1 PCR test positive in BAL fluid
Aspergillus species recovered by culture from sputum, BAL, bronchial brush, or aspirate
*Patients with the following preliminary mycological evidence may be entered into the study: 
1.
A single serum or plasma 
 ∀0.7 or
 in BAL fluid ∀0.8 pending the results of a 
second
 test collected prior to dosing. 
2.
A single positive PCR for Aspergillus from plasma, serum, whole blood, or BAL pending the results of a 
second PCR test collected prior to dosing. 
3.
A positive result from the Karius test which indicates the presence of cell-free DNA for Aspergillus or other 
rare molds. 
4.
A positive result from IMMY’s sōna Aspergillus Lateral Flow Device pending the results of a
 
or PCR test for Aspergillus. 
After inclusion into the study, every effort should be made to upgrade the certainty of diagnosis of IFD. 
BAL = bronchoalveolar lavage; CSF = cerebrospinal fluid; CT = computed tomography; GVHD = graft versus 
host disease; IFD = invasive fungal disease; PCR = polymerase chain reaction; spp. = species; STAT 3 = signal 
transducer and activator of transcription 3; TNF = tumor necrosis factor.
(Donnelly et al.,2019)
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APPENDIX F:    
 DIAGNOSTIC CRITERIA FOR INVASIVE 
ASPERGILLOSIS
Proven Invasive Pulmonary Aspergillosis
  Idem EORTC/MSGERC criteria (refer to APPENDIX D)
Putative invasive pulmonary aspergillosis
A diagnosis of putative IPA requires at least 1 mycological finding, 1 clinical criterion and 1 radiological 
finding 
Host Factor (must be present in all 
 patients)
!
SARS-Cov-2 and/or influenza A/B lower respiratory tract infection
Mycological Criteria (one or more of the following must be present)
!
Aspergillus-positive sputum or tracheal aspirate (only in the presence of findings of plaque, 
pseudomembrane or ulcer in bronchoscopy or in conjunction with cavitation in an area of pulmonary 
consolidation
!
Aspergillus-positive culture from BAL fluid
!
 antigen in serum or plasma ≥ 0.5 
!
 antigen in BAL fluid: ≥1.0
Clinical Criteria (one of the following signs and symptoms must be present)
!
Fever refractory to at least 3 days of appropriate antibiotic therapy
!
Recrudescent fever after a period of defervescence of at least 48 h while still on antibiotics and without 
other apparent cause
!
Dyspnea
!
Hemoptysis
!
Pleuritic friction rub chest pain
!
Worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilatory support
Radiological Criteria (must be present)
!
Abnormal medical imaging by CT scan of the lungs
BAL = bronchoalveolar lavage; CT = computed tomography; EORTC/MSGERC = European Organization for the 
Research and Treatment of Cancer/Mycosis Study Group Education and Research Consortium
Modified from Blot et al., 2012 and Schauwvlieghe et al., 2018
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APPENDIX G:    RESPONSE CRITERIA
General Criteria for Global Responses to Antifungal Therapy
Outcome, Response
Criteria
Success
Complete response
Survival within the prespecified period of observation, resolution of 
all attributable symptoms and signs of disease and radiological 
abnormalities, and mycological evidence of eradication of disease
Partial response
Survival within the prespecified period of observation, improvement 
in attributable symptoms and signs of disease and radiological 
abnormalities, and evidence of clearance of cultures or reduction of 
fungal burden, as assessed by a quantitative and validated laboratory 
marker
Failure
Stable response[1]
Survival within the prespecified period of observation and minor or 
no improvement in fungal disease, but no evidence of progression, 
as determined on the basis of a composite of clinical, radiological, 
and mycological criteria
Progression of fungal disease
Evidence of progressive fungal disease based on a composite of 
clinical, radiological, and mycological criteria
Death
Death during the prespecified period of evaluation, regardless of 
attribution
(Segal B, 2008)
1.
In certain invasive fungal diseases (eg, invasive mold diseases), stabilization of fungal disease during periods 
of severe immunocompromise provides evidence of efficacy of treatment and may be a reasonable short-term 
therapeutic goal until immune recovery occurs.
Clinical Response
Clinical Response to Treatment will be Categorized as One of the Following 4 Possible Outcomes:
Complete response
Resolution of all attributable symptoms, signs, and/or bronchoscopic 
abnormalities present at Baseline
Partial response
Major improvement (usually nearly complete) in attributable 
symptoms, signs, and/or bronchoscopic abnormalities present at 
Baseline
Stable disease
Minor or no improvement in attributable symptoms, signs, and/or 
bronchoscopic abnormalities present at Baseline, but patient 
continued on therapy without deterioration
Failure
Deterioration in attributable symptoms, signs, and/or bronchoscopic 
abnormalities necessitating alternative antifungal therapy or 
resulting in death


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Radiological Response
Radiological Response to Treatment will be Categorized as One of the Following 4 Possible Outcomes:
Complete response
Resolution (normalization of X-ray, CT scan, etc.) of all radiological 
abnormalities attributed to aspergillosis compared to Baseline  
Partial response
Major improvement of radiological abnormalities attributed to 
aspergillosis compared to Baseline  
Stable disease
Minor or no improvement of radiological abnormalities attributed to 
aspergillosis compared to Baseline  
Failure
Worsening of radiological abnormalities attributed to aspergillosis
compared to Baseline
CT = computed tomography.
Mycological Response
Mycological Response to Treatment will be Categorized as One of the Following 4 Possible Outcomes:
Eradication
Absence of Aspergillus in a relevant clinical specimen (culture 
negative and absence of fungal elements by microscopy or 
histopathology, as appropriate) 
Presumed eradication
Inferred in patients with complete clinical and imaging response for 
whom an invasive procedure for obtaining the relevant clinical 
specimen is not performed
Persistence
Any evidence based on culture, microscopy, or histopathology for 
the presence of Aspergillus
Indeterminate
Inadequate data available for categorization as eradication, presumed 
eradication, or persistence


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APPENDIX H:    DRUG-INDUCED LIVER INJURY CRITERIA
For patients with normal liver transaminases and bilirubin at baseline:
If patients with normal baseline liver indices develop new elevations of aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) >3x upper limit of normal 
(ULN) or total bilirubin (TBL) >2xULN values during the study, repeat testing should be 
performed within 48 to 72 hours. Investigators should also ask the patient if he/she has symptoms.
If there are persistent elevations (ALT or AST >3x ULN or TBL >2x ULN) upon repeat testing, 
then close observation (as described below) should be implemented and discontinuation of drug 
should be considered.
Drug should be discontinued, and the patient followed until resolution of symptoms or signs in the 
following situations:
•
ALT or AST >8x ULN
•
ALT or AST >5x ULN for more than 2 weeks.
•
ALT or AST >3x ULN and (TBL >2x ULN or INR >1.5)
•
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
For patients with elevations in baseline transaminases or bilirubin:
If patients with abnormal baseline liver indices develop elevations of AST or ALT >2 x baseline 
or TBL >2 x baseline values during the study, repeat testing should be performed within 
48 to 72 hours. Investigators should also ask to the patient if he/she has symptoms.
If there are persistent elevations (ALT or AST >2x baseline or TBL >2x baseline values) upon 
repeat testing, then close observation (as described below) should be implemented and 
discontinuation of drug should be considered.
Drug should be discontinued, and the patient followed until resolution of symptoms or signs in the 
following situations:
•
If baseline measurements were <2x ULN, discontinue if ALT or AST increases to >5x baseline 
measurements.
•
If baseline average measurements >2x ULN, discontinue if ALT or AST increases to 
>3x baseline measurements.
•
Discontinue if ALT or AST increase >2x baseline measurements AND the increase is 
accompanied by a concomitant increase in TBL to >2x baseline measurements or the INR 
concomitantly increases by >0.2.


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• For any patients who present with a constellation of syndromes indicative of liver disease as 
per the Investigator’s overall assessment (ie, fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia [>5%]).
Close observation for suspected drug-induced liver injury includes the following:
• Repeating liver enzyme (ALT, AST, and ALP) and TBL tests 2 or 3 times weekly. 
The frequency of repeat testing can decrease to once a week or less if abnormalities stabilize or 
the study drug has been discontinued and the patient is asymptomatic.
• Obtaining a more detailed history of symptoms and prior or concurrent diseases.
• Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets.
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease.
• Obtaining a history of exposure to environmental chemical agents.
• Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct bilirubin).
• Considering gastroenterology or hepatology consultations.

SAP_001.pdf: 
Protocol C4791010 (Fosmanogepix PF-07842805) Statistical Analysis Plan (APX001-202)
PFIZER CONFIDENTIAL
Page 1 of 31
Fosmanogepix Clinical Protocol C4791010 (APX001-202)
A Phase 2, Open-Label Study to Evaluate the Safety and Efficacy of APX001 in the 
Treatment of Patients with Invasive Mold Infections Caused by Aspergillus Species or 
Rare Molds
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
14 November 2022


Protocol C4791010 (Fosmanogepix PF-07842805) Statistical Analysis Plan (APX001-202)
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TABLE OF CONTENTS
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Modifications to the Analysis Plan Described in the Protocol..................................6
2.2. Study Objectives, Endpoints, and Estimands............................................................6
2.2.1. Primary Objective.........................................................................................6
2.2.2. Secondary Objectives ...................................................................................6
2.2.3. Primary Estimand(s).....................................................................................6
2.2.4. Secondary Estimand(s).................................................................................7
2.3. Study Design .............................................................................................................7
2.4. Sample Size Determination.......................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Efficacy Endpoint(s)....................................................................................9
3.2. Secondary Efficacy Endpoint(s) Assessed by DRC..................................................9
3.2.1. Other Secondary Endpoints........................................................................10
3.2.1.1. Clinical Response......................................................................10
3.2.1.2. Radiological Response ..............................................................10
3.2.1.3. Mycological Response ..............................................................11
3.2.1.4. Investigator Assessment of Global Response ...........................11
3.2.1.5. Investigator Assessment of Clinical Response..........................12
3.2.1.6. Investigator Assessment of Radiological ..................................12
3.2.1.7. Investigator Assessment of Mycological Response..................12
3.2.1.8. Clinical Signs and Symptoms ...................................................13
3.2.1.9. Next-generation Sequencing of Cell-free Pathogen DNA ........13
3.2.1.10. 
 Levels ............................................................13
3.2.1.11. Fungal Culture.........................................................................13
3.2.1.12. Radiology Assessments...........................................................13
3.4. Pharmacokinetic Assessments.................................................................................14
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3.5. Baseline Variables...................................................................................................14
3.6. Safety Endpoints .....................................................................................................14
3.7. Adverse Events........................................................................................................14
3.8. Clinical Laboratory Evaluations..............................................................................15
3.9. Vital Signs...............................................................................................................15
3.10. Electrocardiograms................................................................................................15
3.11. Physical Examinations ..........................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. General Considerations ...........................................................................................16
5.2. Hypotheses and Decision Rules ..............................................................................16
5.3. General Methods .....................................................................................................17
5.3.1. Analysis Day...............................................................................................17
5.3.2. Analysis Visits............................................................................................17
5.3.3. Definition of Baseline.................................................................................17
5.3.4. Summary Statistics .....................................................................................17
5.3.5. Analyses for Binary Endpoints...................................................................17
5.3.6. Analyses for Continuous Endpoints ...........................................................17
5.3.7. Analyses for Categorical Endpoints ...........................................................17
5.4. Methods to Manage Missing Data ..........................................................................18
6. ANALYSES AND SUMMARIES ......................................................................................18
6.1. Primary Endpoint(s) ................................................................................................18
6.2. Main Analysis .........................................................................................................18
6.3. Secondary Endpoint(s) ............................................................................................19
6.4. Other Endpoint(s)....................................................................................................19
6.4.1. Clinical Responses......................................................................................19
6.4.2. Radiological Response................................................................................19
6.4.3. Mycological Response................................................................................19
6.4.4. Clinical Signs and Symptoms.....................................................................20
6.4.5. Next Generation Sequencing of Cell-free Pathogen DNA.........................20
6.4.6.
 Levels................................................................................20
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6.4.7. Fungal Culture ............................................................................................20
6.4.8. Radiology Assessments ..............................................................................20
6.6. Pharmacokinetic Assessment ..................................................................................20
6.7. Subset Analyses.......................................................................................................21
6.8. Baseline and Other Summaries and Analyses.........................................................21
6.8.1. Baseline Infection Characteristics ..............................................................23
6.8.2. Medical History ..........................................................................................23
6.8.3. Study Conduct and Participant Disposition................................................23
6.8.4. Protocol Deviations ....................................................................................24
6.8.5. Study Drug Exposure and Compliance.......................................................24
6.8.6. Prior and Concomitant Medications and Nondrug Treatments ..................25
6.8.7. Safety Summaries and Analyses.................................................................25
6.8.8. Adverse Events...........................................................................................26
6.8.9. Laboratory Data..........................................................................................26
6.8.10. Vital Signs ................................................................................................27
6.8.11. Electrocardiograms...................................................................................28
6.8.12. Physical Examination ...............................................................................28
7. INTERIM ANALYSIS........................................................................................................28
7.1. Data Review Committee .........................................................................................28
7.2. Data And Safety Monitoring Board ........................................................................28
8. REFERENCES ....................................................................................................................28
APPENDICES .........................................................................................................................29
LIST OF FIGURES
Figure 1.
Study Design...............................................................................................8
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APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................29
Appendix 2. Data Derivation Details.......................................................................................30
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................30
Appendix 3. List of Abbreviations...........................................................................................31


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1. VERSION HISTORY
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Original 
29 Sep 2020
N/A
N/A
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
2. INTRODUCTION
Fosmanogepix, a first-in-class small molecule investigational drug candidate, is the water
soluble methyl-phosphate prodrug of the active moiety, manogepix. Fosmanogepix is rapidly 
converted in vivo to manogepix. Manogepix has a novel mechanism of antifungal action, 
with broad-spectrum activity against major fungal pathogens including Candida species 
(spp.), Aspergillus spp., and a number of rare molds.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4791010, (Amendment 3.0, dated 
29Sept2020). The SAP will be finalized prior to database lock. Any deviations from the SAP 
after database lock will be documented in the final Clinical Study Report.
2.1. Modifications to the Analysis Plan Described in the Protocol
Not applicable.
2.2. Study Objectives, Endpoints, and Estimands
2.2.1. Primary Objective
The primary objective of this study is to evaluate the safety and efficacy of fosmanogepix for 
the treatment of adult patients aged 18 years and above with invasive mold infections (IMIs) 
caused by Aspergillus species (spp.) or rare molds (eg, Scedosporium spp., Fusarium spp., 
and Mucorales fungi), who have limited antifungal treatment options.
2.2.2. Secondary Objectives
The secondary objectives of this study are to:

Evaluate global response at End of Study Treatment (EOST).

Evaluate safety parameters of fosmanogepix.

Evaluate pharmacokinetic (PK) parameters of fosmanogepix and manogepix.
2.2.3. Primary Estimand(s)
Not applicable. This is an open-label single arm Phase 2 study.


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2.2.4. Secondary Estimand(s)
Not applicable. This is an open-label single arm Phase 2 study.
2.3. Study Design
This is a Phase 2, multicenter, open-label, non-comparative study to evaluate the safety and 
efficacy of fosmanogepix for the treatment of Invasive Mold Infections (IMIs) caused by 
Aspergillus spp. or rare molds (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi). 
Patients 18 years of age or older will undergo Screening procedures for up to 5 days, 
following which eligible patients will participate in the study drug Treatment Period for up to 
6 weeks, with a Follow-Up Visit 4 weeks after EOST, and a Follow-Up Phone Call 12 weeks 
after Day 1 (Day 84). The total duration of a patient’s participation in the study will be 
approximately 12 weeks, inclusive of the follow-up telephone call required on Day 84. 
Patients who require treatment for longer than 6 weeks can be switched to other licensed 
antifungal therapy (OLAT) at the discretion of the Investigator and in consultation with the 
Medical Monitor if the situation allows.
This study will be conducted at up to 40 global sites. The study will enroll male and female 
patients aged 18 years and above with a confirmed diagnosis of invasive aspergillosis or 
invasive rare mold infection. Patients will have limited or no treatment options due to 
documented/anticipated resistance, contraindication, intolerance, or lack of clinical 
response to standard of care (SOC) antifungal therapy. The study will enroll two cohorts, 
Cohort A and B. Up to 40 patients will be enrolled in Cohort A, and these patients will have 
an IMI which was diagnosed according to the EORTC/MSGERC criteria. 
 
 
Further details of the study design can be found in the protocol.
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Figure 1.
Study Design
2.4. Sample Size Determination
Approximately 50 patients will be dosed in this open-label, parallel-group study, and will be 
enrolled in one of 2 cohorts, as follows:
Cohort A (~40 participants):
Patients with proven or probable IMI are eligible for inclusion in the mITT Population, 
which is the primary efficacy population (DRC confirmation required of proven or probable 
IMI).
The sample size calculation is based on the mITT Population from the first dose of 
fosmanogepix through EOST (up to 6 weeks) for the all-cause mortality primary endpoint. A 
total of 24 patients in the mITT Population are needed, providing >90% power to detect the 
difference at a 1-sided significance level of 0.1, assuming an all-cause mortality of 20% for 
fosmanogepix and 45% for adjusted amphotericin B-treated all-cause mortality from the 
historical control. Assuming 60% of dosed patients will be eligible to be included in the 
mITT Population, dosing of approximately 40 patients allows for statistical testing of 
proof-of-concept for an estimate of 24 patients in the mITT Population.


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS
3.1. Primary Efficacy Endpoint(s)
The primary efficacy parameter is all-cause mortality through Day 42.
Note: All-cause mortality will represent the percentage of patients who die after the first dose 
of study drug through Day 42 from any cause. 
Every attempt must be made to record survival status at Day 42 or any time thereafter for all 
dosed patients, regardless of their status of treatment, as long as the patient has not 
withdrawn consent from participation in the study. An in-person assessment is preferred; 
however, this assessment may also be performed via a telephone call if an in-person visit is 
not possible.
3.2. Secondary Efficacy Endpoint(s) Assessed by DRC
The secondary efficacy parameter for this study is Global Response at EOST/ET. Global 
response will be classified as follows according to prespecified criteria, as determined by the 
DRC (Guidelines for the DRC are described in the DRC Charter):
•
Complete Response: Survival within the prespecified period of observation, 
resolution of all attributable symptoms and signs of disease and radiological 
abnormalities, and mycological evidence of eradication of disease).
•
Partial Response: Survival within the prespecified period of observation, improvement in 
attributable symptoms and signs of disease and radiological abnormalities, and evidence of 
clearance of cultures or reduction of fungal burden, as assessed by a quantitative and 
validated laboratory marker categorized as treatment success.
•
Stable Response: Survival within the prespecified period of observation and minor or no 
improvement in fungal disease, but no evidence of progression, as determined based on a 
composite of clinical, radiological, and mycological criteria, progression of disease, or death 
(categorized as treatment failure).
•
Progression of fungal disease: Evidence of progressive fungal disease based on a composite 
of clinical, radiological, and mycological criteria.
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
Death: Death during the prespecified period of evaluation, regardless of attribution. If any 
patient has missing global response at EOST, it will be presented as ‘Indeterminate’ 
in the summary.
Treatment outcomes for Global Response based on DRC assessment at EOST are defined as follows: 

Treatment success: Complete response or partial response.

Treatment failure: Stable response, progression of fungal disease and death.
3.2.1. Other Secondary Endpoints
Other secondary endpoints include:

Safety parameters of fosmanogepix (see Section 3.6).

Pharmacokinetic (PK) parameters of fosmanogepix/manogepix (see Section 3.4).
3.2.1.1. Clinical Response 
Clinical response based on DRC Assessment at EOST will be categorized as follows: 

Complete response: Resolution of all attributable symptoms, signs, and/or 
bronchoscopic abnormalities present at Baseline.

Partial response: Major improvement (usually nearly complete) in attributable 
symptoms, signs, and/or bronchoscopic abnormalities present at Baseline.

Stable response: Minor or no improvement in attributable symptoms, signs, and/or
bronchoscopic abnormalities present at Baseline, but patient continued on therapy 
without deterioration.

Failure: Deterioration in attributable symptoms, signs, and/or bronchoscopic
abnormalities necessitating alternative antifungal therapy or resulting in death.
3.2.1.2. Radiological Response 
Radiological Response based on DRC Assessment at EOST will be categorized as follows:

Complete response: Resolution (normalization of X-ray, CT scan, etc.) of all 
radiological abnormalities attributed to aspergillosis compared to Baseline.

Partial response: Major improvement of radiological abnormalities attributed to 
aspergillosis compared to Baseline.

Stable disease: Minor or no improvement of radiological abnormalities attributed to 
aspergillosis compared to Baseline.


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
Failure: Worsening of radiological abnormalities attributed to aspergillosis compared 
to Baseline.
3.2.1.3. Mycological Response 
Mycological Response based on DRC Assessment at EOST will be categorized as follows:

Eradication: Absence of Aspergillus (or other mold) in a relevant clinical specimen
(culture negative and absence of fungal elements by microscopy or histopathology, as 
appropriate).

Presumed eradication: Inferred in patients with complete clinical and imaging 
response for whom an invasive procedure for obtaining the relevant clinical specimen 
is not performed.

Persistence: Any evidence based on culture, microscopy, or histopathology for the 
presence of Aspergillus (or other mold).

Indeterminate: Inadequate data available for categorization as eradication, presumed 
eradication, or persistence.
3.2.1.4. Investigator Assessment of Global Response 
Global response based on investigator assessment at EOST are as follows:

Complete Response: Survival within the prespecified period of observation, 
resolution of all attributable symptoms and signs of disease and radiological 
abnormalities, and mycological evidence of eradication of disease).

Partial Response: Survival within the prespecified period of observation, improvement in 
attributable symptoms and signs of disease and radiological abnormalities, and evidence of 
clearance of cultures or reduction of fungal burden, as assessed by a quantitative and 
validated laboratory marker categorized as treatment success.

Stable Response: Survival within the prespecified period of observation and minor or no 
improvement in fungal disease, but no evidence of progression, as determined based on a 
composite of clinical, radiological, and mycological criteria, progression of disease, or death 
(categorized as treatment failure). 

Progression of fungal disease: Evidence of progressive fungal disease based on a composite 
of clinical, radiological, and mycological criteria. 

Death: Death during the prespecified period of evaluation, regardless of attribution. If any 
patient has missing global response at EOST, it will be presented as ‘Indeterminate’ 
in the summary.


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
Treatment Outcomes for Global Response based on Investigator Assessment at 
EOST:

Treatment success: Complete response or partial response.

Treatment failure: Stable response, progression of fungal disease and death.
3.2.1.5. Investigator Assessment of Clinical Response 
Clinical response based on investigator assessment at EOST are as follows:

Complete response: Resolution of all attributable symptoms, signs, and/or 
bronchoscopic abnormalities present at Baseline.

Partial response: Major improvement (usually nearly complete) in attributable 
symptoms, signs, and/or bronchoscopic abnormalities present at Baseline.

Stable response: Minor or no improvement in attributable symptoms, signs, and/or 
bronchoscopic abnormalities present at Baseline, but patient continued on therapy 
without deterioration.

Failure: Deterioration in attributable symptoms, signs, and/or bronchoscopic 
abnormalities necessitating alternative antifungal therapy or resulting in death.
3.2.1.6. Investigator Assessment of Radiological 
Radiological response based on investigator assessment are as follows:

Complete response: Resolution (normalization of X-ray, CT scan, etc.) of all 
radiological abnormalities attributed to aspergillosis compared to Baseline.

Partial response: Major improvement of radiological abnormalities attributed to 
aspergillosis compared to Baseline.

Stable disease: Minor or no improvement of radiological abnormalities attributed to 
aspergillosis compared to Baseline.

Failure: Worsening of radiological abnormalities attributed to aspergillosis compared 
to Baseline.
3.2.1.7. Investigator Assessment of Mycological Response 
Mycological Response based on Investigator Assessment at EOST as Follows: 

Eradication: Absence of Aspergillus in a relevant clinical specimen (culture negative 
and absence of fungal elements by microscopy or histopathology, as appropriate).


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•
Presumed eradication: Inferred in patients with complete clinical and imaging 
response for whom an invasive procedure for obtaining the relevant clinical specimen 
is not performed.
•
Persistence: Any evidence based on culture, microscopy, or histopathology for the 
presence of Aspergillus.
•
Indeterminate: Inadequate data available for categorization as eradication, presumed 
eradication, or persistence.
3.2.1.8. Clinical Signs and Symptoms 
Clinical signs and symptoms included Cough, Dyspnea, Pleuritic Chest Pain, Fever, 
Hemoptysis, Visual Disturbance, Skin Lesion, Headache, Sinus Pain, Joint Pain and/or 
swelling. Clinical signs and symptoms were assessed as absent, mild, moderate, severe or not 
done. (“Not done” is recorded at the symptoms level).
3.2.1.9. Next-generation Sequencing of Cell-free Pathogen DNA
DNA sequencing was performed by a reference genetic laboratory (Karius) to facilitate the 
identification of infecting pathogens; a subject level listing will be provided.
3.2.1.10.
 Levels
levels were assessed at local LAB (investigator site) and central LAB. 
Subject level listing of 
for local LAB and central LAB will be provided.
3.2.1.11. Fungal Culture
Fungal cultures were assessed at local clinical labs (investigator site). Isolated pathogens
were sent to a central LAB (JMI Labs) for confirmatory identification and susceptibility 
testing. Subject level listing by subject by pathogen will be provided for local LAB and 
central LAB results. 
3.2.1.12. Radiology Assessments
Radiology assessments were performed at screening, Day 14 and at EOST, and if clinically
indicated on Days 7, 21, 28, 35, and 42; at the Follow-Up Visit; and at the E/T Visit 
(if applicable). Subject level listing of imaging will be provided. 
  
 
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3.4. Pharmacokinetic Assessments
Plasma samples for PK (fosmanogepix [prodrug] and manogepix [active moiety]) will be 
collected predose and 3 hours post start of infusion on Days 1 (Baseline), 2, 3, 7, and 14; 
predose on Days 28 and 42; and at any time in clinic at EOST, the Follow-Up Visit, and the 
E/T Visit (if applicable). Additionally, for patients who switch to PO dosing, samples should 
be collected predose and at 3 hours postdose on the initial day of PO dosing, Day 7, and 
Day 14 and at any time in clinic on Days 28 and 42, at EOST, at the Follow-Up Visit, and at 
the E/T Visit (if applicable). If the patient switches back to IV dosing, PK samples should be 
collected predose and at 3 hours post start of infusion on that day as well. 
Optionally, if body fluids are sampled as part of routine patient management (eg, BAL, 
lumbar puncture, paracentesis, vitreal fluid collection, abscess drainage), within 
approximately 2 hours of blood sampling for PK, these samples may be stored for future 
analysis of fosmanogepix and manogepix levels.
3.5. Baseline Variables
Baseline data will be collected according to the schedule of procedures in the protocol.
For all efficacy and safety endpoints, baseline is defined as the last measurement or 
assessment prior to first dose of study drug.
For microbiological data, baseline pathogen(s) are Aspergillus spp. or rare molds 
(eg, Scedosporium spp., Fusarium spp., Lomentospora spp., and Mucorales fungi, etc.) 
isolated from the last positive fungal culture sample collected prior to the first dose of study 
drug.  
3.6. Safety Endpoints
Safety assessments will include treatment-emergent adverse events and serious adverse 
events, including deaths, vital signs (temperature, systolic and diastolic blood pressure, heart 
rate, respiratory rate, oxygen saturation), clinical laboratory evaluations (serum chemistry, 
hematology, coagulation, urinalysis), 12-lead ECGs, physical examination including specific 
neurology assessments.
3.7. Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
patient administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IMP, whether or not related to the IMP. Any adverse event that 
started on or after the administration of study drug will be considered a treatment emergent 
adverse event (TEAE). AEs will be captured from the time of initial dosing through the 
Follow-Up Visit. Events that occur after Day 42 (maximum duration of treatment with 
fosmanogepix) but prior to and including the Follow-Up visit will be considered treatment 


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emergent. All AEs will be coded to system organ class (SOC) and preferred term (PT) using 
the MedDRA.
3.8. Clinical Laboratory Evaluations
Screening laboratory assessments to determine eligibility will be performed at the local 
laboratory and may have been collected as SOC within the previous 24 hours. Laboratory 
assessments collected after Screening will be sent to the central laboratory for analysis. 
Clinical laboratory assessments (serum chemistry, hematology [including CBC with 
differential], coagulation [including PT/INR], and urinalysis) will occur at Screening; 
predose on Days 1 (Baseline), 7, 14, 28, and 42; at EOST; and at the E/T Visit (if applicable). 
A urine or serum pregnancy test will be performed at Screening; on Days 1 (Baseline) (if the 
Screening Visit occurred ³96 hours prior to Day 1 [Baseline]), 28, and 42; at EOST; at the 
Follow-Up Visit; and at the E/T Visit (if applicable) for all women of childbearing potential. 
3.9. Vital Signs
Vital signs will include temperature, blood pressure, heart rate, respiratory rate, and oxygen 
saturation and will be collected at Screening; predose on Days 1 (Baseline), 7, 14, 21, 28, 35, 
and 42; at EOST; at the Follow-Up Visit; and at the E/T Visit (if applicable).
3.10. Electrocardiograms
A 12 lead ECG will be obtained in triplicate at Screening, Days 3, 7, 14 and 42, EOST, and 
the E/T Visit (if applicable).
3.11. Physical Examinations
Complete physical examinations were conducted at Screening, Day 42, EOST, and the E/T 
Visit (if applicable). A complete physical examination will include an assessment of general 
appearance, skin, eyes, heart, chest, abdomen, and a neurological examination. Components 
of the neurological examination include cranial nerve, sensory, and motor examination; 
reflex and gait testing; and coordination assessment. Height will be measured at Screening 
and weight will be measured at Screening; on Days 1 (Baseline), 7, 14, 21, 28, 35, and 42; at 
EOST; at the Follow-Up Visit; and at the E/T Visit (if applicable). 
A neurological examination (all patients) and a symptom-directed physical examination will 
be conducted as clinically indicated (ie, new signs or symptoms and follow-up on earlier 
findings) on Days 1 (Baseline), 7, 14, 21, 28, 35, and at the Follow-Up Visit. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.


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Population
Description
Applicable Analysis 
ITT 
All participant entered to the study
Modified Intent-
to-Treat (mITT)
The modified Intent-to-Treat (mITT) Population will 
include all patients in the ITT Population who satisfy 
the following criteria:
Receive at least 1 dose of study drug.
Cohort a: have a diagnosis of proven or probable IMI 
confirmed by the DRC.
The mITT Population will be the 
primary population used for the 
efficacy analyses
compliance
The Per-Protocol Population will include all patients 
in the mITT Population who satisfy the following 
criteria:
•
Meet the protocol’s key inclusion criteria 
and exclusion criteria.
•
Receive at least 80% of the intended doses; 
and
•
Have no major protocol violations, ie, not 
received any prohibited concomitant 
medications per the protocol that would 
impact the efficacy of study drug.
Per protocol analyses will not be 
performed due to the small size of 
the study and due to design of 
study (eg, open label). This has 
been documented in the study log. 
Safety
All participants who receive at least 1 dose of study 
intervention.  
For all safety endpoints
PK population
The PK Population will include all patients who 
receive any amount of study drug and have evaluable 
PK data.
For PK parameters
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. General Considerations
The mortality rate will be analyzed at Day 42
 with Day 42 being primary. Key 
secondary endpoints and global response at EOST will be summarized descriptively.
 at each scheduled visit and change from baseline will be summarized with 
descriptive statistics.
 at each scheduled visit and change from baseline will be 
summarized with descriptive statistics. The above analyses will be conducted in the mITT 
population for Cohort A. At the time this analysis plan was written, all subjects were enrolled 
in Cohort A
 
5.2. Hypotheses and Decision Rules
The primary hypothesis for Cohort A is that the mortality rate at Day 42 is <45% based on 
1-sided exact binomial test at the alpha = 0.1 level of significance. 
The hypothesis will be as follows:
H0: π ≥45% 
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Ha: π < 45%
where π is the all-cause mortality through Day 42. 1-sided 90% confidence interval (CI) or 
two-sided 80% CIs will be provided. It can be concluded that the all-cause mortality at 
Day 42 is less than 45% (based on historical control data) if the upper limit of the CI is lower 
than 45%.
5.3. General Methods
5.3.1. Analysis Day
Analysis day will be calculated from the date of first dose of study drug. The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1. 
There will be no Day 0.
5.3.2. Analysis Visits
Scheduled visits will be assigned to analysis visits as recorded on the CRF. 
5.3.3. Definition of Baseline 
For microbiological data, baseline pathogen(s) are Aspergillus spp. or rare molds 
(eg, Scedosporium spp., Fusarium spp., Lomentospora spp., and Mucorales fungi, etc.) 
isolated from the last positive fungal culture sample collected prior to the first dose of study 
drug. 
For all efficacy and safety endpoints, baseline is defined as the last measurement or 
assessment prior to first dose of study drug.
5.3.4. Summary Statistics
Summary statistics will be presented for Cohort A only. For continuous variables, the 
number of observations (n), mean, standard deviation, median, minimum, and maximum will 
be provided. For categorical variables, the frequency and percentage in each category will be 
displayed.
5.3.5. Analyses for Binary Endpoints
For all binary endpoints, proportion of participants and 95% CI will be presented.
5.3.6. Analyses for Continuous Endpoints
For continuous endpoints, mean (SD), median, max, min will be presented.
5.3.7. Analyses for Categorical Endpoints
For categorical endpoints, number and percentage will be presented with the associated 
sample size. 


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5.4. Methods to Manage Missing Data
Patients who dropped out or had missing outcome data will be included in the denominator 
for efficacy analyses. If any patient has missing global response, clinical response, 
radiological response, or mycological response from the DRC or Investigator at EOST, it will 
be presented as missing in the summary.
In cases of missing or incomplete dates (eg, Adverse event [AE] and concomitant 
medications), the missing component(s) will be assumed as the most conservative value 
possible. For example, AEs with missing start dates, but with stop dates either overlapping 
into the treatment period or missing, will be counted as treatment-emergent, taking the 
worst-case approach. When partial dates are present in the data, both a partial start date 
and/or a partial stop date will be evaluated to determine whether it can be conclusively 
established that the AE started prior to the start of study drug or ended prior to the start of 
study drug. If the above cannot be conclusively established based on the partial and/or 
present dates, then the AE will be considered as treatment emergent. Actual data values as 
they appear in the original electronic Case Report Form (eCRF) will be presented in the data 
listings. 
Missing values for other variables will not be imputed and only observed values will be used 
in data analyses and summaries.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
All-cause mortality through Day 42 will be summarized for Cohort A using descriptive 
statistics.
6.2. Main Analysis
All-cause mortality through Day 42 is calculated as the percentage of patients who die after 
the first dose of study drug through Day 42 from any cause using the mITT population.
For Cohort A only, the 1-sided exact binomial test at the alpha = 0.1 level of significance will 
be used to test the hypothesis as below:
H0: π ≥45% 
Ha: π <45%
where π is the all-cause mortality through Day 42. 1-sided 90% confidence interval (CI) or 
two-sided 80% CIs will be provided. It can be concluded that the all-cause mortality at 
Day 42 is less than 45% (based on historical control data) if the upper limit of the CI is lower 
than 45%.


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6.3. Secondary Endpoint(s)
Global response at EOST. Global responses will be classified as complete or partial 
response (categorized as treatment success), stable response, progression of fungal disease, 
or death (categorized as treatment failure) by the Investigator and adjudicated by the DRC.
Number and percentage of patients in the mITT Populations with global responses at EOST 
as determined by the DRC will be tabulated for Cohort A. Two-sided 80% exact binomial CIs 
of the treatment success rate will be presented for Cohort A only.
Global response will also be summarized descriptively as, complete response, partial 
response, stable response, progression of fungal disease, death at EOST, ET and EOST/ET 
(LOCF).
6.4. Other Endpoint(s)
6.4.1. Clinical Responses
Clinical responses will be assessed by DRC and by investigator will be classified as complete 
response, partial response, stable response, and failure. Number and percentage of patients in 
the mITT Populations with clinical responses at EOST as determined by the DRC will be 
tabulated for Cohorts A. Two-sided 80% exact binomial CIs of the treatment success 
(complete and partial response) rate will be presented for Cohort A.
Clinical responses at EOST as determined by the Investigator will be tabulated in the same 
manner.
6.4.2. Radiological Response
Radiological responses will be assessed by DRC and by investigator and will be be classified
as (complete response, partial response, stable response, and failure. 
Number and percentage of patients in the mITT Populations with radiological responses at 
EOST as determined by the DRC will be tabulated for Cohort A. -Two-sided 80% exact 
binomial CIs of the treatment success (complete and partial response) rate will be presented 
for Cohort A.
Radiological responses at EOST as determined by the Investigator will be tabulated in the 
same manner.
6.4.3. Mycological Response
Mycological responses will be assessed by DRC and by investigator and will be classified as
eradication, presumed eradication, persistence, or indeterminate.
Number and percentage of patients in the mITT Populations with mycological responses at 
EOST as determined by the DRC will be tabulated for Cohort A. Two-sided 80% exact 
binomial CIs of the treatment success (eradication and presumed eradication) rate will be 
presented for Cohort A.


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Mycological responses at EOST as determined by the Investigator will be tabulated in the 
same manner.
6.4.4. Clinical Signs and Symptoms
Clinical signs and symptoms will be summarized at Baseline and study visit. Number and 
percent of participant with each clinical signs and symptoms of absent, mild, moderate, 
severe, or not done will be presented. 
6.4.5. Next Generation Sequencing of Cell-free Pathogen DNA
DNA sequencing was to be performed by a reference genetic laboratory (Karius) to facilitate 
the identification of infecting pathogens; subject level listing will be provided.
6.4.6.
 Levels
A subject level listing of
 for (local lab investigator site) and (central LAB) 
will be provided.
6.4.7. Fungal Culture
A subject level listing by pathogen will be provided for local (investigator site) and central 
laboratory results. 
6.4.8. Radiology Assessments
A subject level listing of imaging results will be provided.
 
 
 
 
 
 
 
6.6. Pharmacokinetic Assessment
All pharmacokinetic analyses will be performed by an external laboratory vendor and 
described in a standalone PK analysis plan.
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6.7. Subset Analyses
The following sub-group analysis will be provided for primary and key secondary endpoint:
•
Primary endpoint: Day 42 mortality by baseline pathogen.
•
Secondary endpoint: global response at EOST by baseline pathogen.
•
Primary endpoint: Day 42 mortality by limited treatment option criteria.
•
Secondary endpoint: global response at EOST by limited treatment criteria.
•
Primary endpoint: Day 42 mortality by participant who switch to 400 mg BID 
fosmanogepix dose vs. maintained with 800 mg of fosmanogepix dose QD.
•
Secondary endpoint: global response at EOST by participant who switch to 
400 mg BID fosmanogepix dose vs. maintained with 800 mg of fosmanogepix 
dose QD.
6.8. Baseline and Other Summaries and Analyses
For continuous baseline variables, the number of observations (n), mean, standard deviation, 
median, minimum, and maximum will be provided. For baseline categorical variables, the 
frequency and percentage in each category will be displayed. Baseline Summaries.
The following demographic and baseline characteristics will be summarized:
•
Age (years) and age categories (<65 years vs. ≥65 years).
•
Sex.
•
Race.
•
Ethnicity.
•
Height (cm).
•
Weight (kg).
•
Body mass index (BMI) (kg/m2).
•
eGFR (ml/min /1.73 m2) calculated by CKD-EPI equation and categories 
(<30, 30-<60, 60-<90 and ≥90). 
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
Eastern cooperative oncology group (ECOG) status (0, 1, 2, 3, 4, and 5).

Severity of disease assessed by Karnofsky performance status and categories 
(≤30 vs. >30).

Hospitalization status (ICU, non-ICU, emergency room, or other).

Diagnosis of IMI per DRC (possible IMI, probable IMI, proven IMI, and not 
categorized).

Site of IMI as below: 

Cerebral.

Cutaneous abscess.

Eye.

Intraabdominal.

Pulmonary.

Renal.

Sinuses.

Thrombus.

Urogenital.

Other.

Limited Treatment Options Criteria:

Documented or anticipated resistance.

Contraindication to soc.

Intolerance to soc.

Lack of clinical response to soc.

No treatment options.


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Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of patients as appropriate by Cohort A for the ITT/Safety Population, 
mITT, Populations.
6.8.1. Baseline Infection Characteristics
All baseline pathogens will be summarized with counts and percentages of patients in total 
for the mITT Populations.
Details of organism identification and antifungal susceptibility results including MICs of all 
antimicrobials tested will be listed by patient. Data from both local and central 
microbiological laboratories will be listed.
6.8.2. Medical History
Medical history will be coded to SOC and PT using the Medical Dictionary for Regulatory 
Activities (MedDRA, Version 25.0). Counts and percentages of patients with medical history 
by SOC and PT will be summarized for Cohort A based on the ITT/Safety Population and 
mITT Population. Medical history will be listed by patient.
6.8.3. Study Conduct and Participant Disposition
Patient disposition will be summarized for the ITT/Safety Population and mITT Population 
by Cohort A. The following patient disposition categories will be included in the summary:

Patients who received study drug.

Patients who completed the study drug.

Patients who did not complete the study drug (and reason).

Patients who did not complete the study drug due to the impacts of the covid-19 
pandemic.

Patients who completed the study through Day 42.

Patients who did not complete the study through Day 42.

Patients who completed the study through the follow-up visit (4 weeks after EOST).

patients who did not complete the study (and reason).
For patients who did not complete study drug and patients who did not complete the study, a 
summary of reasons for discontinuation will be provided. In addition, the total number of 
patients for each defined population will be tabulated.


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6.8.4. Protocol Deviations
The number of patients with at least one protocol deviation, and the number of patients with 
at least one deviation in each category defined in the study protocol deviation plan. 
Deviations will be presented for Cohort A by category for important protocol deviations 
based on the ITT/Safety Population and mITT Population. In addition, the protocol 
deviations related to COVID-19 pandemic will be categorized and summarized separately.
Protocol deviations will also be listed by patient.
6.8.5. Study Drug Exposure and Compliance
Study drug includes both intravenous and oral fosmanogepix. Days of exposure to study drug 
will be calculated as follows:

Days of exposure Overall (IV + oral dose) as the last dose date of study drug - first 
dose date of study drug +1. 

Days of exposure IV dose only (as the last dose date of IV - the first dose date of 
IV) - number of days that participant was switched to oral dose.

Day of exposure oral dose only (as the last date of oral dose - first date of oral 
dose) - number of days that the participant was in IV dose. 
Descriptive statistics with count and percentage of participants with overall (oral + iv dose), 
oral dose and iv dose, for cohort a based on the ITT/safety population and mITT population 
will be provided with exposure in the following categories:

≤14 days.

>14 to ≤28 days.

>28 to ≤42 days.

>42 days.
For patients who switch from intravenous to oral dose, the compliance rate for oral dose will 
be calculated as the total amount of doses received divided by the total amount of doses 
expected then multiplied by 100. The total amount of expected doses is the number of 
medication days multiplied by the expected doses per day. Number of medication days is the 
total number of days from the date of the first oral dose of study drug to the date of the last 
oral dose of study drug. In addition for oral dose, for participant who switch from 
800 mg/day QD to 400 mg BID, number and presence of participant will be provided. 
For patients who did not switch from intravenous (IV) to oral dose, the compliance rate for 
IV dose will be calculated as the total amount of doses received divided by the total amount 
of doses expected then multiplied by 100. The total amount of expected doses is the number 
of medication days multiplied by the expected doses per day. Number of medication days is 


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the total number of days from the date of the first IV dose of study drug to the date of the last 
IV dose of study drug. 
The overall study drug compliance will be the oral dose compliance plus the IV dose 
compliance. 
Percent compliance with study drug will be calculated using the following formula:
%"compliance"= ("total amount of doses received * " 100)/"expected doses per day 
* the total number of medication days" 
The compliance rate will be summarized with descriptive statistics overall (Oral + IV) dose, 
oral dose, and IV dose for Cohort A for the ITT/Safety Population and mITT Population. In 
addition, contingency tables will be provided to show the number and percentage of patients 
with compliance in the following categories: <80% and ≥80%.
6.8.6. Prior and Concomitant Medications and Nondrug Treatments
Prior and Concomitant medications will be coded by class and preferred term using the 
World Health Organization (WHO) Drug Dictionary.
Prior medications are medications used before the first dose of study drug. Concomitant 
medications are medications that were taken on or after first dose of study drug.
The number and percentages of patients who receive the following prior and concomitant 
medications will be summarized by class and preferred term by Cohort A for the ITT/Safety 
Population and mITT Population:

Prior medications.

Concomitant medications.

Prior systemic mold antifungals.

Other Licensed Antifungal Treatments that were optionally prescribed by investigator 
after 6 week of study drug treatment (this data has been collected in the prior 
antifungal module).

Concomitant systemic mold antifungals.
In addition, duration of prior systemic antifungals prior to first dose of study drug will be 
tabulated in the following categories: 1 day, 2 days, 3 days, 4 days, 5 days, and >5 days.
All prior and concomitant medications and procedures will be listed by patient. 
6.8.7. Safety Summaries and Analyses
Safety data will be summarized based on the Safety Population for Cohort A.


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6.8.8. Adverse Events
An overview of AEs will be provided including counts and percentages of patients (and event 
counts) with the following:

Any AEs.

Any TEAEs (overall and by maximum severity).

Any study drug related TEAEs (overall and by maximum severity).

Any serious AEs (SAEs).

Any treatment-emergent SAEs (TESAEs).

Any TRSAEs).

Any TEAEs leading to discontinuation of study drug.

Any TRAEs leading to discontinuation of study drug.

Any AEs leading to death.
The number and percentage of patients who experienced at least one TEAE will be presented 
by SOC and PT. TEAEs, TRAEs, study drug withdrawals due to TEAEs and TRAEs, and all 
SAEs will be summarized in the same manner. 
Summaries will be provided by worst grade for the number and percentage of patients with 
TEAEs and TRAEs by SOC and PT.
Although a patient may have two or more TEAEs, the patient is counted only once within a 
SOC and PT category. The same patient may contribute to two or more PTs in the same
SOC category.
A list of patients who have SAEs, a list of patients who discontinue from study drug due to 
TEAEs or TRAEs, and a list of death due to AEs will be provided. All AEs will be listed.
6.8.9. Laboratory Data
Central laboratory test results (chemistry, hematology, coagulation, and urinalysis) at each 
scheduled visit and change from baseline will be summarized with descriptive statistics.
Shift tables from baseline to each scheduled post-baseline visit will be provided for selected 
chemistry parameters (ALT, AST, ALP, Total Bilirubin, Creatinine, and Creatinine Kinase) 
and hematology parameters (Hematocrit, Hemoglobin, Platelets, White blood cell count and 
differential). For chemistry parameters, the following categories will be used: < the lower 
limit of normal (LLN), normal, >ULN to ≤2×ULN, >2×ULN to ≤3×ULN, >3×ULN to 


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≤5×ULN, >5×ULN, and missing. For hematology parameters, the following categories will 
be used: low, normal, high, and missing.
The number and percentage of patients with the following potentially clinically significant 
abnormal liver function tests at any post-baseline visit will be summarized:

ALT ≥3×ULN.

ALT ≥5×ULN.

ALT ≥10×ULN.

AST ≥3×ULN.

AST ≥5×ULN.

AST ≥10×ULN.

ALT or AST ≥3×ULN.

Total Bilirubin >1.5×ULN.

Total Bilirubin >2×ULN.

ALP ≥1.5×ULN.

ALP ≥2×ULN.

ALT or AST ≥3×ULN and Total Bilirubin >1.5×ULN.

ALT or AST ≥3×ULN and Total Bilirubin >2×ULN.

Potential Hy’s Law cases: ALT or AST ≥3×ULN and Total Bilirubin >2×ULN, and 
ALP ≤2×ULN.
A listing of patients with any post-baseline clinically significant abnormal liver function tests 
will be presented.
All clinical laboratory data will be listed. Values outside the normal ranges will be flagged.
6.8.10. Vital Signs
Descriptive statistics will be provided for vital sign data (systolic and diastolic blood 
pressure, heart rate, respiratory rate, body temperature, and oxygen saturation) presented as 
both actual values and changes from baseline over time. A listing of all vital signs will be 
provided by patient.


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6.8.11. Electrocardiograms
Descriptive statistics will be provided for 12-lead ECG interval data (Heart rate, PR, QRS, 
QT, and RR) and changes from baseline for each scheduled visit. The average of the 
triplicates at each visit will be used in the summary. All 12-lead ECG findings will be listed 
by patient.
6.8.12. Physical Examination
Physical examination including neurological findings will be listed by patient.  
7. INTERIM ANALYSIS
No interim analysis is planned for this study.
7.1. Data Review Committee
A DRC comprised of infectious disease experts will adjudicate the diagnosis of IMI at 
enrollment. This committee will also provide systematic assessment for clinical, 
mycological, radiological, and global responses at EOST and at the E/T Visit (if applicable).
Global responses will be classified as complete or partial response (categorized as treatment
success), stable response, progression of disease, or death (categorized as treatment failure)
according to prespecified criteria. Guidelines for the DRC are described in the DRC Charter.
7.2. Data And Safety Monitoring Board
A DSMB comprised of members with pertinent expertise will be responsible for the periodic
review of cumulative data from the study as set forth in the DSMB Charter, or more 
frequently at the request of the DSMB. The DSMB will advise the Sponsor on the continuing 
safety of patients and those yet to be recruited to the study, as well as the continuing validity 
and scientific merit of the study. The DSMB may recommend to the Sponsor that dosing in 
the study be suspended if, in the opinion of the DSMB, further dosing in the study would 
pose an inappropriate safety risk. Guidelines for what constitutes inappropriate safety risks 
are described in the DSMB Charter.
8. REFERENCES
Not Applicable.


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APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and 
Rules for Handling 
Intercurrent Events 
and Missing Data 
Analysis Model
Primary endpoint: 
Mortality rate at 
Day 42.
Primary
mITT
All observed data. 
Cohort A: 
One-sided exact 
binomial test at the 
alpha = 0.1 level of 
significance: 
Secondary Endpoint: 
Global response at 
EOST
Secondary
mITT
All observed data
Cohort A: 
Two-sided 80% 
exact binomial CI
Clinical responses
Other
mITT
All observed data
Cohort A: 
Two-sided 80% 
exact binomial CI
Radiological response
Other
mITT
All observed data
Cohort A: 
Two-sided 80% 
exact binomial CI
Mycological response 
Other
mITT
All observed data
Cohort A: 
Two-sided 80% 
exact binomial CI
 
 
CCI


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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
The following table defines the visit windows and labels to be used for reporting:
Visit 
Number
Visit Label 
Definition [Day window]
1
Screening
Day -5 to -1
2
Baseline
Day 1
3
Day 2
= Day 2
4
Day 3
= Day 3
5
Day 7
= Day 7, with a window of ±1 days, (ie, days 6 to 8)
6
Day 14
= Day 14, with a window of  ±1 days, (ie, days 13 to 16)
7
Day 21
= Day 21, with a window of ±2 days, (ie, days 19 to 23)
8
Day 28
= Day 28, with window from 26 to 30
9
Day 35
= Day 35, with window from 33 to 37
10
Day 42
= Day 42, with window from 40 to 44
11
EOST2
End of study treatment (Date of last treatment) +2 days
12
FU 
(Date of FU) ±3 days
13
FU Phone call
Day 84 ±3 days


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Appendix 3. List of Abbreviations
Abbreviation
Definition
AE
Adverse event
AspUTest
Aspergillosis urine test
ATC
Anatomical therapeutic chemical
BAL
Bronchoalveolar lavage
BID
Twice daily
BMI
Body mass index
CBC
Complete blood count
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CSR
Clinical study report
CT
Computed tomography
DRC
Data Review Committee
DSMB
Data and Safety Monitoring Board
E/T
Early Termination
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EORTC
European Organization for Research and Treatment of Cancer
EOST
End of Study Treatment
IA
Invasive Aspergillosis
IMI
Invasive mold infection
INR
International normalized ratio
ITT
Intent-to-Treat
IV
Intravenous(ly)
LLN
Lower limit of normal
LTO
Limited Treatment Option
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
MSG
Mycosis Study Group
OLAT
Other licensed antifungal therapy
PCR
Polymerase chain reaction
PK
Pharmacokinetic(s)
PO
Oral(ly)
PT
Prothrombin time
QD
Once daily
qPCR
Quantitative polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SOC
Standard of care
spp.
Species
TEAE
Treatment-emergent adverse event
TRAE
Treatment-related adverse event
ULN
Upper limit of normal
WHO
World Health Organization