Study to Assess Amphotericin B Cystetic for Inhalation (ABCI) Doses in Healthy Volunteers & People With Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
This is a 3-part, single-ascending dose Phase 1a randomized, double-blind, placebo-controlled study in healthy volunteers (Part A) and multiple-ascending dose Phase 1a randomized, double-blind, placebo-controlled study in healthy volunteers (Part B), and a Phase 1b open-label study in subjects with CF (Part C) to assess the safety, tolerability, PK, and preliminary efficacy of ABCI. Subjects will be evaluated for eligibility during Screening within 30 days prior to Day 1 (Randomization; Visit 3). In Parts A and B, eligible healthy volunteers may be enrolled in the study and randomly allocated to treatment with ABCI or placebo as described below. In Part C, eligible subjects with CF may be enrolled in the study and receive treatment with ABCI as described below. Approximately 72 healthy subjects total will be randomized to 9 cohorts (48 subjects in 6 cohorts in Part A, 24 subjects in 3 cohorts in Part B) and up to 12 subjects with CF will receive the medium dose (2 sentinel subjects) or high dose (up to 10 subjects) of ABCI in Part C.

Official Title
-----------------
A 3-part Study of ABCI: A Randomized, Double-blind, Placebo-controlled, Single-ascending Dose Phase 1a Study in Healthy Volunteers (Part A), a Randomized, Double-blind, Placebo-controlled, 14- and 28-day Multiple-ascending Dose Phase 1a Study in Healthy Volunteers (Part B), and a 28-day Open-Label Phase 1b Study in Subjects With Cystic Fibrosis (Part C)

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Combination Product: ABCI
* Combination Product: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part A and Part B: Each subject must meet the following criteria to be enrolled in Part A and Part B of this study. Subject has signed, dated, and received a copy of the IRB/IEC-approved written ICF. Subject is male or female aged ≥18 to ≤55 years. Subject has a BMI between 18 and 32 kg/m2 Subject has an FEV1 of >90% of predicted normal value Subject has normal or clinically acceptable physical examination, vital signs, clinical laboratory values, and ECG at Screening. Female subjects must be of non-childbearing potential or male/female subjects of childbearing potential agree to use highly effective contraception/preventive exposure measures Part C: Each subject must meet the following criteria to be enrolled in Part C of this study. Subject has signed, dated, and received a copy of the IRB/IEC-approved written ICF. Age 16 years or older Confirmed diagnosis of CF, including sweat chloride >60 mM. Subject is either: Being treated with an approved CFTR modulator for at least 28 days prior to Screening, or Not being treated with a CFTR modulator FEV1 ≥40% and ≤90% of predicted normal value Stable CF disease and treatment regiment Female subjects must be of non-childbearing potential or male/female subjects of childbearing potential agree to use highly effective contraception/preventive exposure measures Exclusion Criteria: Part A and Part B: Any subject who meets any of these criteria must be excluded from Part A and Part B of this study: Subject has history or evidence of any clinically significant pulmonary condition Subject has history or evidence of any clinically significant diseases or conditions Subject has history of malignancy of any type Subject has an active COVID-19 infection within 4 weeks Subject is positive for human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C antibodies, or has a positive QuantiFERON®-tuberculosis Gold (QFT-G) test for tuberculosis at Screening Subject has a self-reported lower respiratory tract infection within 6 weeks Subject has evidence of any active or suspected bacterial, viral, fungal or parasitic infections within the past 4 weeks A subject who is an active smoker or a former smoker Subject has history of alcohol or drug abuse in the past year Subject has tested positive for drugs (including cannabis), nicotine/cotinine, and/or alcohol use at Screening, subject has consumed alcohol within 24 hours prior to Visit 3 Subject has participated in any clinical study or had been treated with any investigational drugs within 28 days or 5 half-lives Female subject who is pregnant or breastfeeding. Subject has any episode of paradoxical bronchospasm in the past 12 months. Subject has pacemaker; is not in sinus rhythm; has a corrected QT interval (QTc; using Fridericia's [QTcF] formula) of >450 ms (for males) and >470 ms (for females); or has a left bundle branch block or bifascicular block. Subject has a pulse <40 or >100 bpm; systolic blood pressure >140 mmHg, or diastolic blood pressure >90 mmHg at Screening Subject has Type I or II diabetes requiring medication. Subject has received any vaccine within 30 days prior to Day 1. Subject has received any of the following immunosuppressant therapies within 6 months prior to Screening: imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporine A, bosentan, or methotrexate. Subject has received any antibody or therapeutic biologic product during the 6 months prior to Screening. Subject has received any oral, intravenous, or intramuscular steroid within 4 weeks prior to Screening. Intrathecal or intraarticular steroids are permitted. A subject who is not vaccinated with the COVID-19 vaccine with appropriate window from last dose of vaccine to Screening per local guidelines, policies, and availability within 30 days prior to Day 1. Part C: Any subject who meets any of these criteria must be excluded from Part C of this study: History of any illness or any clinical condition that might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. Any of the following abnormal laboratory tests: Hemoglobin, Total bilirubin, liver enzymes or creatine clearance An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for sinopulmonary disease within 28 days before the screening visit. An acute illness not related to CF within 14 days before the first dose of study drug. Subject has an active COVID-19 infection within 4 weeks prior to screening. Ongoing or prior participation in a study of an investigational treatment within 28 days or 5 terminal half-lives (whichever is longer) before screening. Female subject who is pregnant or breastfeeding. Please refer to study protocol for the complete inclusion/exclusion criteria list.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Healthy Volunteer<br>Subjects will be assigned to one of six planned dose cohorts and receive single doses of ABCI (0.5mg, 1.0mg, 2.0mg, 4.0mg, 6.0mg, 10.0mg). In each cohort, six subjects will receive ABCI and 2 will receive placebo | Combination Product: ABCI<br>* Subjects will receive ABCI via oral inhalation<br>* Other names: Amphotericin B Cystetic for Inhalation;Combination Product: Placebo<br>* Subjects will receive ABCI via oral inhalation<br>|
| Experimental: Part B Healthy Volunteer<br>Subjects will be assigned to one of three planned dose cohorts and receive a loading dose and multiple ascending doses of ABCI (loading dose 1.5mg/0.5mg daily, loading dose 6.0mg/2.0 daily, loading dose 10.0mg/4.0mg daily). In each cohort, six subjects will receive ABCI and 2 will receive placebo. | Combination Product: ABCI<br>* Subjects will receive ABCI via oral inhalation<br>* Other names: Amphotericin B Cystetic for Inhalation;Combination Product: Placebo<br>* Subjects will receive ABCI via oral inhalation<br>|
| Experimental: Part C People with Cystic Fibrosis<br>Subjects will be assigned to one of two planned dose cohorts of ABCI (loading dose 6.0mg/2.0mg daily, loading dose 10.0mg/4.0mg daily) for a total of 28 days of open-label study drug administration. Up to 12 subjects with CF, 6 subjects on cystic fibrosis transmembrane conductance regulator (CFTR) modulators and 6 subjects not on CFTR modulators. | Combination Product: ABCI<br>* Subjects will receive ABCI via oral inhalation<br>* Other names: Amphotericin B Cystetic for Inhalation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs), and Serious Adverse Events (SAEs) | The safety and tolerability of ABCI following oral inhalation of single and multiple ascending doses in healthy subjects (Parts A and B), and in people with Cystic Fibrosis (Part C) will be assessed | up to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) Profile - SAD Cmax | Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Observed maximum concentration (Cmax) | 1 day | 
| Pharmacokinetics (PK) Profile - SAD Tmax | Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: time to reach maximum concentration (Tmax) | 1 day | 
| Pharmacokinetics (PK) Profile - SAD AUC0-24 | Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Area under the concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) | 1 day | 
| Pharmacokinetics (PK) Profile - SAD AUClast | Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast) | 1 day | 
| Pharmacokinetics (PK) Profile - SAD AUCinf | Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) | 1 day | 
| Pharmacokinetics (PK) Profile - SAD AUCtau | Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Area under the concentration- concentration-time curve over the dosing interval (AUCtau) | Up to 28 days | 
| Pharmacokinetics (PK) Profile - MAD Cmax | Pharmacokinetics Characteristics in Multiple Ascending Dose HV Subjects: Observed maximum concentration (Cmax) | Up to 28 days | 
| Pharmacokinetics (PK) Profile - MAD Tmax | Pharmacokinetics Characteristics in Multiple Ascending Dose HV Subjects: time to reach maximum concentration (Tmax) | Up to 28 days | 
| Pharmacokinetics (PK) Profile - MAD AUC0-24 | Pharmacokinetics Characteristics in Multiple Ascending Dose HV Subjects: Area under the concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) | Up to 28 days | 
| Pharmacokinetics (PK) Profile - MAD Plasma AmB trough assessments | Pharmacokinetics Characteristics in Multiple Ascending Dose HV Subjects: Plasma AmB trough assessments | Up to 84 days | 
| Pharmacokinetics (PK) Profile - MAD AmB concentrations in BAL fluid | Pharmacokinetics Characteristics in Multiple Ascending Dose HV Subjects: AmB concentrations in BAL fluid after study drug administration | Up to 29 days | 
| AmB concentrations - Subjects with CF | Cumulative effect on pre-dose AmB concentrations through Day 29 and assessment of washout through Day 42 | Through 42 days |