SAD and MAD of Inhaled AR-501 in Health Adults and P. Aeruginosa Infected Cystic Fibrosis Subjects
SAD and MAD of Inhaled AR-501 in Health Adults and P. Aeruginosa Infected Cystic Fibrosis Subjects
This is a Phase 1/2a randomized, double-blind, two-part, dose-ascending, multicenter study of
 AR-501 (gallium citrate) solution, administered via inhalation, in healthy adult and P.
 aeruginosa infected cystic fibrosis (CF) subjects. Phase 1 of the study in HV subjects will
 consist of a single-ascending-dose (SAD) cohort, followed by the HV multiple-ascending-dose
 (MAD) cohort. Phase 2a of the study in CF subjects will consist of a MAD study design. The
 study will evaluate the safety and pharmacokinetic (PK) profile of single and repeat
 administrations of inhaled AR-501 solution in healthy adults, and the safety, PK and efficacy
 of repeat administrations of inhaled AR-501 solution in P. aeruginosa infected CF subjects.
Three dose levels (low, medium and high) will be assessed in succession, first in healthy
 volunteer (HV) subjects, then in cystic fibrosis (CF) subjects. The study will be performed
 in 2 parts: Phase 1 part of the study in HV subjects will consist of a single-ascending-dose
 (SAD) cohort, followed by the HV multiple-ascending-dose (MAD) cohort. Phase 2a part of the
 study in CF subjects will consist of a MAD study design.

 The HV cohort will include up to 48 subjects. The CF cohort will have 42 subjects. Thus, the
 total number of subjects is 90.

 The Phase 1 HV study will be performed at a Phase 1 Clinical Study Unit and the Phase 2a will
 be performed at approximately 24 clinical trial sites located in the United States and
 possibly in Europe, some of which may be part of the Cystic Fibrosis Foundation
 (CFF)-accredited Therapeutic Development Network (TDN) or the European Cystic Fibrosis
 Society Clinical Trial Network (ECFS-CTN). Subjects who meet all eligibility criteria,
 including giving informed consent, will be enrolled and undergo a screening period of 28
 days.

 The HV cohort will include up to 24 adult subjects in 3 dose groups (8 per dose group [Low,
 Medium and High]) for the SAD phase of the study. In each dose group, subjects will be
 randomly assigned in a 3:1 ratio to the active drug or placebo, resulting in 6 subjects
 receiving inhaled AR-501 and 2 receiving inhaled placebo in a double-blind manner. The HV MAD
 phase of the study will include 24 adult subjects in 3 dose groups (8 per dose group [Low,
 Medium and High]). In each dose group, subjects will be randomly assigned in a 3:1 ratio to
 active study drug or placebo, resulting in 6 subjects receiving inhaled AR-501 and 2
 receiving inhaled placebo in a double-blind manner. All subjects in HV MAD cohorts will
 receive once weekly inhaled study drug (either AR-501 or matching placebo) for 4 weeks for a
 total of 5 doses.

 The CF MAD cohort will evaluate 3 different dose levels for a total of 42 adult CF. Of the 42
 subjects, 30 will be randomized to receive one of the three ascending doses of AR-501, while
 12 will be randomized to receive placebo. All subjects in CF cohorts will receive once weekly
 inhaled study drug (either AR-501 or matching placebo) for 2 weeks for a total of 3 doses.

 The primary purpose of this study is to assess preliminary clinical safety of inhaled AR-501.
 The true frequency of AEs is unknown, and the sample size cannot be estimated accurately. For
 unknown AEs, the probabilities of observing at least 1 AE among 36 total healthy adult
 subjects and 30 adult CF subjects receiving any AR-501 dose are ≥ 80% if the true rate of
 such events are at least 4.4% and 4.8% respectively.
Inclusion Criteria (HV Subjects):

 1. Written informed consent given by the subject.

 2. At least ≥ 18 years old and < 50 years of age.

 3. Healthy with no acute medical condition for ≥ 2 weeks prior to screening and no known
 chronic medical condition requiring regular medical follow up and care.

 4. Body mass index (BMI) between 18 and 30 kg/m2, inclusive.

 5. Currently nonsmoking and no history of using nicotine/tobacco-containing products for
 ≥ 5 years prior to screening.

 6. Normal chest X-ray, per opinion of the Investigator.

 7. FEV1 ≥ 80% of predicted values.

 8. No history or current illicit, pharmaceutical drug or alcohol abuse within ≤ 5 years
 prior to screening.

 9. A female subject must meet one of the following criteria:

 If of childbearing potential - agrees to use one of the accepted contraceptive
 regimens from at least 30 days prior to the first administration of the study
 medication, during the study, and for at least 90 days after the last dose of the
 study medication. An acceptable method of contraception includes one of the following:

 -  Abstinence from heterosexual intercourse

 -  Hormonal contraceptives (birth control pills, injectable/implant/insertable
 hormonal birth control products, transdermal patch)

 -  Intrauterine device (with or without hormones), OR

 -  Agrees to use a double barrier method (e.g., condom and spermicide) during the
 study and for at least 90 days after the last dose of the study medication

 If a female of non-childbearing potential, the subject should be surgically sterile
 (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation)
 or in a menopausal state (at least 1 year without menses), as confirmed by follicle
 stimulating hormone (FSH) levels.

 10. A male subject must agree to use a double barrier method (e.g., condom and spermicide)
 during the study and for at least 90 days after the last dose of the study medication.

 Inclusion Criteria (CF Subjects):

 1. Written informed consent given by the subject.

 2. At least18 years old

 3. Documentation of a CF diagnosis as evidenced by one or more clinical features
 consistent with the CF phenotype and one or more of the following criteria:

 -  Sweat chloride equal to or greater than 60 mmol/liter by quantitative pilocarpine
 iontophoresis test (QPIT)

 -  Two well-characterized, disease-causing mutations in the cystic fibrosis
 transmembrane conductance regulator (CFTR) gene.

 4. Confirmation of prior and current colonization/infection with P. aeruginosa defined
 as:

 at least 2 positive cultures for PA in the last 12 months and a positive culture at
 screening.

 5. Respiratory symptoms and CF status are stable with no acute exacerbation at the time
 of randomization.

 6. Subject either using 1 alternating monthly suppressive inhaled antimicrobial therapy
 (at the time of randomization) OR using no suppressive inhaled antimicrobial therapy.

 7. BMI between 18 and 30 kg/m2, inclusive.

 8. Currently non-smoking and no history of using nicotine/tobacco-containing products or
 smoking/vaping (inhaled tobacco products or other inhaled substances) for ≥ 1 year
 prior to screening.

 9. 1st 3 sentinels subjects in each dose group must have a FEV1 ≥ 60% of predicted
 values. The remaining 3 sentinel subjects and expanded dosing cohort in each dose
 group must have a FEV1 ≥ 45% of predicted values.

 10. Serum creatinine and total bilirubin are both < 1.5 x upper limit of normal (ULN)
 range (isolated bilirubin > 1.5 x ULN range is acceptable if bilirubin is fractionated
 and direct bilirubin is < 35%).

 11. A female subject must meet one of the following criteria:

 -  If of childbearing potential - agrees to use one of the accepted contraceptive
 regimens from at least 21 days prior to the first administration of the study
 medication, during the study, and for at least 28 days after the last dose of the
 study medication. An acceptable method of contraception includes one of the
 following:

 -  Abstinence from heterosexual intercourse

 -  Hormonal contraceptives (birth control pills, injectable/implant/insertable
 hormonal birth control products, transdermal patch)

 -  Intrauterine device (with or without hormones), OR

 -  Agrees to use a double barrier method (e.g., condom and spermicide) during
 the study and for at least 28 days after the last dose of the study
 medication

 -  If a female of non-childbearing potential, the subject should be surgically
 sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or
 tubal ligation) or in a menopausal state (at least 1 year without menses), as
 confirmed by FSH levels.

 12. A male subject must agree to use a double barrier method (e.g., condom and spermicide)
 during the study and for at least 28 days after the last dose of the study medication.

 13. Ability to produce/expectorate sputum sample.

 Exclusion Criteria (HV Subjects):

 None of the following criteria can be met.

 1. Female subjects who are currently pregnant or lactating.

 2. Oral temperature above 37.5ºC at the time of screening or prior to randomization.

 3. Clinically abnormal renal function, evidenced by serum creatinine > 1.5 mg/dL.

 4. Need for using any nephrotoxic agents during the study.

 5. Known allergy or hypersensitivity to albuterol.

 6. Significantly abnormal liver function:

 1. Total bilirubin >1.5 x upper limit of the normal range (ULN),

 2. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 x ULN
 and alkaline phosphatase (ALP) > 2 x ULN

 7. Hemoglobin <10 g/dL

 8. Abnormal corrected serum calcium concentration prior to enrollment.

 9. History or current use of illicit, pharmaceutical drug or alcohol abuse within 5 years
 prior to screening.

 10. Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening and
 admission.

 11. Positive test results for Human Immunodeficiency Virus (HIV)-1/HIV-2 antibodies,
 Hepatitis B surface antigen (HBsAg) or Hepatitis C virus antibody (HCVAb).

 12. Inability to comply with any study requirements based on judgement of the
 Investigator.

 13. Any medical, psychological, cognitive, social or legal conditions that would interfere
 in the ability to give an informed consent and/or participate fully in the study.

 14. Participation in another clinical trial involving receipt of an investigative product
 within 30 days before screening.

 15. Any other reason as determined by an Investigator.

 Exclusion Criteria (CF Subjects):

 None of the following criteria can be met.

 1. Female subjects who are currently pregnant or lactating.

 2. Oral temperature above 37.5ºC at the time of screening or prior to randomization.

 3. Serum creatinine > 1.5 mg/dL or known significant kidney disease.

 4. Significantly abnormal liver function:

 1. Total bilirubin > 1.5 x ULN range,

 2. ALT and/or AST > 3 x ULN range and ALP > 2 x ULN range.

 5. History of medically attended hemoptysis, requiring hospitalization (small amount of
 blood streaking in sputum is acceptable).

 6. Pulmonary exacerbations within 3 months prior to randomization.

 7. Hemoglobin < 10 g/dL.

 8. Abnormal corrected serum calcium concentration prior to randomization (normal range is
 typically 8.5-10.2 mg/dL).

 9. Any change (initiation, change in type of drug, dose modification, schedule
 modification, interruption, discontinuation, or re-initiation) in a chronic
 treatment/prophylaxis regimen for CF or CF-related conditions within 2 weeks prior to
 randomization.

 10. Known allergy or hypersensitivity to albuterol or any component of the study drug or
 placebo

 11. History or current use of illicit, pharmaceutical drug or alcohol abuse within 5 years
 prior to screening.

 12. Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening
 (positive results for a subject on Orkambi should have a confirmatory test for
 cannabinoids performed, e.g., reflex testing, to rule out cross reaction with Orkambi)

 13. History of positive test result for human immunodeficiency virus (HIV) HIV-1/HIV-2
 antibodies, HBsAg or chronic hepatitis C virus infection.

 14. Inability to comply with any study requirements based on judgement of the
 Investigator.

 15. Any medical, psychological, cognitive, social or legal conditions that would interfere
 in the ability to give an informed consent and/or participate fully in the study.

 16. Participation in another clinical trial involving receipt of an investigative product
 within 30 days before randomization.

 17. Suspected or confirmed acute respiratory infection (Examples: bacterial pneumonia,
 influenza, COVID-19).

 18. Any other reason as determined by an Investigator.