A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)

A Double-Blind, Placebo-Controlled, Dose-Escalating, Phase 1 Study to Determine the Safety, Tolerability, Pharmacokinetics and Effect of Circulating Alpha-1 Antitrypsin Levels of ARC-AAT in Healthy Volunteer Subjects and in Patients With Alpha-1 Antitrypsin Deficiency (AATD)

The purpose of the study is to determine the safety and tolerability of escalating doses of ARC-AAT and to evaluate the pharmacokinetics of ARC-AAT and the effect of ARC-AAT on circulating levels of alpha-1 antitrypsin (AAT). The study will consist of two parts, Part A (conducted in healthy volunteers) and Part B (conducted in AATD patients) at up to 9 escalating dose levels with 6 participants per dose level.

Healthy volunteers and AATD patients will be randomized to receive a single intravenous injection of either ARC-AAT or Placebo in double-blind fashion. Up to thirteen cohorts (6 participants per cohort) will be enrolled. Participants in all cohorts will be confined to the clinical facility beginning on Day -1 with discharge on Day 2. Escalation to the next dose level will proceed until a participant experiences a dose-limiting toxicity (DLT) or there is achievement of pre-determined threshold reductions in AAT levels. Dosing in participants with AATD will commence based on pre-determined threshold reductions in AAT levels for healthy volunteers. For each participant, the duration of the study clinic visits is up to 11 weeks, from Screening to the End-of-Study examination. However, including a Day 90 Follow-Up telephone call, the maximum study duration is approximately 20 weeks.

Inclusion Criteria:

(Part A - Healthy Volunteers)

• Male or female healthy volunteers 18-50 years of age
• Written informed consent
• Body mass index between 18.0 and 28.0 kg/m2
• 12-lead electrocardiogram (ECG) at Screening and pre-dose assessment with no clinically significant abnormalities
• Non-pregnant/non-nursing females
• Non-smoker for at least one year with current non-smoking status confirmed by urine cotinine
• Normal lung function (or not clinically significant per investigator assessment) based on spirometry and diffusion capacity of lung for carbon monoxide (DLCO) according to American Thoracic Society (ATS) - European Respiratory Society (ERS) criteria
• Highly effective, double barrier contraception (both male and female partners) during the study and for 3 months following the dose of ARC-AAT
• Willing and able to comply with all study assessments and adhere to protocol schedule
• Suitable venous access for blood sampling
• No abnormal finding of clinical relevance at screening
• Normal AAT level

(Part B-Patients) - As for Part A with the following exceptions:

• Male or female patients 18-70 years of age
• Confirmed diagnosis of homozygous alpha 1-protease inhibitor deficiency (PiZZ genotype) not receiving alpha-1 antitrypsin augmentation therapy for more than 4 weeks
• BMI between 18.0 and 35.0 kg/m2
• Non-smoker for at least three years with current non-smoking status confirmed by urine cotinine

Exclusion Criteria:

(Part A-Healthy Volunteers)

• Current regular smoker of cigarettes or cigars or was a regular smoker over the past 1 year
• Recent (within last 6 weeks) transfusion of fresh frozen plasma, platelets, or packed red blood cells, or anticipated need for transfusion during study
• Acute signs of hepatitis/other infection within 4 weeks of screening and/or baseline
• Concurrent anticoagulants
• Use of dietary and/or herbal supplements that can interfere with liver metabolism within 7 days of screening
• Use of any drugs known to induce or inhibit hepatic drug metabolism within 14 days prior to study treatment
• Depot injection/implant of any drug other than birth control within 3 months prior to study treatment
• Diagnosis of diabetes mellitus or history of glucose intolerance
• History of poorly controlled autoimmune disease or any history of autoimmune hepatitis
• Human immunodeficiency virus (HIV) infection
• Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV), and/or history of delta virus hepatitis
• Uncontrolled hypertension (blood pressure > 150/100 mmHg)
• History of cardiac rhythm disturbances
• Family history of congenital long QT syndrome or unexplained sudden cardiac death
• Symptomatic heart failure (per New York Heart Association [NYHA] guidelines)
• Unstable angina, myocardial infarction, severe cardiovascular disease, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within past 6 months
• History of malignancy within last 5 years except adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer.
• History of major surgery within 3 months of screening
• Regular use of alcohol within 1 month prior to screening (i.e., more than fourteen units of alcohol per week)
• Evidence of acute inflammation, sepsis or hemolysis or clinical evidence of lower respiratory tract infection
• Diagnosis of significant psychiatric disorder
• Use of illicit drugs (such as cocaine, phencyclidine [PCP] and crack) within 1 year prior to screening or positive urine drug screen
• History of allergy or hypersensitivity reaction to bee venom
• Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study
• Clinically significant history/presence of any gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease
• Other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs
• Any clinically significant history/presence of poorly controlled neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease
• Blood donation (500 mL) within 7 days prior to study treatment
• History of fever within 2 weeks of screening
• Concomitant medical/psychiatric condition or social situation that would affect compliance or result in additional safety risk
• Excessive exercise/physical activity within 3 days of screening or enrollment or planned during the study
• History of thromboembolic disease, stroke within 6 months of baseline, and/or concurrent anticoagulant medication(s)

(Part B-Patients) - As for Part A with the following exceptions:

• History of major surgery within 2 months of Screening
• Forced expiratory volume at one second (FEV1) at baseline < 60%
• AATD patients with liver elastography score > 11 at Screening