A Study of ARC-AAT in Healthy Volunteer Subjects and 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.

Eligibility Criteria:
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