A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)
Condition: Alpha-1 Antitrypsin Deficiency
MeSH terms: Alpha 1-Antitrypsin Deficiency
Intervention: ARC-AAT Injection; Placebo; Diphenhydramine
Intervention description: RNA interference-based, liver-targeted therapeutic; 0.9 % normal saline; Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.
Intervention MeSH terms: Diphenhydramine; Promethazine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: alpha-1 antitrypsin; AATD

Summary:

      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.
    

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