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

• Status: Terminated
• Trial end date: 2016-11-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Arrowhead Pharmaceuticals
• Treatments: Alpha 1-Antitrypsin; Diphenhydramine; Promethazine; Protein C Inhibitor

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