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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Alpha-1 Antitrypsin Deficiency

Intervention / Treatment
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* Drug: ARC-AAT Injection
* Other: Placebo
* Drug: Diphenhydramine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: 0.38 mg/kg<br>Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 1.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 2.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 3.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 4.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 5.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 6.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 7.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part A: 8.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Placebo Comparator: Part A: Placebo<br>Single dose administration of 0.9% normal saline IV injection in healthy volunteers | Other: Placebo<br>* 0.9 % normal saline<br>Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part B: 2.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part B: 4.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part B: 6.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in participants with AATD | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Experimental: Part B: 7.0 mg/kg<br>Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in participants with AATD | Drug: ARC-AAT Injection<br>* RNA interference-based, liver-targeted therapeutic<br>* Other names: ARC-AAT;Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|
| Placebo Comparator: Part B: Placebo<br>Single dose administration of 0.9% normal saline IV injection in participants with AATD | Other: Placebo<br>* 0.9 % normal saline<br>Drug: Diphenhydramine<br>* Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs | An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as defined as AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. SAEs are defined as is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. | From the first dose of study treatment through Day 29 ± 1 day | 
| Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Laboratory Values | Laboratory values collected include: hematology (haemoglobin, lymphocytes, neutrophils, platelets, white cell count, monocytes); biochemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatine kinase, creatinine, gamma-glutamyltransferase, fasting glucose, troponin I); coagulation parameters (fibrinogen, international normalized ratio); and C-reactive protein. | Day 1 through Day 29 ± 1 day | 
| Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Vital Signs, Electrocardiograms (ECGs), Pulmonary Function, Physical Findings, and Other Observations | Values collected include: vital signs (clinically concerning or symptomatic treatment emergent changes in heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate, or temperature); ECGs (clinically significant changes from baseline were observed for ventricular rate, RR interval, QRS duration, QT interval or QT interval corrected for heart rate using Fridericia's formula [QTcF]; treatment emergent clinically significant changes in ST segments, P wave or T wave morphology; cardiac telemetry monitoring); clinically significant abnormal physical examination findings; treatment emergent sensitivity to bee venom; pulmonary function (clinically significant worsening in spirometry parameters and carbon monoxide diffusing capacity of the lung for carbon monoxide [DLCO]). | Day 1 through Day 29 ± 1 day | 
| Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A) |  | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose | 
| Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A) |  | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose | 
| Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Time 24 Hours (AUC0-24) for the Analytes AD00370 and ARC-MLP (Part A) |  | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose | 
| Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From From Zero to Infinity (AUCinf) for the Analytes AD00370 and ARC-MLP (Part A) |  | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose | 
| Pharmacokinetics of ARC-AAT: Terminal Elimination Rate Constant Obtained From the Slope of the Line (Kel) for the Analytes AD00370 and ARC-MLP (Part A) |  | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose | 
| Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A) |  | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose | 
| Percentage Reduction From Baseline of AAT Up to Day 29 | Clinical assay for total serum AAT level was used for Part A. A quantitative measurement of AAT was used for Part B. A negative percent reduction indicates a percentage increase. Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1. | Baseline, Days 3, 8, 15, 22 and 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence) | Data presents the study visit day upon which a participant had the first occurrence of AAT reduction of > 30% from Baseline, and the number of participants who had a > 30% reduction at any visit (overall). Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1. | Baseline, Days 3, 8, 15, 22 and 29 | 
| Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT) |  | Study Day for Nadir of Mean AAT: Day 8 (for Part B 2 mg/kg arm), Day 15 (for Part A 0.38 mg/kg, 2 mg/kg, 4 mg/ kg, Placebo arms; Part B 4 mg/kg, Placebo arms), Day 22 (Part A 3 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg arms), Day 29 (1 mg/kg, 8 mg/kg arms) | 
| Number of Participants With a Return From Nadir AAT Blood Levels to Above Normal or Within 15% of Baseline in > 100 Days | Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1. | Baseline, up to Day 29, and through 100 days of follow-up | 
| Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose |  | Pre-dose, 2 hours post-dose | 
| Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose |  | Pre-dose, 2 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alpha-1 antitrypsin, AATD