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

NCT02363946 | Terminated Phase 1 Results

• 3 other identifiers: ARCAAT-1001U1111-1171-02472015-001147-36
• Study Type: interventional
• Target: 65
• Locations: 4 countries
• Sites: 4

Brief 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.

Conditions

Alpha-1 Antitrypsin Deficiency

Keywords

alpha-1 antitrypsin; AATD

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (5)

• Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence)

  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, 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

Study Arms (15)

Part A: 0.38 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 1.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 2.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 3.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 4.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 5.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 6.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 7.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: 8.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part A: Placebo

PLACEBO COMPARATOR

Single dose administration of 0.9% normal saline IV injection in healthy volunteers

Other: Placebo; Drug: Diphenhydramine

Part B: 2.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part B: 4.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part B: 6.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in participants with AATD

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part B: 7.0 mg/kg

EXPERIMENTAL

Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in participants with AATD

Drug: ARC-AAT Injection; Drug: Diphenhydramine

Part B: Placebo

PLACEBO COMPARATOR

Single dose administration of 0.9% normal saline IV injection in participants with AATD

Other: Placebo; Drug: Diphenhydramine

Interventions

ARC-AAT Injection DRUG

RNA interference-based, liver-targeted therapeutic

Also known as: ARC-AAT

Part A: 0.38 mg/kg; Part A: 1.0 mg/kg; Part A: 2.0 mg/kg; Part A: 3.0 mg/kg; Part A: 4.0 mg/kg; Part A: 5.0 mg/kg; Part A: 6.0 mg/kg; Part A: 7.0 mg/kg; Part A: 8.0 mg/kg; Part B: 2.0 mg/kg; Part B: 4.0 mg/kg; Part B: 6.0 mg/kg; Part B: 7.0 mg/kg

Placebo OTHER

0.9 % normal saline

Part A: Placebo; Part B: Placebo

Diphenhydramine DRUG

Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.

Part A: 0.38 mg/kg; Part A: 1.0 mg/kg; Part A: 2.0 mg/kg; Part A: 3.0 mg/kg; Part A: 4.0 mg/kg; Part A: 5.0 mg/kg; Part A: 6.0 mg/kg; Part A: 7.0 mg/kg; Part A: 8.0 mg/kg; Part A: Placebo; Part B: 2.0 mg/kg; Part B: 4.0 mg/kg; Part B: 6.0 mg/kg; Part B: 7.0 mg/kg; Part B: Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• (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
• 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

You may not qualify if:

• (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

Sponsors & Collaborators

• Arrowhead Pharmaceuticals: lead

Study Sites (4)

Research Site 1

Melbourne, Victoria, 3004, Australia

Location

Research Site 2

Homburg, Germany

Location

Research Site 3

Leiden, 2333ZA, Netherlands

Location

Research Site 4

Edgbaston, Birmingham, B15 2WB, United Kingdom

Location

Related Publications (1)

• Turner AM, Stolk J, Bals R, Lickliter JD, Hamilton J, Christianson DR, Given BD, Burdon JG, Loomba R, Stoller JK, Teckman JH. Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients. J Hepatol. 2018 Aug;69(2):378-384. doi: 10.1016/j.jhep.2018.03.012. Epub 2018 Mar 21.

  PMID: 29572094 DERIVED

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Interventions

Diphenhydramine

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethylamines; Amines; Organic Chemicals; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Results Point of Contact

• Title: Chief Operating Officer
• Organization: Arrowhead Pharmaceuticals, Inc.

6263043400

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2015
• First Posted: February 16, 2015
• Study Start: February 1, 2015
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: January 12, 2026
• Results First Posted: August 3, 2018

Record last verified: 2025-12

Locations

AU (1); DE (1); NL (1); GB (1)