alpha-1 antitrypsin deficiency (AATD)-associated liver disease MedDRA version: 23.0 Level: LLT Classification code 10001806 Term: Alpha-1 anti-trypsin deficiency System Organ Class: 10001806 - Alpha-1 anti-trypsin deficiency
Conditions
Sponsors
Arrowhead Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or non-nursing female patients 18-75 years of age, inclusive, at the time of Screening with previous diagnosis of PiZZ genotype Alpha-1 Antitrypsin Deficiency. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, patients must undergo PiZZ confirmatory testing at Screening. PiMZ or PiSZ genotypes are not permitted. 2. Able and willing to provide written informed consent prior to the performance of any study specific procedures. 3. Liver biopsy indicating a liver fibrosis score less than F4 based on local pathologist read. a. Metavir F1- F3 (or equivalent on other grading scales) may participate in Part A and Part B. A previous biopsy conducted as part of an AROAAT study within 1 year is acceptable if there is sufficient baseline material for Part B analysis. b. A patient with no fibrosis (F0) may participate in Part A only. A previous biopsy conducted within 1 year is acceptable if source verifiable medical record specifies F0. 4. A 12-lead ECG at Screening that, in the opinion of the Investigator, has no new acute abnormalities (e.g., new onset atrial fibrillation) that compromise participant’s safety in this study. Stable disease (e.g., stable atrial fibrillation) is acceptable. 5. Non-smoker (defined as does not smoke cigarettes daily for at least 12 months) with current non-smoking status confirmed by urine cotinine at screening AND any previous smoking history prior to 12 months must be =65 years) yes F.1.3.1 Number of subjects for
Exclusion criteria
Exclusion criteria: 1. INR = 1.2 at Screening (one retest permitted). If based on opinion of Investigator and/or prescribing physician patient is appropriate for anticoagulant holiday, patient may stop taking anticoagulant for an appropriate washout period and if indicated a repeat INR within 250 U/L at Screening (one retest permitted) 4. eGFR 170 and diastolic BP >100 mmHg at Screening). Patients may rescreen once BP is successfully controlled. 11. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular tachycardia or fibrillation), untreated heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new acute ST segment elevation or depression or new acute Q wave on ECG. Stable atrial dysrhythmias (e.g., stable atrial fibrillation) are acceptable. 12. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to Screening 13. History of malignancy within the last 1 year except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. 14. History of major surgery within the prior 1 month prior to Screening 15. Regular use of alcohol within one month prior to the Screening visit (i.e., more than 14 units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]) 16. Use of illicit drugs (such as cocaine, phencyclidine [PCP]) within 1 year prior to the Screening visit or positive urine drug screen at Screening (a urine drug screen positive for benzodiazepines, opioids or THC is acceptable for enrollment at the discretion of the Investigator). 17. Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving a therapeutic intervention. 18. Blood donation (=500 mL) within 7 days prior to study treatment administration. 19. Any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the participant at additional safety risk. Patients with NASH, NAFLD, metabolic syndrome, well controlled diabetes mellitus (even if on insulin) or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: • To select a single dose level for use in Part B of the study based on a combined evaluation of safety and pharmacodynamic dose response in each Part A cohort using change over time from baseline to Day 113 in serum Z-AAT levels Part B: • To evaluate efficacy (as assessed by the proportion of ARO-AAT treated patients relative to placebo achieving a 2-point improvement in a histologic grading scale of alpha-1 antitrypsin deficiency associated liver disease AND no worsening of liver fibrosis based on Ishak score on end of study biopsy).;Secondary Objective: Part B: • To evaluate change in total liver Z-AAT (insoluble + soluble) protein at end of study versus baseline • To evaluate change in liver Z-AAT soluble protein at end of study versus baseline • To evaluate change in liver Z-AAT insoluble protein at end of study versus baseline • To determine the effect of multiple doses of ARO-AAT on circulating levels of total and Z-AAT alpha-1 antitrypsin at multiple post-dose time points versus baseline • To evaluate change from baseline on a histologic grading scale of alpha-1 antitrypsin deficiency (AATD)-associated liver disease on end of study biopsy in ARO-AAT treated patients relative to placebo • To evaluate the effect of ARO-AAT on changes in serum biomarkers including PT, PTT, INR, albumin, ALT, AST, GGT, platelet count, total bilirubin, and alkaline phosphatase at timepoints throughout the study versus baseline • Safety of ARO-AAT administration versus placebo based on occurrence of adverse events (AEs);Primary end point(s): The primary efficacy endpoint of Part B of the study is the proportion of ARO-AAT treated patients relative to placebo who achieve a 2-point improvement in a histologic grading scale of alpha-1 antitrypsin associated liver disease AND no worsening of liver fibrosis based on Ishak fibrosis score on end of study biopsy. ;Timepoint(s) of evaluation of this end point: Part A: -Patients without fibrosis (F0) are not eligib | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part B secondary endpoints include: • change in total liver Z-AAT (insoluble + soluble) protein at end of study versus baseline • change in liver Z-AAT soluble protein at end of study versus baseline • change in liver Z-AAT insoluble protein at end of study versus baseline • the effect of multiple doses of ARO-AAT on circulating levels of total and Z-AAT alpha-1 antitrypsin at multiple post-dose time points versus baseline (patients on and not on AAT augmentation therapy will be evaluated separately) • change from baseline on a histologic grading scale (including, but not limited to histological features such as inflammation, PASD globules, cell death, steatosis, etc.) of AATD associated liver disease on end of study biopsy in ARO-AAT treated patients relative to placebo • the effect of ARO-AAT on changes in serum biomarkers including PT, PTT, INR, albumin, ALT, AST, GGT, platelet count, total bilirubin, and alkaline phosphatase at timepoints throughout the study versus baseline • safety of ARO-AAT administration versus placebo based on occurrence of AEs;Timepoint(s) of evaluation of this end point: Part B: Days 1, 29, 113 then every 84 days (Days 197, 281, 365, 449, 533, 617) | — |
Countries
Austria, Canada, Germany, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactMei Ling Chang-Lok
Arrowhead Pharmaceuticals, Inc.
Outcome results
None listed