A Study to Determine the Safety, Tolerability and Effect on Liver Histologic Parameters of ARO-AAT


About this study

The purpose of this study is to evaluate the safety, tolerability and effect on liver histologic parameters with administration of the investigational product, ARO-AAT, in participants with alpha-1 antitrypsin deficiency (AATD). Participants will receive multiple subcutaneous doses of ARO-AAT.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Male or non-nursing female patients, 18-75 years of age, inclusive, at the time of Screening.
  • 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.
  • Able and willing to provide written informed consent prior to the performance of any study specific procedures.
  • Liver biopsy indicating a liver fibrosis score less than F4 based on local pathologist read.
    • A patient with no fibrosis may participate based in a previous biopsy conducted within one year if a source verifiable medical record specifies no evidence of fibrosis.
  • 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 patient’s safety in this study. Stable disease (e.g., stable atrial fibrillation) is acceptable.
  • 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 < 15 pack years. Patients may be on nicotine replacement (patch or gum). e-cigarettes (vapor) is not permitted. A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the Investigator.
  • Use highly effective contraception during the study and for 3 months following the last dose of ARO-AAT. Males must not donate sperm for at least 3 months post last dose of study treatment. Females of childbearing potential must have a negative urine pregnancy test at Screening and on Day 1 pre-dose. Females not of childbearing potential must be post-menopausal (defined as cessation of regular menstrual periods for at least 12 months without an alternative medical cause), confirmed by follicle-stimulating hormone (FSH) consistent with post-menopausal state based on lab reference ranges.
    • Using twice the normal protection of birth control by using a condom AND one other form of either birth control pills (The Pill), depot or injectable birth control, IUD (Intrauterine Device), birth Control Patch (e.g., Ortho Evra), NuvaRing®, OR Surgical sterilization as a single form of birth control; i.e., tubal ligation, hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective surgical form of birth control, is acceptable.
    • True abstinence for the duration of the study and 12 weeks after the dose of AROAAT is acceptable only when in line with the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not considered “true” abstinence and are not acceptable methods of contraception. * All laboratory tests used as inclusion criteria may be repeated once and the repeat value may be used for inclusion purposes.

Exclusion Criteria:

  • 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 < 1.2 would be acceptable. Vitamin K may be used for reversal. If INR is not indicated (direct thrombin inhibitors or Xa inhibitors) then appropriate washout period alone may be acceptable. (Note: Anti-platelet agents, aspirin, clopidogrel or NSAIDS are acceptable but must be held 7 days before and 7 days after liver biopsy).
  • Platelet count < 150 x 10^9 /L at Screening (one retest permitted).
  • ALT and AST levels > 250 U/L at Screening (one retest permitted).
  • eGFR < 60ml/min/1.73m^2 at Screening (one retest permitted).
  • FEV1 < 65% of predicted (preferentially post-bronchodilatory reading) at Screening (one retest permitted).
  • Recent (last 3 months) pneumonia or lower respiratory infection (which must be verifiable from the medical record). Patient reported infection is not sufficient to meet this criterion.
  • Unavoidable exposure to inhaled environmental toxins that in the clinical judgement of the Investigator could impair pulmonary function significantly over the course of the study.
  • Human immunodeficiency virus infection, as shown by the presence of anti-HIV antibody (sero-positive).
  • Seropositive for HBV (HBsAg positive at Screening) or HCV (detectable HCV RNA at Screening). Cured HCV (positive antibody test without detectable HCV RNA is acceptable).
  • Uncontrolled hypertension (Systolic BP > 170 and diastolic BP > 100 mmHg at Screening). Patients may rescreen once BP is successfully controlled.
  • 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.
  • 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. 
  • 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. Patients with other curatively treated malignancies who have no evidence of metastatic disease and > 1-year disease-free interval may be entered following approval by the Medical Monitor.
  • History of major surgery within the prior 1 month prior to Screening.
  • 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]).
  • 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). The patient may still be eligible at discretion of Medical Monitor and Investigator if positive urine drug screen is due to a prescription medication.
  • Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving a therapeutic intervention. Patients who have participated in the ARCAAT-1001 study or observational studies are acceptable. Patients previously enrolled in but no longer enrolled in gene therapy studies are acceptable. Patients receiving AAT augmentation therapy as part of a post-marketing study or other access program for approved therapies are acceptable.
  • Blood donation (≥ 500 mL) within 7 days prior to study treatment administration.
  • Any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the patient at additional safety risk. Patients with NASH, NAFLD, metabolic syndrome, well controlled diabetes mellitus (even if on insulin) or hemochromatosis are acceptable if disease is stable and does not pose a significant threat to patient participation. Patients enrolled with NASH should have no plans to undergo bariatric surgery or have initiated or plan to initiate pharmaceutical therapy for NASH (such as Vitamin E or pioglitazone) during the course of the study.
  • A history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism), myocardial infarction, stroke within three (3) months of screening.
  • Any other condition or finding of clinical relevance at Screening, that in the opinion of the Investigator would render the patient unsuitable for enrollment or could interfere with participating in and completing the study.
  • Previous diagnosis of definitive liver cirrhosis based on biopsy or complications of cirrhosis (e.g., varices, ascites, hepatic encephalopathy) based on source verifiable medical record.
  • Patients who have undergone lung or liver transplant for AATD are excluded.
    • Note: Sponsor Medical Monitor has the option to exclude the enrollment of a patient if, based upon the patient’s medical history or Screening results, it is felt that a patient’s safety may be at risk.

* All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be used for exclusion purposes.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Hugo Vargas, M.D.

Closed for enrollment

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