Alpha-1 antitrypsin deficiency-associated liver disease liver disease
Conditions
Interventions
The study drug, Belcesiran, uses an RNAi strategy to silence SERPINA1, which
reduces the total hepatic Z-AAT expression leading to decreased accumulation of
toxic Z-AAT in the liver.
The study will
Sponsors
Dicerna Pharmaceuticals, Inc., a wholly owned subsidiary of Novo Nordisk
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Age 18 to 75 years, inclusive, at the time of signing the informed consent form (ICF). 2. Documented diagnosis of PiZZ-type AATD, confirmed by genotyping. Historical genotyping data may be used, if available. 3. AATLD, with a liver fibrosis score categorized as F1, F2, F3, or F4 in the METAVIR scoring system, documented by liver biopsy during Screening. 4. Post-bronchodilator FEV1> 45% of predicted at Screening 5. Participants receiving augmentation therapy on a regular basis and intending to continue augmentation therapy during the study are eligible to participate. 6. Estimated glomerular filtration rate at Screening >= 60 mL/min/1.73 7. Non-smokers (defined as having not smoked cigarettes daily for at least the preceding12 months) with current non-smoking status confirmed by urine cotinine at Screening AND any previous smoking history prior to 12 months must be
Exclusion criteria
Exclusion criteria: Medical Conditions 1. Any condition which, in the investigator's opinion might jeopardize participant's safety or compliance with the protocol. 2. History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type AATD. 3. Child-Pugh Score B or C 4.History of one single severe exacerbation of underlying lung disease in the past year prior to randomization. A severe exacerbation is defined as an exacerbation that requires hospitalization or a visit to the emergency room. 5. History of rapid decline in pulmonary function, as assessed by the Investigator. 6. Known or suspected abuse of drugs in the opinion of the Investigator. 7. Known or suspected excessive consumption of alcohol (>= 21 units of alcohol per week in men and >= 14 units of alcohol per week in women; where a "unit" of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor as defined by the World Health Organization) 8. Any of the following: myocardial infarction, stroke, classification of heart failure New York Heart Association (NYHA) Class IV, hospitalization for unstable angina pectoris or transient ischaemic attack within the past 90 days prior to the day of screening (V2A) and between screening and randomization. 9. History of malignancy, unless the malignancy (other than hepatocellular or lung cancer) has been in complete remission off chemotherapy and without additional medical or surgical interventions within the preceding 5 years, or unless the malignancy has been an adequately treated skin cancer (other than melanoma) or, superficial bladder tumor, or in situ cervical cancer in the preceding 1 year. Prior/Concomitant Therapy 10. Use of an RNAi drug at any time. 11. History of one or more of the following reactions to an oligonucleotide-based therapy: a. severe thrombocytopenia (platelet count 3 × upper limit of normal (ULN) and total bilirubin > 2 × ULN or INR > 1.5 c. severe flu-like symptoms leading to discontinuation of therapy d. localized skin reaction from the injection (graded severe) leading to discontinuation of therapy e. coagulopathy/clinically significant prolongation of clotting time Prior/Concurrent Clinical Study Experience 12. Participation in any clinical study in which they received an IMP within 4 months (or 5 times the half-life, whichever is longer) before Screening Diagnostic assessments 13. AST and ALT > 5 × ULN at Screening For individuals with any serum aminotransferase elevation > 2 × ULN, autoimmune hepatitis should be ruled out through the appropriate screening tests, which may include total IgG or gamma-globulin levels and/or serologic markers (antinuclear antibodies, anti-smooth-muscle antibodies at a titer of at least 1:40, anti-liver/kidney microsomal-1 antibodies, anti-liver cytosol antibody [anti-LC 1], or antisoluble liver/liver pancreas [anti-SLA/LP] antibodies). 14. alkaline phosphatase (ALP) 2 × ULN at Screening 15. Serum AFP value > 100 ng/mL at Screening If AFP at screening is > ULN but < 100 ng/mL, the participant is still eligible if an appropriate hepatic imaging study reveals no lesions 16. Positive screening for antimit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary outcomes Cohort 1 and 2: 1. The incidence and nature of treatment emergent adverse events (TEAEs), and the change from Baseline in pulmonary function tests (PFTs), 12-lead ECGs, physical examination findings, vital signs, and clinical laboratory tests. 2. Changes from baseline to weeks 24 (Cohort 1)/48 (Cohort 2) in serum AAT protein concentrations Cohort 3: 1. Change from baseline to week 24 in serum Z-AAT protein levels 2. Change from baseline to week 24 in liver Z-AAT protein levels | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Pharmacokinetics profile of belcesiran 2. Change from Baseline up until week 96 in liver fibrosis 3. Change from Baseline up until week 96 in diastase-resistant PAS-positive AAT globules | — |
Countries
Netherlands
Outcome results
None listed