A clinical study to evaluate safety, tolerability, Pharmacokinetics and Pharmacodynamis of Belcesiran in patients with PiZZ Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Phase 1

• Conditions: MedDRA version: 23.1Level: LLTClassification code 10001806Term: Alpha-1 anti-trypsin deficiencySystem Organ Class: 100000004850; PiZZAlpha-1 Antitrypsin Deficiency Associated Liver Disease; Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

• Registration Number: EUCTR2020-003313-35-AT
• Lead Sponsor: Dicerna Pharmaceuticals, Inc., a wholly owned subsidiary of Novo Nordisk

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2022-01-04
• Last Update Posted: 21 August 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

1. Age 18 to 75 years, inclusive, at the time of signing the 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 during the study are eligible to participate.
6. eGFR at Screening = 60 mL/min normalized to 1.73 m2 BSA.
7. Non-smokers (defined as having not smoked cigarettes daily for at least the preceding 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, including use of e-cigarettes. Participants may be on nicotine replacement (patch or gum). A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the Investigator.
8. Male or female
Male participants:
A male participant with a partner of childbearing potential must agree to use contraception, as detailed in Section 10.4.2, during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Female participants:
A female participant is eligible to participate if she is not pregnant (see Section 10.4.3) and not breastfeeding. WOCBP must be using a highly effective method of contraception, as defined in Section 10.4.2.
9. Capable of giving signed informed consent, which includes compliance with the requirements (including consent to undergo paired liver biopsies) and restrictions listed in the ICF and in this protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 41
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion Criteria

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. Diagnostic testing exclusions are defined in the Diagnostic Assessments section below.
3. Child-Pugh Score B or C
4. History of one single severe exacerbation of underlying lung disease in the 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.
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 < 100,000/ mm^3)
b. hepatotoxicity, defined as ALT or AST > 3 × 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
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
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 (i.e., antinuclear antibodies, anti-smooth-muscle antibodies at a titer of at least 1:40, anti-liver/kidney microsomal-1 antibodies, antiliver cytosol antibody [anti-LC 1], or antisoluble liver/liver pancreas [anti-SLA/LP] antibodies).
14. 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 antimitochondrial antibodies (only required if primary biliary cirrhosis is suspected)
17. Platelets < 100,000/mm 3 at Screening
18. INR > 1.6 × ULN at Screening
19. Positive screening for HBsAg, HCV antibodies, or HIV1 and 2 antibodies. If a participant has been tested in the past 3 months,
medical record documentation of this testing

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified