A Study of Belcesiran in Patients With AATLD (ESTRELLA)

A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

This is a multiple dose, randomized, placebo-controlled, double-blind study of belcesiran to evaluate the safety, tolerability, PK, and PD in adult patients with PiZZ AATD-associated liver disease (AATLD).

The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.

Study Overview

• Status: Terminated
• Conditions: Alpha 1-Antitrypsin Deficiency
• Intervention / Treatment: Drug: Belcesiran; Drug: Belcesiran; Drug: Belcesiran; Other: Placebo; Other: Placebo; Other: Placebo

Detailed Description

AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of AAT in the lung, no treatment exists for the associated liver disease.

Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • St Vincent's Hospital Melbourne
• Austria
  • Innsbruck, Austria
    • Medizinische Universitaet Innsbruck
• Belgium
  • Leuven, Belgium
    • Universitaire Ziekenhuizen Leuven
• Canada
  • Quebec
    • Montreal, Quebec, Canada
      • Centre Hospitalier de l'Universite de Montreal (CHUM)
• France
  • Pessac, France
    • CHU Bordeaux - Hopital Haut-Leveque - Centre Francois Magendie
• Germany
  • Aachen, Germany
    • Universitaetsklinikum Aachen, AoeR
  • Kiel, Germany
    • Universitaetsklinikum Schleswig-Holstein Campus Kiel
• Ireland
  • Dublin, Ireland
    • Beaumont Hospital
• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
• New Zealand
  • Hamilton, New Zealand
    • Waikato Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1010
      • Auckland Clinical Studies
• Portugal
  • Creixomil, Portugal
    • Hospital da Senhora da Oliveira - Guimarães
  • Porto, Portugal
    • Centro Hospitalar Universitario de Sao Joao
  • Vila Real, Portugal
    • Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE
• Spain
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Cantabria
    • Santander, Cantabria, Spain
      • Hospital Universitario Marques de Valdecilla Santander
• Sweden
  • Uppsala, Sweden
    • CTC Clinical Trial Consultants AB Uppsala
• United Kingdom
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital, Cambridge University
  • Leeds, United Kingdom
    • Leeds Teaching Hospitals NHS Trust
  • London, United Kingdom
    • Royal Free London NHS Foundation Trust, Royal Free Hospital
• United States
  • California
    • La Jolla, California, United States, 92093
      • University of California - San Diego
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 to 75 years, inclusive, at the time of consent.
• Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available.
• AATD-associated liver disease documented by liver biopsy at Screening.
• Consent to undergo paired liver biopsies.
• Lung, renal and liver function within acceptable limits
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

• History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency.
• Child-Pugh Score B or C.
• History of one single severe exacerbation of underlying lung disease in the year prior to randomization.
• History of clinically significant respiratory infections (including pneumonia and lower respiratory tract infections), as determined by the Investigator, in the 3 months prior to screening
• Use of an RNAi drug at any time.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Cohort 1	Other: Placebo; Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.; Other: Placebo; Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.; Other: Placebo; Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.
Experimental: Belcesiran Cohort 1	Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.; Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.; Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.
Experimental: Belcesiran Cohort 2	Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.; Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.; Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.
Placebo Comparator: Placebo Cohort 2	Other: Placebo; Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.; Other: Placebo; Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.; Other: Placebo; Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.
Experimental: Belcesiran Cohort 3	Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.; Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.; Drug: Belcesiran; Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.
Placebo Comparator: Placebo Cohort 3	Other: Placebo; Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.; Other: Placebo; Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.; Other: Placebo; Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Number of TEAEs and SAEs is presented. An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were defined as TEAEs if they had a start date on or after the administration of study drug during the treatment period, or if they occurred prior to the administration of study drug and worsened in severity/grade or relationship to the study intervention after the administration of study intervention during the treatment period. A SAE was defined as any untoward medical occurrence that, at any dose: a) resulted in death, b) is life-threatening, c) required inpatient hospitalization or prolongation of existing hospitalization, d) resulted in persistent disability/incapacity, e) was a congenital anomaly/birth defect.	Up to 2.6 years
Number of Participants With TEAEs and SAEs	Number of participants with TEAEs and SAEs is presented. An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were defined as TEAEs if they had a start date on or after the administration of study drug during the treatment period, or if they occurred prior to the administration of study drug and worsened in severity/grade or relationship to the study intervention after the administration of study intervention during the treatment period. A SAE was defined as any untoward medical occurrence that, at any dose: a) resulted in death, b) is life-threatening, c) required inpatient hospitalization or prolongation of existing hospitalization, d) resulted in persistent disability/incapacity, e) was a congenital anomaly/birth defect.	Up to 2.6 years
Change From Baseline in Pulmonary Function Tests (PFTs): Forced Vital Capacity (FVC)	Change in FVC from baseline (Day 1) to week 96 is presented. FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, that is, VC performed with a maximally forced expiratory effort.	Baseline (Day 1), week 96
Change From Baseline in PFT: Forced Expiratory Volume in One Second (FEV1)	Change in FEV1 from baseline (Day 1) to week 96 is presented. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration.	Baseline (Day 1), week 96
Change From Baseline in PFT: FEV1/FVC Ratio	Change in FEV1/FVC ratio from baseline (Day 1) to week 96 is presented. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, that is, VC performed with a maximally forced expiratory effort.	Baseline (Day 1), week 96
Change From Baseline in PFT: Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)	Change in DLCO from baseline (Day 1) to week 96 is presented. DLCO is a measure of the quantity of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (specifically hemoglobin) in pulmonary capillaries. It is expressed as millimoles per minute per kilopascal (mmol/min/kPa).	Baseline (Day 1), week 96
Change From Baseline in 12 -Lead Electrochardiograms (ECGs): Mean Heart Rate	Change from baseline (Day 1) to week 96 in mean heart rate is presented.	Baseline (Day 1), week 96
Change From Baseline in 12 -Lead ECGs: Mean Ventricular Rate	Change from baseline (Day 1) to week 96 in mean ventricular rate is presented.	Baseline (Day 1), week 96
Change From Baseline in 12 -Lead ECGs: PR Interval, QRS Interval, QT Interval, QTcF Interval and RR Interval	Change from baseline (Day 1) to week 96 in PR interval, QRS interval, QT interval, QTcF interval and RR interval is presented.	Baseline (Day 1), week 96
Number of Participants With Physical Examination Findings	Number of participants with physical examination findings at week 96 is presented. The data is presented under categories:a) Normal, b) Abnormal, not clinically significant, c) Abnormal, clinically significant.	At week 96
Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure	Change from baseline (Day 1) to week 96 in diastolic blood pressure and systolic blood pressure is presented.	Baseline (Day 1), week 96
Change From Baseline in Vital Signs: Heart Rate	Change from baseline (Day 1) to week 96 in heart rate is presented.	Baseline (Day 1), week 96
Vital Signs: Height at Baseline	Height at baseline is presented.	Baseline (Day 1)
Change From Baseline in Vital Signs: Respiratory Rate	Change from baseline (Day 1) to week 96 in respiratory rate is presented.	Baseline (Day 1), week 96
Change From Baseline in Vital Signs: Temperature	Change from baseline (Day 1) to week 96 in temperature is presented.	Baseline (Day 1), week 96
Change From Baseline in Vital Signs: Weight	Change from baseline (Day 1) to week 96 in weight is presented.	Baseline (Day 1), week 96
Change in Clinical Laboratory Tests: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Creatine Kinase, Glutamate Dehydrogenase, Lactate Dehydrogenase, Biomarker Creatine Kinase (M30) and Biomarker Creatine Kinase (M65)	Change from baseline (Day 1) to week 96 in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatine kinase, glutamate dehydrogenase, lactate dehydrogenase, biomarker creatine kinase (M30) and biomarker creatine kinase (M65) is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Albumin, Apolipoprotein A1, Protein, Biomarker Haptoglobin	Change from baseline (Day 1) to week 96 in albumin, apolipoprotein A1, protein and biomarker haptoglobin is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Bilirubin, Creatinine and Direct Bilirubin	Change from baseline (Day 1) to week 96 in bilirubin, creatinine and direct bilirubin is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglycerides and Urea Nitrogen	Change from baseline (Day 1) to week 96 in chloride, cholesterol, glucose, potassium, sodium, triglycerides and urea nitrogen is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Gamma Glutamyl Transferase	Change from baseline (Day 1) to week 96 in gamma glutamyl transferase is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Basophils, Eosinophils, Leucocytes, Lymphocytes, Monocytes, Neutrophils and Platelets	Change from baseline (Day 1) to week 96 in basophils, eosinophils, leucocytes, lymphocytes, monocytes, neutrophils and platelets is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Basophils/Leucocytes	Change from baseline (Day 1) to week 96 in basophils/leucocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Eosinophils/Leucocytes	Change from baseline (Day 1) to week 96 in eosinophils/leucocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Haematocrit	Change from baseline (Day 1) to week 96 in haematocrit is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Lymphocytes/Leucocytes	Change from baseline (Day 1) to week 96 in lymphocytes/leucocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Monocytes/Leucocytes	Change from baseline (Day 1) to week 96 in monocytes/leucocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Neutrophils/Leucocytes	Change from baseline (Day 1) to week 96 in neutrophils/leucocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Reticulocytes/Erythrocytes	Change from baseline (Day 1) to week 96 in reticulocytes/erythrocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin Concentration and Haemoglobin	Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin concentration and haemoglobin is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin	Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Volume	Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular volume is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Erythrocytes	Change from baseline (Day 1) to week 96 in erythrocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Specific Gravity	Change from baseline (Day 1) to week 96 in specific gravity is reported.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Urine Erythrocytes and Urine Leucocytes	Change from baseline (Day 1) to week 96 in urine erythrocytes and urine leucocytes is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Potential of Hydrogen (pH)	Change from baseline (Day 1) to week 96 in pH is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Activated Partial Thromboplastin Time and Prothrombin Time	Change from baseline (Day 1) to week 96 in activated partial thromboplastin time and prothrombin time is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Prothrombin International Normalized Ratio	Change from baseline (Day 1) to week 96 in prothrombin international normalized ratio is presented.	Baseline (Day 1), week 96
Change in Clinical Laboratory Tests: Alpha Fetoprotein, Biomarker Hyaluronic Acid, Biomarker Matrix Metalloproteinase 9, Biomarker Procollagen 3 N-Terminal Propeptide, Biomarker Tissue Inhibitor of Metalloproteinase 1, Complement C3a and Complement C5a	Change from baseline (Day 1) to week 96 in alpha fetoprotein, biomarker hyaluronic acid, biomarker matrix metalloproteinase 9, biomarker procollagen 3 N-Terminal propeptide, biomarker tissue inhibitor of metalloproteinase 1, complement C3a and complement C5a is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: C-Reactive Protein	Change from baseline (Day 1) to week 96 in C-reactive protein is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Complement Bb	Change from baseline (Day 1) to week 96 in complement Bb is presented.	Baseline (Day 1), week 96
Change From Baseline in Clinical Laboratory Tests: Complement Total (CH50)	Change from baseline (Day 1) to week 96 in CH50 is presented.	Baseline (Day 1), week 96
Cohort 1: Change From Baseline in Serum Alpha-1 Antitrypsin (AAT) Protein Concentrations	Change from baseline (Day 1) to week 24 in serum AAT protein concentrations in Cohort 1 is presented.	Baseline (Day 1), week 24
Cohort 2: Change From Baseline in Serum AAT Protein Concentrations	Change from baseline (Day 1) to week 48 in serum AAT protein concentrations in Cohort 2 is presented.	Baseline (Day 1), week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Liver Fibrosis Ishak Score	Change from Baseline up until week 48 in liver fibrosis based on Ishak score is presented. The Ishak staging system for liver fibrosis is a 1995 update to the algorithm initially developed by De Groote et al. Ishak scores range from 0 (no fibrosis) to 6 (cirrhosis) which are as follows: 0-no fibrosis, 1-fibrous expansion of some portal areas, with or without short fibrous septa, 2-Fibrous expansion of most portal areas, with or without short fibrous septa, 3-Fibrous expansion of most portal areas with occasional portal-to-portal bridging, 4-Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to central), 5-Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis), 6-Cirrhosis, probable or definite.	Baseline (Day 1), week 48

Collaborators and Investigators

• Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Investigators: Study Director: Thomas Bowman, MD, Dicerna Pharmaceuticals / Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2021
• Primary Completion (Actual): December 8, 2023
• Study Completion (Actual): May 29, 2024

Study Registration Dates

• First Submitted: January 27, 2021
• First Submitted That Met QC Criteria: February 17, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Liver Diseases; Subcutaneous Emphysema; Emphysema; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: DCR-A1AT-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes