A Study of Belcesiran in Patients With AATLD

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04764448

Acronym

ESTRELLA

Enrollment

Registered

2021-02-21

Start date

2021-02-12

Completion date

2024-05-29

Last updated

2026-04-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alpha 1-Antitrypsin Deficiency

Brief summary

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.

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.

Interventions

DRUGBelcesiran

Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.

OTHERPlacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Masking description

Double blind

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Up to 2.6 years	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.
Number of Participants With TEAEs and SAEs	Up to 2.6 years	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.
Change From Baseline in Pulmonary Function Tests (PFTs): Forced Vital Capacity (FVC)	Baseline (Day 1), week 96	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.
Change From Baseline in PFT: Forced Expiratory Volume in One Second (FEV1)	Baseline (Day 1), week 96	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.
Change From Baseline in PFT: FEV1/FVC Ratio	Baseline (Day 1), week 96	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.
Change From Baseline in PFT: Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)	Baseline (Day 1), week 96	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).
Change From Baseline in 12 -Lead Electrochardiograms (ECGs): Mean Heart Rate	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in mean heart rate is presented.
Change From Baseline in 12 -Lead ECGs: Mean Ventricular Rate	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in mean ventricular rate is presented.
Change From Baseline in 12 -Lead ECGs: PR Interval, QRS Interval, QT Interval, QTcF Interval and RR Interval	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in PR interval, QRS interval, QT interval, QTcF interval and RR interval is presented.
Number of Participants With Physical Examination Findings	At week 96	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.
Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in diastolic blood pressure and systolic blood pressure is presented.
Change From Baseline in Vital Signs: Heart Rate	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in heart rate is presented.
Vital Signs: Height at Baseline	Baseline (Day 1)	Height at baseline is presented.
Change From Baseline in Vital Signs: Respiratory Rate	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in respiratory rate is presented.
Change From Baseline in Vital Signs: Temperature	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in temperature is presented.
Change From Baseline in Vital Signs: Weight	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in weight is presented.
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)	Baseline (Day 1), week 96	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.
Change From Baseline in Clinical Laboratory Tests: Albumin, Apolipoprotein A1, Protein, Biomarker Haptoglobin	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in albumin, apolipoprotein A1, protein and biomarker haptoglobin is presented.
Change From Baseline in Clinical Laboratory Tests: Bilirubin, Creatinine and Direct Bilirubin	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in bilirubin, creatinine and direct bilirubin is presented.
Change From Baseline in Clinical Laboratory Tests: Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglycerides and Urea Nitrogen	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in chloride, cholesterol, glucose, potassium, sodium, triglycerides and urea nitrogen is presented.
Change From Baseline in Clinical Laboratory Tests: Gamma Glutamyl Transferase	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in gamma glutamyl transferase is presented.
Change From Baseline in Clinical Laboratory Tests: Basophils, Eosinophils, Leucocytes, Lymphocytes, Monocytes, Neutrophils and Platelets	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in basophils, eosinophils, leucocytes, lymphocytes, monocytes, neutrophils and platelets is presented.
Change From Baseline in Clinical Laboratory Tests: Basophils/Leucocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in basophils/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Eosinophils/Leucocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in eosinophils/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Haematocrit	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in haematocrit is presented.
Change From Baseline in Clinical Laboratory Tests: Lymphocytes/Leucocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in lymphocytes/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Monocytes/Leucocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in monocytes/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Neutrophils/Leucocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in neutrophils/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Reticulocytes/Erythrocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in reticulocytes/erythrocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin Concentration and Haemoglobin	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin concentration and haemoglobin is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Volume	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular volume is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in erythrocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Specific Gravity	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in specific gravity is reported.
Change From Baseline in Clinical Laboratory Tests: Urine Erythrocytes and Urine Leucocytes	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in urine erythrocytes and urine leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Potential of Hydrogen (pH)	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in pH is presented.
Change From Baseline in Clinical Laboratory Tests: Activated Partial Thromboplastin Time and Prothrombin Time	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in activated partial thromboplastin time and prothrombin time is presented.
Change From Baseline in Clinical Laboratory Tests: Prothrombin International Normalized Ratio	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in prothrombin international normalized ratio is presented.
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	Baseline (Day 1), week 96	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.
Change From Baseline in Clinical Laboratory Tests: C-Reactive Protein	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in C-reactive protein is presented.
Change From Baseline in Clinical Laboratory Tests: Complement Bb	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in complement Bb is presented.
Change From Baseline in Clinical Laboratory Tests: Complement Total (CH50)	Baseline (Day 1), week 96	Change from baseline (Day 1) to week 96 in CH50 is presented.
Cohort 1: Change From Baseline in Serum Alpha-1 Antitrypsin (AAT) Protein Concentrations	Baseline (Day 1), week 24	Change from baseline (Day 1) to week 24 in serum AAT protein concentrations in Cohort 1 is presented.
Cohort 2: Change From Baseline in Serum AAT Protein Concentrations	Baseline (Day 1), week 48	Change from baseline (Day 1) to week 48 in serum AAT protein concentrations in Cohort 2 is presented.

Secondary

Measure	Time frame	Description
Change From Baseline in Liver Fibrosis Ishak Score	Baseline (Day 1), week 48	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.

Countries

Australia, Austria, Belgium, Canada, France, Germany, Ireland, Netherlands, New Zealand, Portugal, Spain, Sweden, United Kingdom, United States

Contacts

STUDY_DIRECTORThomas Bowman, MD

Dicerna Pharmaceuticals / Novo Nordisk

Participant flow

Recruitment details

The trial was conducted at 8 sites in 8 countries. The number of sites that randomised participants are as follows: Australia (1), Belgium (1), Germany (1), Netherlands (1), New zealand (1), Portugal (1), Spain (1) and United states of America (1).

Pre-assignment details

The study was planned to be conducted in 3 separate cohorts: cohort 1, 2 and 3 however, due to early termination of the study, cohort 3 was not enrolled. Participants were randomized in a 1:1 fashion to either Cohort 1 or 2. In each cohort participants were further randomized to receive either Belcesiran or placebo. Randomization was stratified based on fibrosis stage (METAVIR Score F1, F2, F3, or F4) in both cohorts 1 and 2

Participants by arm

Arm	Count
Pooled Placebo All participants in cohort 1 and 2 received belcesiran matched placebo as subcutaneous injection, in Cohort 1 participants received monthly dosing for the first 24 weeks and then shifted to quarterly dosing thereafter until week 96 and in Cohort 2 participants received monthly dosing for the first 48 weeks and then shifted to quarterly dosing thereafter until week 96. Due to study termination participants were followed up to 2 months.	5
Cohort 1: Belcesiran Participants received a fixed dose of belcesiran 210 milligrams (mg) injection monthly for the first 24 weeks and then shifted to quarterly dosing thereafter until week 96.	5
Cohort 2: Belcesiran Participants received a fixed dose of belcesiran 210 mg injection subcutaneously monthly for the first 48 weeks and then shifted to quarterly dosing thereafter until week 96.	6
Total	16

Baseline characteristics

Characteristic	Pooled Placebo	Cohort 1: Belcesiran	Cohort 2: Belcesiran	Total
Age, Continuous	40.2 Years STANDARD_DEVIATION 17.31	57.2 Years STANDARD_DEVIATION 10.18	52.5 Years STANDARD_DEVIATION 11.86	50.1 Years STANDARD_DEVIATION 14.36
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants	5 Participants	6 Participants	16 Participants
Race/Ethnicity, Customized White	5 Participants	5 Participants	6 Participants	16 Participants
Sex: Female, Male Female	1 Participants	3 Participants	2 Participants	6 Participants
Sex: Female, Male Male	4 Participants	2 Participants	4 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 5	0 / 5	0 / 6
other Total, other adverse events	5 / 5	5 / 5	5 / 6
serious Total, serious adverse events	0 / 5	2 / 5	2 / 6