A Study of Belcesiran in Patients With AATLD

Phase 2TerminatedNCT04764448

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company16 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

OTHER

Masking

TRIPLE

Enrollment

Conditions

Alpha 1-Antitrypsin Deficiency

Interventions

BelcesiranDRUG

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

PlaceboOTHER

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.

BelcesiranDRUG

Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Locations (23)

University of California - San Diego

La Jolla, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline (Day 1), week 96

Data from ClinicalTrials.gov

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Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.

BelcesiranDRUG

Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.

PlaceboOTHER

Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.

University of Florida

Gainesville, Florida, United States

Medical University of South Carolina

Charleston, South Carolina, United States

St Vincent's Hospital Melbourne

Melbourne, Australia

Medizinische Universitaet Innsbruck

Innsbruck, Austria

Universitaire Ziekenhuizen Leuven

Leuven, Belgium

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, Canada

CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie

Pessac, France

Universitaetsklinikum Aachen, AoeR

Aachen, Germany

Universitaetsklinikum Schleswig-Holstein Campus Kiel

Kiel, Germany

...and 13 more locations

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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline (Day 1), week 96

Vital Signs: Height at Baseline

Height at baseline is presented.

Time frame: Baseline (Day 1)

Change From Baseline in Vital Signs: Respiratory Rate

Change from baseline (Day 1) to week 96 in respiratory rate is presented.

Time frame: Baseline (Day 1), week 96

Change From Baseline in Vital Signs: Temperature

Change from baseline (Day 1) to week 96 in temperature is presented.

Time frame: Baseline (Day 1), week 96

Change From Baseline in Vital Signs: Weight

Change from baseline (Day 1) to week 96 in weight is presented.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline (Day 1), week 48

Secondary Outcomes

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.

Time frame: Baseline (Day 1), week 48