A Study of Belcesiran in Patients With AATLD

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Drug: Belcesiran
* Other: Placebo
* Drug: Belcesiran
* Other: Placebo
* Drug: Belcesiran
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence and nature of treatment emergent adverse events (TEAE) |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in pulmonary function tests (PFTs): Forced Vital Capacity (FVC) |  | Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in pulmonary function tests (PFTs): Forced Expiratory Volume in One Second (FEV1) |  | Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in pulmonary function tests (PFTs): Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: Heart Rate |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: Ventricular Rate |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: RR interval |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: PR interval |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: QRS interval |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: QT interval |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in 12-lead ECGs: corrected QT interval |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| The incidence of clinically significant physical examination (PE) findings |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in vital sign measurements: temperature |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in vital sign measurements: pulse rate |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in vital sign measurements: respiratory rate |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in vital sign measurements: blood pressure |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: clinical chemistry |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: hematology |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: Coagulation |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: Serum AFP |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: Total complement hemolytic activity CH50 |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: C-reactive protein (CRP) |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline in clinical laboratory tests: Antidrug antibodies |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from Baseline in serum AAT concentration |  | up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) | 
| Change from baseline to Week 24 in serum Z-AAT protein levels |  | up to 24 weeks (Cohort 3) | 
| Change from baseline to Week 24 in liver Z-AAT liver protein levels |  | up to 24 weeks (Cohort 3) |