Study of DCR-A1AT in Healthy Adult Volunteers

Study Overview
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Brief Summary
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This is a research study to test an experimental study drug (belcesiran, also known as DCR-A1AT). This drug is being tested to see if it helps people with a rare condition known as Alpha-1 Antitrypsin Deficiency, or A1ATD. Prior to initiation of this study belcesiran had not yet been tested in humans. All study participants will be randomly assigned to either receive the study drug or a placebo. This will allow for the sponsor to compare the effects of the study drug with that of the placebo. A placebo looks like the study drug but does not contain any of the study drug. The main purpose of the first part of the study is to evaluate the safety profile of the study drug in people who do not have A1ATD. This part of the study will also help find the dose of the study drug that has an acceptable safety profile for testing.

Detailed Description
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A1ATD- associated liver disease is a progressive Alpha-1 Antitrypsin-Deficiency Associated Liver Disease condition resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma. The lack of functional A1AT in individuals with PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity in neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism can be addressed with intravenous augmentation therapy, which aims to substitute the missing A1AT by infusing alpha1 proteinase inhibitor (A1PI), purified from pooled human plasma. While augmentation therapy can address the loss of A1AT in the lungs, 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 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 in this particular patient population.

Official Title
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A Phase 1 Single Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered Belcesiran in Healthy Adult Volunteers

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Drug: belcesiran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female aged 18 to 55 years, inclusive. Female participants must be either surgically sterile or postmenopausal. No women of childbearing potential are eligible for enrollment. Overtly Healthy, as determined by the investigator. Serum A1AT protein concentration >100 mg/dL Adequate forced expiratory volume in one second (FEV1) and adequate FEV1/forced vital capacity (FVC) ratio Non-smokers with a <2 pack-year history and smoking cessation for at least 6 months with a negative urinary cotinine test a screening Exclusion Criteria: Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially affect participant safety Clinically significant abnormal laboratory tests Received an experimental drug within past 4 months Prior to use of RNAi drug or oligonucleotide-based therapy Known human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B (HBV) Serum creatinine or estimated glomerular filtration rate (eGFR) outside normal reference ranges.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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<br>Healthy volunteers will be administered a single dose of belcesiran. | Drug: belcesiran<br>* belcesiran will be administered subcutaneously (SC) at dose levels planned.<br>|
| Placebo Comparator: Placebo<br>Healthy volunteers will be administered a single dose of matching placebo. | Drug: Placebo<br>* Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | The incidence of adverse events (AE), serious adverse events (SAE), DLT, and AE leading to study drug discontinuation | approximately up to 2 months | 
| Evaluating safety and tolerability through physical exams | The incidence of clinically significant physical examination (PE) findings | approximately up to 2 months | 
| Changes in 12-lead electrocardiograms (ECG) | Absolute QTc > 500 msec and/or QTc change of > 60 msec from baseline will be evaluated | approximately up to 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine pharmacokinetics (PK) of belcesiran | Maximum observed concentration (Cmax) | up to Day 3 | 
| Plasma pharmacokinetics (PK) of belcesiran | Maximum observed concentration (Cmax) | up to 57 days | 
| Plasma pharmacokinetics (PK) of belcesiran | Area under the curve (AUC) | up to 57 days | 
| Urine pharmacokinetics (PK) of belcesiran | Area under the curve (AUC) | up to Day 3 | 
| Urine pharmacokinetics (PK) of belcesiran | Minimum observed concentration (Cmin) | up to Day 3 | 
| Plasma pharmacokinetics (PK) of belcesiran | Minimum observed concentration (Cmin) | up to 57 days | 
| Plasma pharmacokinetics (PK) of belcesiran | Time to maximum concentration (Tmax) | up to 57 days | 
| Urine pharmacokinetics (PK) of belcesiran | Time to maximum concentration (Tmax) | up to Day 3 | 
| Urine pharmacokinetics (PK) of belcesiran | Terminal elimination half-life (t1/2) | up to Day 3 | 
| Plama pharmacokinetics (PK) of belcesiran | Terminal elimination half-life (t1/2) | up to 57 days | 
| Change in protein concentration | Changes in A1AT protein concentrations | up to day 57 |