Alpha 1-Antitrypsin Deficiency
Conditions
Brief summary
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
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.
Interventions
DRUGbelcesiran
belcesiran will be administered subcutaneously (SC) at dose levels planned.
DRUGPlacebo
Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).
Sponsors
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability | approximately up to 2 months | The incidence of adverse events (AE), serious adverse events (SAE), DLT, and AE leading to study drug discontinuation |
| Evaluating safety and tolerability through physical exams | approximately up to 2 months | The incidence of clinically significant physical examination (PE) findings |
| Changes in 12-lead electrocardiograms (ECG) | approximately up to 2 months | Absolute QTc \> 500 msec and/or QTc change of \> 60 msec from baseline will be evaluated |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urine pharmacokinetics (PK) of belcesiran | up to Day 3 | Maximum observed concentration (Cmax) |
| Change in protein concentration | up to day 57 | Changes in A1AT protein concentrations |
| Plasma pharmacokinetics (PK) of belcesiran | up to 57 days | Maximum observed concentration (Cmax) |
| Plama pharmacokinetics (PK) of belcesiran | up to 57 days | Terminal elimination half-life (t1/2) |
Countries
New Zealand, Sweden
Outcome results
None listed