Clinical trial NCT04174118: Study of DCR-A1AT in Healthy Adult Volunteers
Official title: A Phase 1 Single Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered Belcesiran in Healthy Adult Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alpha 1-Antitrypsin Deficiency
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2019-11-22
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and tolerability
timeFrame: approximately up to 2 months
measure: Evaluating safety and tolerability through physical exams
timeFrame: approximately up to 2 months
measure: Changes in 12-lead electrocardiograms (ECG)
timeFrame: approximately up to 2 months
Secondary outcomes:
measure: Urine pharmacokinetics (PK) of belcesiran
timeFrame: up to Day 3
measure: Plasma pharmacokinetics (PK) of belcesiran
timeFrame: up to 57 days
measure: Plasma pharmacokinetics (PK) of belcesiran
timeFrame: up to 57 days
measure: Urine pharmacokinetics (PK) of belcesiran
timeFrame: up to Day 3
measure: Urine pharmacokinetics (PK) of belcesiran
timeFrame: up to Day 3
measure: Plasma pharmacokinetics (PK) of belcesiran
timeFrame: up to 57 days
measure: Plasma pharmacokinetics (PK) of belcesiran
timeFrame: up to 57 days
measure: Urine pharmacokinetics (PK) of belcesiran
timeFrame: up to Day 3
measure: Urine pharmacokinetics (PK) of belcesiran
timeFrame: up to Day 3
measure: Plama pharmacokinetics (PK) of belcesiran
timeFrame: up to 57 days
measure: Change in protein concentration
timeFrame: up to day 57
Other outcomes:
Locations:
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies
state: Auckland
city: Uppsala
country: Sweden
facility: Clinical Trial Consultants AB
Study officials:
affiliation: Dicerna Pharmaceuticals
name: Thomas Bowman, MD
role: STUDY_DIRECTOR
References:
citation: Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: New therapies on the horizon. Curr Opin Pharmacol. 2021 Aug;59:149-156. doi: 10.1016/j.coph.2021.06.001. Epub 2021 Jul 10.