Study of DCR-A1AT in Healthy Adult Volunteers

Alpha 1-Antitrypsin Deficiency Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04174118
• Other study ID #: DCR-A1AT-101
• Status: Completed
• Phase: Phase 1
• Start date: October 24, 2019
• Est. completion date: March 6, 2023

Study information

• Verified date: March 2024
• Source: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: March 6, 2023
• Est. primary completion date: July 6, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency

Intervention

Drug:
• belcesiran
belcesiran will be administered subcutaneously (SC) at dose levels planned.
• Placebo
Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).

Locations

Country	Name	City	State
New Zealand	Auckland Clinical Studies	Grafton	Auckland
Sweden	Clinical Trial Consultants AB	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Countries where clinical trial is conducted

New Zealand,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Evaluating safety and tolerability through physical exams	The incidence of clinically significant physical examination (PE) findings	approximately up to 2 months
Primary	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	Urine pharmacokinetics (PK) of belcesiran	Maximum observed concentration (Cmax)	up to Day 3
Secondary	Plasma pharmacokinetics (PK) of belcesiran	Maximum observed concentration (Cmax)	up to 57 days
Secondary	Plasma pharmacokinetics (PK) of belcesiran	Area under the curve (AUC)	up to 57 days
Secondary	Urine pharmacokinetics (PK) of belcesiran	Area under the curve (AUC)	up to Day 3
Secondary	Urine pharmacokinetics (PK) of belcesiran	Minimum observed concentration (Cmin)	up to Day 3
Secondary	Plasma pharmacokinetics (PK) of belcesiran	Minimum observed concentration (Cmin)	up to 57 days
Secondary	Plasma pharmacokinetics (PK) of belcesiran	Time to maximum concentration (Tmax)	up to 57 days
Secondary	Urine pharmacokinetics (PK) of belcesiran	Time to maximum concentration (Tmax)	up to Day 3
Secondary	Urine pharmacokinetics (PK) of belcesiran	Terminal elimination half-life (t1/2)	up to Day 3
Secondary	Plama pharmacokinetics (PK) of belcesiran	Terminal elimination half-life (t1/2)	up to 57 days
Secondary	Change in protein concentration	Changes in A1AT protein concentrations	up to day 57