Study of DCR-A1AT in Healthy Adult Volunteers

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

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.

Study Overview

• Status: Completed
• Conditions: Alpha 1-Antitrypsin Deficiency
• Intervention / Treatment: Drug: belcesiran; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1010
      • Auckland Clinical Studies
• Sweden
  • Uppsala, Sweden
    • Clinical Trial Consultants AB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: belcesiran; Healthy volunteers will be administered a single dose of belcesiran.	Drug: belcesiran; belcesiran will be administered subcutaneously (SC) at dose levels planned.
Placebo Comparator: Placebo; Healthy volunteers will be administered a single dose of matching placebo.	Drug: Placebo; Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Investigators: Study Director: Thomas Bowman, MD, Dicerna Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2019
• Primary Completion (Actual): July 6, 2021
• Study Completion (Actual): March 6, 2023

Study Registration Dates

• First Submitted: November 6, 2019
• First Submitted That Met QC Criteria: November 20, 2019
• First Posted (Actual): November 22, 2019

Study Record Updates

• Last Update Posted (Actual): November 6, 2024
• Last Update Submitted That Met QC Criteria: November 4, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Liver Diseases; Subcutaneous Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: DCR-A1AT-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No