Study of DCR-A1AT in Healthy Adult Volunteers

• ClinicalTrials.gov Identifier: NCT04174118
• Recruitment Status: Active, not recruiting
• First Posted: November 22, 2019
• Last Update Posted: September 14, 2022
• Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Information provided by (Responsible Party): Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Alpha 1-Antitrypsin Deficiency	Drug: belcesiran; Drug: Placebo	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Phase 1 Single Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered Belcesiran in Healthy Adult Volunteers
• Actual Study Start Date: October 24, 2019
• Actual Primary Completion Date: July 6, 2021
• Estimated Study Completion Date: May 2023

Arms and Interventions

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).

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Urine pharmacokinetics (PK) of belcesiran [ Time Frame: up to Day 3 ]
   Maximum observed concentration (Cmax)
2. Plasma pharmacokinetics (PK) of belcesiran [ Time Frame: up to 57 days ]
   Maximum observed concentration (Cmax)
3. Plasma pharmacokinetics (PK) of belcesiran [ Time Frame: up to 57 days ]
   Area under the curve (AUC)
4. Urine pharmacokinetics (PK) of belcesiran [ Time Frame: up to Day 3 ]
   Area under the curve (AUC)
5. Urine pharmacokinetics (PK) of belcesiran [ Time Frame: up to Day 3 ]
   Minimum observed concentration (Cmin)
6. Plasma pharmacokinetics (PK) of belcesiran [ Time Frame: up to 57 days ]
   Minimum observed concentration (Cmin)
7. Plasma pharmacokinetics (PK) of belcesiran [ Time Frame: up to 57 days ]
   Time to maximum concentration (Tmax)
8. Urine pharmacokinetics (PK) of belcesiran [ Time Frame: up to Day 3 ]
   Time to maximum concentration (Tmax)
9. Urine pharmacokinetics (PK) of belcesiran [ Time Frame: up to Day 3 ]
   Terminal elimination half-life (t1/2)
10. Plama pharmacokinetics (PK) of belcesiran [ Time Frame: up to 57 days ]
    Terminal elimination half-life (t1/2)
11. Change in protein concentration [ Time Frame: up to day 57 ]
    Changes in A1AT protein concentrations

Eligibility Criteria

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

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.

Contacts and Locations

Locations

New Zealand

Auckland Clinical Studies

Grafton, Auckland, New Zealand, 1010

Sweden

Clinical Trial Consultants AB

Uppsala, Sweden

Sponsors and Collaborators

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Investigators

• Study Director: Thomas Bowman, MD; Dicerna Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• ClinicalTrials.gov Identifier: NCT04174118
• Other Study ID Numbers: DCR-A1AT-101
• First Posted: November 22, 2019
• Last Update Posted: September 14, 2022
• Last Verified: September 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alpha 1-Antitrypsin Deficiency; Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Pathologic Processes