A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease

• ClinicalTrials.gov Identifier: NCT04174118
• Recruitment Status: Recruiting
• First Posted: November 22, 2019
• Last Update Posted: November 22, 2019
• Sponsor: Dicerna Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Dicerna Pharmaceuticals, Inc.

Study Description

Brief Summary:

This is a research study to test an experimental study drug (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 DCR-A1AT has not yet been tested in humans. This study will have 2 parts: Group A and Group B. Group A is for people who do not have A1ATD. Group B is for people who have been diagnosed with A1ATD. 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 placebo. A placebo looks like the study drug but does not contain any of the study drug.

Group A: 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.

Group B: This is the second part of the study. This part of the study is for people who have been diagnosed with A1ATD, so the people in the first part of the study cannot participate in the second part of the study. The main purpose of this part of the study is different because the drug will now be given to people who have A1ATD. This part of the study will also help find the dose of the study drug that is safest and works the best, but with people who have A1ATD. This way, this part of the study will show if the drug is potentially safe for and could potentially be effective against A1ATD.

Condition or disease	Intervention/treatment	Phase
Alpha 1-Antitrypsin Deficiency	Drug: DCR-A1AT; Drug: Placebo	Phase 1; Phase 2

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 function 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 lung, 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)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: Double-Blind
• Primary Purpose: Other
• Official Title: A Phase 1/2 Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered DCR-A1AT in Healthy Adult Volunteers and Patients With Alpha1-Antitrypsin-Deficiency-Associated Liver Disease
• Actual Study Start Date: October 24, 2019
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: June 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: DCR-A1AT; SAD Group A: Healthy volunteers will be administered a single dose of DCR-A1AT. MAD Group B: Participants will be administered multiple doses of DCR-A1AT.	Drug: DCR-A1AT; DCR-A1AT will be administered subcutaneously (SC) at dose levels planned for group A. Group B dose levels to be determined upon review of data from group A.
Placebo Comparator: Placebo; Group A: Healthy volunteers will be administered a single dose of matching placebo. Group B: Participants will be administered multiple doses of matching placebo.	Drug: Placebo; Sterile normal saline (0.9% NaCL) matching volume of DCR-A1AT doses will be administered subcutaneously (SC).

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability [ Time Frame: Group A: approximately up to 2 months; Group B: approximately up to 6 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: Group A: approximately up to 2 months; Group B: approximately up to 6 months ]
   The incidence of clinically significant physical examination (PE) findings
3. Changes in 12-lead electrocardiograms (ECG) [ Time Frame: Group A: approximately up to 2 months; Group B: approximately up to 6 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 DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
   Maximum observed concentration (Cmax)
2. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
   Maximum observed concentration (Cmax)
3. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
   Area under the curve (AUC)
4. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
   Area under the curve (AUC)
5. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
   Minimum observed concentration (Cmin)
6. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
   Minimum observed concentration (Cmin)
7. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
   Time to maximum concentration (Tmax)
8. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
   Time to maximum concentration (Tmax)
9. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
   Terminal elimination half-life (t1/2)
10. Plama pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
    Terminal elimination half-life (t1/2)
11. Change in protein concentration [ Time Frame: Group A: up to day 57; Group B: up to 6 months ]
    Changes in A1AT protein concentrations
12. Change in protein content [ Time Frame: Group A: not applicable; Group B: up to 6 months ]
    Change in hepatic Z-AAT protein content

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Group A:

• 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

Group B

• Male or female aged 18 to 70 years, inclusive. Female participants must be either surgically sterile or postmenopausal. No women of childbearing potential are eligible for enrollment.
• Documented diagnosis of PiZZ-type A1ATD
• Documented A1ATD-associated liver disease
• Serum A1AT protein concentration >10mg/dL
• Has adequate pulmonary function test results per protocol
• Smoking cessation for at least 3 months
• Agrees to undergo liver biopsies

Exclusion Criteria:

Group A:

• 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.

Group B:

• History of chronic liver disease from any cause other than PiZZ-type A1ATD
• History of gastrointestinal bleeding from esophageal or gastric varices
• History of hepatic encephalopathy
• History of acute exacerbations of underlying lung disease defined per protocol
• Use of augmentation therapy within prior to 6 months
• Prior use of RNAi drug
• History of reactions to prior oligonucleotide-based therapy defined per protocol.
• Received an experimental drug within the past 4 months.
• Known human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B (HBV)
• Lab values out of protocol-defined ranges and/or any lab value deemed as clinically significant and unacceptable.
• Liver elastography per protocol

Contacts and Locations

Contacts

Contact: Dicerna Pharmaceuticals; 617-621-8097; clinicaltrials@dicerna.com

Locations

Sweden

Clinical Trial Consultants AB; Recruiting

Uppsala, Sweden

Sponsors and Collaborators

Dicerna Pharmaceuticals, Inc.

Investigators

• Study Director: Hardean Achneck, MD; Dicerna Pharmaceuticals

More Information

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

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

Additional relevant MeSH terms:

Liver Diseases; Alpha 1-Antitrypsin Deficiency; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Alpha 1-Antitrypsin; Trypsin Inhibitors; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action