Brief Title
A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease
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
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.
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 Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Safety and tolerability
Secondary Outcome
Urine pharmacokinetics (PK) of DCR-A1AT
Condition
Alpha 1-Antitrypsin Deficiency
Intervention
DCR-A1AT
Study Arms / Comparison Groups
DCR-A1AT
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
60
Start Date
October 24, 2019
Completion Date
June 2022
Primary Completion Date
December 2021
Eligibility 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
Gender
All
Ages
18 Years - 70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
Hardean Achneck, MD, 617-621-8097, [email protected]
Location Countries
Sweden
Location Countries
Sweden
Administrative Informations
NCT ID
NCT04174118
Organization ID
DCR-A1AT-101
Responsible Party
Sponsor
Study Sponsor
Dicerna Pharmaceuticals, Inc.
Study Sponsor
Hardean Achneck, MD, Study Director, Dicerna Pharmaceuticals
Verification Date
November 2019