Dicerna™ to Begin Clinical Development of DCR-A1AT for Treatment of Patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Jul 02, 2019
— Company Submitted Clinical Trial Application and Plans to Initiate Multicenter Phase 1/2 Trial in Third Quarter of 2019 —
— Alpha-1 Antitrypsin Deficiency-Associated Liver Disease Program Broadens Dicerna’s Commitment to Addressing Chronic Liver Diseases—
“We are pleased to begin the clinical development phase of our A1AT deficiency-associated liver disease program, which serves two roles in Dicerna’s portfolio,” said
The proposed parallel-group, placebo-controlled, Phase 1/2 study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of DCR-A1AT in adult healthy volunteers (HVs) and patients with A1AT deficiency-associated liver disease. The study will consist of two phases:
- Group A: a single ascending-dose phase in HVs, enrolling up to 36 participants in as many as six cohorts
- Group B: a multiple ascending-dose phase in patients with A1AT deficiency-associated liver disease, consisting of up to 24 participants in three or fewer cohorts
Pending approval from the Swedish MPA, Dicerna aims to initiate screening of HVs for Group A in the third quarter of 2019, and to begin enrolling Group B participants in the first quarter of 2020. Dicerna plans to conduct the study in up to 16 sites across
“A1AT deficiency is a genetic condition that can lead to liver disease with potentially devastating complications including scarring of the liver and liver cancer,” commented
“The launch of the DCR-A1AT clinical program is welcome news to the A1AT deficiency community, as there are currently no approved therapies that treat the liver manifestations of this condition,” commented
About DCR-A1AT and the GalXC™ Technology Platform
DCR-A1AT is a ribonucleic acid interference (RNAi) therapeutic being investigated for the treatment of liver disease in patients with alpha-1 antitrypsin (A1AT) deficiency. The compound incorporates Dicerna’s proprietary GalXC™ technology, which amplifies the Company’s ability to create selective and safe RNAi therapies that are specific and potent in the way they target disease. Dicerna scientists invented GalXC as a method to discover and develop next-generation RNAi therapies designed to silence disease-causing genes. With these therapies, we aim to restore health by addressing the underlying causes of disease. Drug candidates produced via GalXC are intended to be broadly applicable across multiple therapeutic areas with a current focus on diseases involving the liver, including rare diseases, chronic liver diseases, cardiovascular diseases and viral infectious diseases. Data from clinical and preclinical studies suggest that GalXC may offer several distinct benefits for the treatment of disease, including:
- potency that has the potential to surpass comparable RNAi platforms;
- highly specific binding to disease-causing targets;
- long duration of action; and
- an infrequent dosing regimen via subcutaneous (under the skin) injection, which can minimize the treatment burden for patients.
About Alpha-1 Antitrypsin (A1AT) Deficiency
Alpha-1 antitrypsin (A1AT) deficiency is an inherited disorder that can lead to liver disease in children and adults and lung disease in adults. The disorder is caused by mutations in a gene called SERPINA1. When functioning normally, this gene provides instructions for making a protein called A1AT, which protects the body from an enzyme called neutrophil elastase. This enzyme is released from white blood cells to fight infection, but it can attack normal tissues if not tightly controlled by A1AT. Mutations in the SERPINA1 gene can result in a deficiency (shortage) of A1AT and an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled neutrophil elastase can destroy alveoli (small air sacs in the lungs) and cause lung disease.1 In the liver, the accumulation of abnormal A1AT can trigger an injury cascade, which can lead to liver injury.2
Approximately 10% of infants with A1AT deficiency develop liver disease, which often causes jaundice (yellowing of the skin and whites of the eyes). About 15% of adults with A1AT deficiency develop cirrhosis (liver damage) due to formation of scar tissue in the liver. Individuals affected by A1AT deficiency are also at risk of developing hepatocellular carcinoma, a type of liver cancer. People with A1AT deficiency typically develop the first symptoms of lung disease between the ages of 20 and 50 years. Symptoms can include shortness of breath following mild activity, reduced ability to exercise, wheezing, unintentional weight loss, recurring respiratory infections, fatigue and rapid heartbeat upon standing. Some individuals with A1AT deficiency develop emphysema, a lung disease caused by damage to the alveoli.1
A1AT deficiency occurs all over the world, though its prevalence varies by population. The disorder affects roughly one in 1,500 to 3,500 individuals with European ancestry and is uncommon in people of Asian descent. Many individuals with A1AT deficiency are thought to be undiagnosed, particularly those who also have chronic obstructive pulmonary disease (COPD). Some people with A1AT deficiency are misdiagnosed with asthma.1
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements we make regarding: (i) research and development plans and timelines related to DCR-A1AT and the potential of DCR-A1AT to treat liver disease; and (ii) the potential of Dicerna™’s technology and drug candidates in the Company’s research and development pipeline. The process by which an early stage investigational therapy such as DCR-A1AT and an early stage platform such as GalXC™ could potentially lead to an approved product or have a major impact on liver disease is a long-term effort and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’s clinical research and other risks identified under the heading "Risk Factors" included in the Company’s most recent Form 10-Q filing and in other future filings with the
Dicerna™ and GalXC™ are trademarks of
Genetics Home Reference. Alpha-1 antitrypsin deficiency. Bethesda, Md.: U.S. Department of Health and Human Services, National Institutes of Health, National Library of Medicine; 2013. Available at: https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency#genes. Accessed June 26, 2019.
Patel D, Teckman JH. Alpha-1-antitrypsin deficiency liver disease. Clinical Liver Disease. 2018;22(4):643-655.
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