A1AT deficiency is a genetic disorder that can cause lung and liver disease. Children with the liver manifestations of the disease may present with yellowing of the skin and whites of the eyes (jaundice) and may progress to forming scar tissue in the liver (cirrhosis). Adults with the liver disease may also develop cirrhosis, progress to liver failure or develop a type of liver cancer called hepatocellular carcinoma.
“The FDA’s orphan drug designation is an important milestone in our development plan for DCR-A1AT for alpha-1 antitrypsin deficiency-associated liver disease and underscores the treatment need that exists for this complex disorder,” said Ralf Rosskamp, M.D., chief medical officer of Dicerna. “RNAi technology has shown significant potential in the treatment of liver-related diseases, and we look forward to continuing to investigate DCR-A1AT’s potential to make a meaningful difference for this underserved patient population.”
In June 2019, the Company submitted a clinical trial application to the Swedish Medical Products Agency for DCR-A1AT for the treatment of patients with A1AT deficiency-associated liver disease and began enrolling healthy volunteers in the Phase 1/2 trial of DCR-A1AT (EudraCT number 2019-001999-11) in the fourth quarter of 2019. The Company expects to dose the first patient in the second half of 2020.
Orphan drug status is intended to advance drug development for rare diseases. The FDA provides ODD to drugs and biologics that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions that affect fewer than 200,000 people in the U.S. The designation can provide development and commercial incentives for designated compounds and medicines, including eligibility for a seven-year period of market exclusivity in the U.S. after product approval, FDA assistance in clinical trial design and an exemption from FDA user fees.
In December 2019, the European Commission granted ODD to DCR-A1AT for the treatment of congenital alpha-1 antitrypsin deficiency based on a positive opinion from the Committee for Orphan Medicinal Products of the European Medicines Agency.
DCR-A1AT is a subcutaneously administered ribonucleic acid interference (RNAi) therapeutic that is being investigated for the treatment of liver disease in patients with alpha-1 antitrypsin (A1AT) deficiency. A1AT is a protein primarily produced in and released from the liver. A1AT plays a role in several biological functions, including regulating the activity of neutrophil elastase, which helps the body fight infection. In A1AT deficiency, the SERPINA1 gene encodes a mutated form of A1AT, the majority of which cannot be released from the liver. As a result, insufficient levels of A1AT are available to protect the lungs from harmful effects of neutrophil elastase. Additionally, the accumulation of mutated A1AT in the liver can lead to liver disease. There are currently no approved therapies to treat A1AT deficiency-associated liver disease. DCR-A1AT, which incorporates Dicerna’s proprietary GalXC™ technology, is designed to target SERPINA1, reducing production of abnormal A1AT in the liver. A clinical trial program investigating the safety and efficacy of DCR-A1AT is currently underway.
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, or shortage, of functional 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
About 10% of adults with A1AT deficiency develop cirrhosis, or liver damage, due to formation of scar tissue in the liver.3 Individuals affected by A1AT deficiency are also at risk of developing hepatocellular carcinoma, a type of liver cancer. People with A1AT deficiency may 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, unintended 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.1 Congenital A1AT deficiency is estimated to affect 2.4 people out of every 10,000 in the European Union.4 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
Dicerna’s proprietary ribonucleic acid interference (RNAi) technology platform, called GalXC™, aims to advance the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver and other body systems. Liver-targeted GalXC-based compounds enable subcutaneous delivery of RNAi therapies that are designed to specifically bind to receptors on liver cells, leading to internalization and access to the RNAi machinery within the cells. The GalXC approach seeks to optimize the activity of the RNAi pathway so that it operates in the most specific and potent fashion.
Source: Company Press Release