CAMBRIDGE, Mass.—Dicerna Pharmaceuticals, Inc., announced today that it submitted a Clinical Trial Authorization (CTA) application to the Swedish Medical Products Agency (MPA) last week to conduct a first-in-human Phase 1/2 study of DCR-A1AT, an investigational therapy from Dicerna’s GalXC technology platform, for the treatment of alpha-1 antitrypsin (A1AT) deficiency-associated liver disease.
“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 Douglas Fambrough, president and chief executive officer of Dicerna. “First, A1AT deficiency-associated liver disease fits with our rare disease strategy as an indication with a significant unmet medical need and a clear biomarker, presenting a rapid development path to approval. Second, the program will inform and aid our efforts in the much broader chronic liver disease field, where we believe our GalXC platform can have a major impact, and which provides ample opportunities to collaborate with larger pharmaceutical company partners.”
A1AT deficiency is a genetic disorder that can lead to liver disease in children and 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. Neutrophil elastase is released from white blood cells to fight infection, but can attack normal tissues if not tightly controlled by A1AT.
Mutations in the SERPINA1 gene can result in a deficiency of A1AT and an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled neutrophil elastase can destroy alveoli and cause lung disease. In the liver, the accumulation of abnormal A1AT can trigger an injury cascade, which can lead to liver injury. This leads to complications such as weight loss, fatigue, jaundice and life-threatening conditions such as cirrhosis. Patients with A1AT deficiency are also at risk for developing hepatocellular carcinoma.
“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 Jeffrey Teckman, M.D., professor of Biochemistry and Molecular Biology at Saint Louis University School of Medicine in St. Louis, MO. “With this CTA filing, and the expected initiation of a first-in-human Phase 1/2 clinical trial of DCR-A1AT once the MPA authorizes the CTA, Dicerna is pursuing an exciting and important approach that addresses a high unmet medical need in A1AT deficiency-associated liver disease.”
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; and 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 Europe, with the first clinical trial site in Sweden.
“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,” added Miriam O'Day, president and chief executive officer of the Alpha-1 Foundation. “We look forward to working with Dicerna as they advance DCR-A1AT through clinical trials.”