Clinical Trial for Liver Disease Treatment Imminent After Orphan Drug Designation

Arrowhead Pharmaceuticals Inc. announced last week that the company’s second-generation investigational medicine ARO-AAT was granted orphan drug designation by the U.S. Food and Drug Administration (FDA).

ARO-AAT is being developed for the treatment of a rare genetic liver disease associated with alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a hereditary disease that increases a patient’s risk of developing liver disease, chronic obstructive pulmonary disease (COPD), and certain skin problems. Symptoms of the condition include: shortness of breath and wheezing, repeated infections of the lungs or liver, and weight loss. Patients can be diagnosed with AATD-related liver disease through a blood test.

Mutations in the SERPINA1 gene limit the amount of alpha-1 antitrypsin (AAT) produced by the body, causing the enzyme neutrophil elastase to attack healthy tissues. Neutrophil elastase is uncontrollable when a lack of AAT protein is produced by the liver and sent through the bloodstream, resulting in the deterioration of organs. Environmental factors, like chemicals and tobacco smoke, can increase the severity of AATD.

ARO-AAT is a subcutaneous injection of an RNA interference (RNAi) therapeutic candidate for AATD-related liver disease patients, inducing rapid, deep, and durable knockdown of target genes. After one dose, ARO-ATT produced deep and prolonged knockdown of AAT to levels of almost full suppression of the liver production.

Efficacy of ARO-ATT was measured in a transgenic PiZ mouse model and in nonhuman primates by evaluating the reduction in plasma or serum levels of AAT. Reduction of the mutant Z-AAT accumulation in the liver could lead to the prevention and the potential reversal of liver disease.

The safety of ARO-ATT was assessed in rats and primates at dose levels of up to 300 mg/kg, approximately 100 times the expected human clinical dose. Clinical laboratory values were indistinguishable between the control groups and the cohort receiving ARO-AAT. There were also no histopathology findings associated with ARO-AAT and there were no abnormal clinical observations, body weight fluctuations, clinical chemistries, or organ weight findings accounted for in the mouse and nonhuman primate models.

“The Orphan Drug Act provides important incentives for sponsors to develop drugs that treat rare diseases and we look forward to more engagement with the FDA as the development of ARO-AAT progresses,” said Bruce D. Given, M.D., Arrowhead’s chief operating officer and head of R&D in a press release.

In October, data from preclinical studies measuring safety and efficacy of ARO-ATT were presented at the Annual Meeting of the American Association for the Study of Liver Disease held in Washington, D.C. The company filed a Clinical Trial Application in December requesting regulatory permission to begin first-in-human studies of the drug. The investigational therapy leverages Arrowhead’s subcutaneously administered Targeted RNAi Molecule (TRiM) technology.

Based on positive results, Arrowhead expects to file a clinical trial application in the coming weeks.