Pasadena-based Arrowhead Pharmaceuticals, Inc. has been granted Breakthrough Therapy designation (BTD) by the U.S. Food and Drug Administration for ARO-AAT, the company’s second-generation investigational RNA interference therapeutic being developed as a treatment for alpha-1 antitrypsin (AAT) deficiency, an inherited condition that increases the risk of lung and liver disease.
By receiving a BTD, Arrowhead Pharmaceuticals can expedite the development and review of drugs that can treat a serious life-threatening disease or condition. The company said preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over other treatments for AAT deficiency.
The drug, also known as TAK-999, was also previously granted Orphan Drug designation and Fast Track designation from the FDA, and Orphan designation from the European Commission.
The purpose of both designations is to get important new drugs to the patient earlier.
“Patients with AATD-associated liver disease currently have no available treatment options other than a liver transplant,” said Dr. Javier San Martin, chief medical officer at Arrowhead.
“We intend to utilize the benefits that BTD provides, including enhanced access to and guidance from senior management and experienced review staff at the FDA, to expedite the development of ARO-AAT. We hope to get this important investigational medicine to patients rapidly,” San Martin said.
AAT deficiency is associated with liver disease in children and adults, and pulmonary disease in adults. It is estimated that one per 3,000 to 5,000 people in the United States, and one per 2,500 in Europe, are affected by this disorder. The protein AAT is naturally synthesized and secreted by hepatocytes – the major parenchymal cells in the liver that play pivotal roles in metabolism – and inhibits enzymes that can break down normal connective tissue.
The most common variant of the disease, called the Z mutant, has a single amino acid substitution that results in improper folding of the protein. The mutant protein cannot be effectively secreted and accumulates in globules inside the hepatocytes, triggering continuous hepatocyte injury that leads to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.
San Martin said the company’s ARO-AAT Phase 2 SEQUOIA study has recently reached full enrollment of 40 patients.
“The interim results we recently presented at the 2021 European Association for the Study of the Liver (EASL) International Liver Congress from the AROAAT2002 Phase 2 open label study were highly encouraging,” he said. “We believe these interim results suggest that investigational ARO-AAT consistently reduced the production of the toxic mutant Z-AAT protein. Further, these reductions over six and 12 months led to multiple important signals associated with healing of liver disease in patients with fibrosis due to AATD.”
Arrowhead is developing the treatment in cooperation with Takeda Pharmaceutical Co. in Japan.