Rare Daily Staff

The U.S. Food and Drug Administration granted Arrowhead Pharmaceuticals Breakthrough Therapy designation for ARO-AAT, also known as TAK-999, the company’s second-generation investigational RNA interference (RNAi) therapeutic being co-developed with Takeda Pharmaceutical as a treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency.

Alpha-1 Antitrypsin-Associated Deficiency (AATD) is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AATD is estimated to affect 1 per 3,000-5,000 people in the United States and 1 per 2,500 in Europe. The protein AAT is primarily synthesized and secreted by hepatocytes. Its function is to inhibit enzymes that can break down normal connective tissue. The most common disease variant, 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. This triggers continuous hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.

“Patients with AATD associated liver disease currently have no available treatment options other than a liver transplant. Being granted Breakthrough Therapy designation from the FDA is an important milestone for the investigational ARO-AAT program,” said Javier San Martin, chief medical officer at Arrowhead. “Arrowhead and our collaborators at Takeda share a commitment to patients with AATD. 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.

The ARO-AAT phase 2 SEQUOIA study has recently reached full enrollment of 40 patients. Interim results 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 suggest ARO-AAT consistently reduced the production of the toxic mutant Z-AAT protein, which has been identified as the cause of progressive liver disease in patients with AATD. Further, these reductions over 6 and 12 months led to multiple important signals associated with healing of liver disease in patients with fibrosis due to AATD.

Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. A drug that receives BTD is eligible for all Fast Track designation features, intensive FDA guidance on an efficient drug development program, and organizational commitment involving senior managers at the FDA.

ARO-AAT was also previously granted Orphan Drug designation and Fast Track designation from the FDA, and Orphan designation from the European Commission.

Photo:  Javier San Martin, chief medical officer at Arrowhead

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