RNAi therapy improves overall liver health in antitrypsin deficiency


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Strnad P. LBO-2592. Presented at the International Liver Congress; 23-26 June 2021 (virtual meeting).

Disclosures: Strnad reports giving sponsored lectures for Grifols Inc., CSL Behring and Alnylam; receive grants from Grifols Inc., CSL Behring, Arrowhead Pharmaceuticals and Vertex Pharmaceuticals; and acting as a consultant for Arrowhead Pharmaceuticals, Dicerna Pharmaceuticals, Vertex Pharmaceuticals and Takeda.


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The use of a new RNA interference therapy improved fibrosis and reduced toxic proteins and blood load in alpha-1 antitrypsin deficiency, according to a presenter at the International Liver Congress.

Liver disease associated with AATD is an inherited disease manifested by mutations in alpha-1 antitrypsin, or AAT uncomfortable,” Pavel Strnad, MD, of Rwth Aachen University Hospital in Aachen, Germany, said during his Late Breaker presentation. “The homozygous PiZZ mutation is the focus of today’s presentation and is responsible for the majority of severe cases of AATD. “

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In AATD with the PiZZ mutation, hepatocytes produce a misfolded and poorly secreted AAT protein known as protein Z. The accumulation of hepatotoxic Z-AAT protein is what causes the progression of liver disease. ARO-AAT inhibits the expression of Z-AAT to help remove polymers and blood cells and improve liver health, he said.

“To change this vicious circle, ARO AAT was developed. It is a small interfering RNAi designed to specifically target hepatocytes and inhibit c protein expression in patients with AATD, ”said Strnad.

The endpoints for this open-label study will be serum hepatic Z-AAT and Z-AAT levels, histology examining blood cells and stage of fibrosis, serum ALT, GGT, hepatic stiffness, Pro-C3 and adverse events. In this interim analysis, all nine participants received 200 mg of ARO-AAT. Cohort 1 (n = 4) underwent a 24 week biopsy and 48 week labs while Cohort 2 (n = 5) underwent a 48 week biopsy and 52 week labs.

“Our AAT treatment resulted in a substantial reduction in serum protein Z in all nine patients after the initial dose and, importantly, these reductions were maintained over time,” Strnad said. “At about 1 year, reductions from baseline for serum protein Z ranged from 78% to 90%.”

Total intrahepatic Z-AAT decreased by 80.1% in the group, monomer concentration by 89.8%, and polymer concentration by 80.8%.

“By silencing the production of AAT, our AAT treatment results in an improvement in the histological burden of the blood cells,” Strnad said. “All nine patients showed a reduction in red cell load from baseline.”

This reduction translated into an improvement in fibrosis, he added. Six of the nine participants showed improvement of stage I or greater in their fibrosis and three remained unchanged. None worsened during the study. In addition, the stiffness of the liver was reduced by 21.6% and Pro-C3 by 30.8%.

There were no treatment-related adverse events that led to the discontinuation or discontinuation, Strnad said. Three serious adverse events were reported in the 200 mg cohort, but all were of moderate severity and all resolved.

“In PiZZ AATD patients, treatment with ARO-AAT, an experimental RNAi treatment, for 24 or 48 weeks showed six of the nine [participants] with stage I or greater improvement in liver fibrosis, two of which [participants] who had stage IV fibrosis, cirrhosis to begin with, ”said Strnad. “We found substantial and sustained reductions in serum and intrahepatic Z-AAT, decreased histologic hepatic blood load, sustained reductions in clinically relevant biomarkers of liver injury, and, in all participants, a profile of hepatic injury. acceptable safety. “


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