RNAi therapeutic improves overall liver health in antitrypsin deficiency

Using a novel RNA interference therapeutic improved fibrosis and reduced toxic proteins and globular burden in alpha-1 antitrypsin deficiency, according to a presenter at the International Liver Congress.

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

In AATD with the PiZZ mutation, hepatocytes produce misfolded and poorly secreted AAT protein known as Z protein. The accumulation of hepatotoxic Z-AAT protein is what causes the progression of liver disease. ARO-AAT inhibits the Z-AAT expression to allow clearance of polymers and globules and improvement in liver health, he said.

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

The endpoints of this open-label study will be serum Z-AAT and liver Z-AAT levels, histology looking at globules and fibrosis stage, serum ALT, GGT, liver stiffness, Pro-C3 and adverse events. In this interim analysis, the 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 substantial reduction in serum Z protein in all nine patients after initial dose and, importantly, these reductions were sustained over time,” Strnad said. “At approximately 1 year, reductions from baseline in serum Z protein ranged from 78% to 90%.”

Total intra-hepatic Z-AAT declined by 80.1% in the group, monomer concentration by 89.8% and polymer concentration by 80.8%.

“By silencing the AAT production, our AAT treatment results in improved histological globule burden,” Strnad said. “All nine patients showed reduction from baseline in globular burden.”

That reduction translated to fibrosis improvement, he added. Six of the nine participants showed a stage I or greater improvement in their fibrosis and three remained unchanged. None worsened over the course of the study. Additionally, liver stiffness declined by 21.6% and Pro-C3 declined by 30.8%.

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

“In PiZZ AATD patients, treatment with ARO-AAT, an investigational RNAi therapeutic, for 24 or 48 weeks showed six of nine [participants] with a stage I or greater improvement in liver fibrosis, including two [participants] who had stage IV fibrosis, cirrhosis at baseline,” Strnad said. “We saw substantial and sustained reductions in serum and intra-hepatic Z-AAT, a decrease in histological liver globular burden, sustained reductions in clinically relevant biomarkers of liver injury and, in all participants, an acceptable safety profile.”