RNA Interference Therapeutic Reduces Hepatotoxic Mutant Z-AAT Levels in Patients with Alpha1-Antitrypsin Deficiency

In a Phase II trial of participants with hepatic disease associated with congenital alpha1-antitrypsin deficiency (AATD), subcutaneous administration of fazirsiran, an investigational RNA interference therapeutic, reduced both serum and hepatic levels of the mutant hepatotoxic AAT protein Z-AAT, with concurrent improvements in enzymatic and histological markers of liver function. Individuals with the homozygous PiZZ genotype produce mutant Z-AAT protein that accumulates in hepatocytes, leading to progressive liver disease and fibrosis.

Twelve patients with the PiZZ genotype and liver fibrosis received fazirsiran at a dose of 200 mg, and four others received 100 mg, on day 1, week 4 and then every 12 weeks. Reduced liver accumulation of Z-AAT was documented in all patients, with a median reduction of 83 percent at week 24 or 48. Concentrations of alanine aminotransferase decreased in all 12 patients whose levels were above the upper limit of the normal range at baseline.

Fibrosis regression was observed in seven of 12 patients receiving the 200 mg dose of fazirsiran after 24 or 48 weeks, including two patients with cirrhosis, but in none of the three patients who received the lower 100 mg dose. Fazirsiran treatment was also associated with a 69 percent reduction in histologic globule burden, from a mean score of 7.4 at baseline to mean score of 2.3 after 24 or 48 weeks. Four serious adverse events resolved spontaneously, and there were no adverse events leading to trial or drug discontinuation. Fazirsiran is being co-developed by Arrowhead Pharmaceuticals and Takeda Pharmaceuticals.