1. Fazirsiran is associated with a signifcant reduction of Z-AAT protein concentration in the serum and liver of those with alpha1-antitrypsin (AAT) deficiency.

2. Fazirsiran is associated with improvement in liver enzyme concentrations in AAT deficiency patients.

Evidence Rating Level: 1 (Excellent)

Study Rundown: AAT deficiency results in loss-of-function pulmonary disease and gain-of-function liver disease. Mechanistically, AAT deficiency results in the production of a Z-AAT protein that is retained in the liver and causes a deficiency of AAT in serum. Serum deficiency subsequently predisposes patients to emphysema. Further, in the liver, the mutation increases the risk of hepatocellular injury, inflammation, and eventually fibrosis, which can lead to cirrhosis and/or portal hypertension. It has been proposed that Fazirsiran, an RNAi therapeutic, can cause degradation of Z-AAT and AAT messenger RNA, thus reducing both AAT and Z-AAT protein synthesis in hepatocytes. However, there is a gap in knowledge as to understanding whether Fazirsiran is effective in patients with liver disease associated with homozygous AAT deficiency. This study found that Fazirsiran reduced the production and accumulation of intrahepatic Z-AAT, the protein that causes liver disease associated with AAT deficiency. This study was limited by a limited time period of controlled study and a smaller group of patients without centralized monitoring. Nevertheless, the present study’s findings demonstrate that Fazirsiran provides a significant benefit in reducing liver disease associated with AAT deficiency.

Click to read the study in NEJM

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In-Depth [randomized control trial]: This multicenter, open-label trial was conducted in Austria, Germany, and the United Kingdom. Patients who were between 18 to 75 years of age, with the PI ZZ genotype and F1 to F3 liver fibrosis on the basis of a local pathological reading at screening were eligible for the study. Patients who had F4 fibrosis, significant hepatic or renal dysfunction, or a postbronchodilator FEV1 of less than 65% (if not receiving AAT augmentation) were excluded from the study. The primary outcome was change in liver Z-AAT concentrations over time as measured with the use of liquid chromatography-tandem mass spectrometry that was sensitive and specific for a signature peptide containing the Z allele amino acid mutation. Outcomes in the primary analysis were assessed via quantifying with medians and corresponding distribution-free 95% confidence intervals. Based on the primary analysis, 16 patients were enrolled in the study. All patients enrolled had a reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The maximum reduction of Z-AAT in serum was approximately 90%, and treatment with Fazirsiran was also associated with a reduction in histologic globule burden. Fibrosis reduction was also observed in seven of 15 patients and fibrosis progression in two of 15 patients after 24 or 28 weeks. In total, four adverse events were noted (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) and fully resolved. Overall, this study demonstrates that Fazirsiran is associated with a strong reduction in liver and serum Z-AAT concentrations, though did not lead to uniform regression of fibrosis during the first 24 or 48 weeks of treatment. Therefore, longer treatment duration and larger sample size placebo-controlled clinical trials will be needed to confirm the effect of Fazirsiran on fibrosis.

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