Background Homozygous PiZZ alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant genetic disorder causing pulmonary and liver disease in children and adults. Wild type alpha-1 antitrypsin (AAT) is synthesized by hepatocytes and secreted into circulation to protect the lung during inflammation by inhibition of neutrophil proteases. The mutant Z protein (Z-AAT) misfolds and is retained in the hepatocyte rather than secreted. This triggers liver injury which can lead to cirrhosis and the reduced serum activity can lead to lung injury. Intracellular proteolysis pathways are activated in the hepatocyte to reduce Z-AAT accumulation, but liver injury still results in some individuals. ARO-AAT is a hepatocyte targeted RNAi therapeutic designed to silence expression of Z-AAT mRNA leading to reduced Z-AAT protein synthesis. Herein, we report initial results from Cohort 1 in the AROAAT2002 phase 2 clinical trial.
Methods 4 PiZZ AATD patients with liver fibrosis were enrolled to receive open label ARO-AAT 200 mg by subcutaneous injection at Weeks 1, 4 and 16. Patients underwent liver biopsy at Screening and Week 24. Assessments include safety (e.g. AEs, labs, spirometry and DLCO), serum and intra-hepatic Z-AAT, serum biomarkers of liver injury and fibrogenesis (e.g. ALT, GGT, Pro-C3) and transient elastography (FibroScan).
Results At Week 24, serum and total intra-hepatic Z-AAT decreased by 86-93 % and 72-95 % respectively. Three of four patients demonstrated reductions in intra-hepatic Z-AAT polymer at Week 24 with a range of 68-97 %. All four patients showed reductions in ALT and GGT from baseline to Week 24 ranging from 36-66 % and 43-58 % respectively. Liver stiffness (FibroScan) improved in all patients, with 3 of 4 patients demonstrating > 20 % reductions at Week 24. Three of 4 patients demonstrated reductions in the fibrogenesis biomarker Pro-C3 ranging from 31-51 % at Week 24. One SAE (EBV related myocarditis) was reported. No clinically meaningful changes in FEV1 were observed.
Conclusion ARO-AAT is the first investigational therapeutic to demonstrate reductions in intra-hepatic Z-AAT in humans. The associated improvement in clinically relevant biomarkers of liver disease is consistent with pre-clinical studies showing that Z-AAT accumulation is the causative factor in AATD liver disease. These data confirm that when Z-AAT synthesis is halted, endogenous proteolysis can clear accumulated Z-AAT with associated improvements in liver health.
