“People that are homozygous for the mutant Z allele make up approximately 95% of patients with AAT deficiency. These individuals have a lifetime risk of liver disease of 10% to 50%, which manifests as cholestatic disease, cirrhosis, and hepatocellular carcinoma. Severe liver disease can occur in children and adults and is currently managed with supportive care, or in the case of liver failure, with liver transplantation. Clearly, there is a very high unmet need for novel therapies for AAT-deficient patients with liver disease,” said Jeffrey Teckman, M.D., Professor in the Department of Pediatrics and Director of Gastroenterology and Hepatology at Saint Louis University School of Medicine. “In collaboration with Alnylam scientists, we have demonstrated in pre-clinical studies that RNAi therapeutics targeting AAT can significantly ameliorate AAT-mediated liver pathology, including reducing levels of liver AAT aggregates and improving hepatocyte morphology. Our new pre-clinical data with GalNAc-siRNA conjugates extend these findings with a clinically viable, subcutaneously administered RNAi therapeutic, where we have also demonstrated reductions in the development of liver fibrosis and hepatocellular carcinoma. I very much look forward to the further advancement of ALN-AAT as a potential treatment for this devastating genetic disease with limited treatment options.”

New data presented at The Liver Meeting are based on an AAT-targeted siRNA conjugated to an N-acetylgalactosamine (GalNAc) ligand, which is designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Studies were performed in transgenic mice overexpressing the human Z-AAT protein. Subcutaneous administration of a GalNAc-siRNA conjugate targeting Z-AAT led to dose-dependent knockdown of serum levels of human Z-AAT. A single dose of 3 mg/kg led to greater than 95% knockdown of Z-AAT protein that lasted for greater than two weeks. In a multi-dose experiment, twice-weekly dosing at 0.5 mg/kg led to greater than 90% knockdown. Finally, in aged mice (25-46 weeks old) with advanced, established liver disease, repeat administration of a GalNAc-siRNA conjugate against AAT every other week for 18 weeks resulted in a significant reduction (p<0.05) in the incidence of liver tumors associated with Z-AAT overexpression (1/6, 16.7%) when compared to those mice treated with PBS (4/6, 66.7%). Animals treated with the AAT-targeted GalNAc-siRNA also exhibited significant (p<0.05) reductions in levels of Col1a2 (a marker of fibrosis) and PtPrc (a marker of immune cell infiltration) relative to PBS-treated animals.

About Alpha-1 Antitrypsin (AAT) and AAT Deficiency

Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). A deficient serum level of the protein can render the lungs susceptible to emphysema. About 95% of patients with alpha-1 antitrypsin deficiency carry two copies of the abnormal Z allele (PiZZ patients). There are approximately 120,000 in the U.S. and major European countries thought to be homozygous for the Z allele (PiZZ), and it is estimated that about 10% have an associated liver pathology caused by the misfolded protein encoded by the pathogenic Z-allele. Treatment for lung disease associated with AAT deficiency consists of routine emphysema care and, in some instances, augmentation therapy, which utilizes purified AAT from the plasma of healthy donors to increase circulating and airway levels of AAT and restore its function in the lungs. The only treatment options presently available for patients with cirrhosis caused by mutant AAT accumulation in the liver are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in AAT-deficient PiZZ patients may represent a promising new way to treat this rare disease.

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