ALN RNAi therapeutic program represents novel approach for treatment of AAT deficiency

Nov 15 2012

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) , a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of liver disease associated with AAT deficiency. These data were presented at the 63^rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, "The Liver Meeting") held November 9-13, 2012 in Boston. AAT deficiency is a rare genetic disease that can result in severe lung and liver pathology; approximately 10,000 patients are diagnosed worldwide. In a presentation titled "Developing an RNAi Therapeutic for Liver Disease Associated with Alpha-1 Antitrypsin Deficiency," Alnylam scientists presented results showing robust RNAi-mediated silencing of AAT liver mRNA and serum protein in a transgenic mouse model of mutant AAT ("Z-AAT") protein overexpression. The new RNAi therapeutic program, ALN-AAT, represents a novel approach for the treatment of liver disease associated with AAT deficiency.

“Liposome mediated delivery of siRNA to hepatic stellate cells”

"In line with our 'Alnylam 5x15' product strategy, we are excited about the potential for RNAi therapeutics for the treatment of AAT deficiency, a rare, genetic condition that causes lung and liver disease," said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead Development at Alnylam. "We are very encouraged by these new pre-clinical data with ALN-AAT showing potent knockdown of AAT that results in significant improvements in liver pathology in disease models."

"Approximately 10,000 people worldwide have been diagnosed with severe AAT deficiency, a rare genetic disease that results in severe lung and liver pathology. AAT patients can develop early onset emphysema as well as liver disease, including hepatitis, cirrhosis, and hepatocellular carcinoma. While lung disease associated with AAT deficiency has been addressed with AAT replacement therapy, there are limited treatment options for 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. "We are very encouraged by these data with ALN-AAT and look forward to further advancement of an RNAi therapeutic approach for the treatment of this genetic disease."

ALN-AAT is a new RNAi therapeutic program for the treatment of liver disease associated with AAT deficiency. New data presented at the Liver Meeting are based on an AAT-targeting siRNA formulated in a lipid nanoparticle (LNP). The AAT siRNA was administered at doses ranging from 0.03 to 1.0 mg/kg in mice overexpressing a human Z-AAT transgene, resulting in robust, dose-dependent silencing of the target mRNA and protein. Specifically, a single intravenous dose of the drug resulted in 90% knockdown of liver mRNA and a greater than 80% decrease in serum AAT at 48 hours post-dose. Furthermore, a 90% reduction in soluble protein monomers in the liver was observed at 1.0 mg/kg, with an 80% reduction seen at 0.3 mg/kg. In addition, in long-term dosing studies, in which transgenic mice overexpressing Z-AAT were dosed every other week for 12 weeks at 0.3 mg/kg, ALN-AAT resulted in a 45% reduction of pathogenic protein polymers and a significant decrease in the size and number of AAT globules in hepatocytes. Long-term dosing also significantly decreased hepatocyte proliferation and liver collagen levels, known markers of liver dysfunction and fibrosis, respectively. Further, ALN-AAT administration resulted in marked improvements in hepatocyte cellular morphology as assessed by electron microscopy. Finally, 98% suppression of liver mRNA and serum protein was observed 48 hours after a single dose of the drug in transgenic mice that had fibrotic livers, illustrating key pre-clinical proof of concept for RNAi-mediated treatment in diseased livers. Alnylam has also identified a GalNAc-siRNA targeting AAT that enables subcutaneous dose administration for further development.

In addition, in a poster titled "Liposome mediated delivery of siRNA to hepatic stellate cells," Alnylam scientists presented new data on the systemic delivery of RNAi therapeutics to quiescent and activated hepatic stellate cells (HSCs). HSCs play a key role in the initiation and progression of liver fibrosis, the excessive accumulation of tough, fibrous scar tissue that occurs in most types of chronic liver diseases. These new data show that siRNA formulated in LNPs result in effective silencing of the HSC-specific gene target, collagen 1a1 (col1a1). Specifically, a single intravenous dose of siRNA against col1a1 yielded robust, dose-dependent silencing of target mRNA in activated HSCs at 48 hours, with an approximate ED₅₀ of 0.1 mg/kg. Furthermore, silencing of col1a1 was confirmed to be RNAi-mediated. These data point to a potential strategy for development of RNAi therapeutics for the treatment of liver fibrosis.

Source Alnylam Pharmaceuticals