Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency is a rare genetic 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.

Mutations in AAT, most commonly in the “Z-allele” – Z-AAT – cause the protein to misfold, which hinders its normal release into the blood, thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma. There are approximately 200,000 people in the U.S. and major European countries thought to be homozygous for the Z allele (PiZZ), and it is estimated that at least 10% have an associated liver pathology.

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. There exists a very high unmet need for therapies toward liver disease associated with AAT deficiency. RNAi-mediated inhibition of AAT in PiZZ patients may represent a promising new way to treat this rare disease.

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ALN-AAT for the Treatment of AAT Deficiency Liver Disease

ALN-AAT utilizes our proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

In June 2014, we entered into a collaboration with The Alpha-1 Project (TAP), the venture philanthropy subsidiary of the Alpha-1 Foundation, for the continued advancement of ALN-AAT. TAP’s mission is to work with patients, academia, pharmaceutical and biotech companies, and public health organizations in the pursuit of cures and therapies for chronic obstructive pulmonary disease (COPD) and liver disease caused by AAT deficiency. TAP is partially funding research activities for ALN-AAT.

Please read the latest press releases and data presentations for ALN-AAT here.

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Pre-Clinical Data on ALN-AAT at Digestive Disease Week

Pre-Clinical Data on ALN-AAT at Digestive Disease Week

We presented pre-clinical data on ALN-AAT, an investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease. New data, presented at the Digestive Disease Week (DDW) meeting, held May 16 – 19, 2015, showed a robust knockdown of serum AAT of up to 93% in non-human primates (NHPs) with monthly subcutaneous dosing. This level of knockdown was highly durable, lasting for greater than 30 days following the final dose. Further, ALN-AAT was found to have a wide therapeutic index based on results from GLP toxicology studies. In addition, study results were reported from a transgenic mouse model of alpha-1 liver disease, where mice overexpress the human Z-AAT protein.

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Pre-Clinical Data on ALN-AAT for the Treatment of Alpha-1 Antitrypsin (AAT) Deficiency-Associated Liver Disease

We presented new pre-clinical data supporting the advancement of a Development Candidate (DC) for ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease. Data were presented in a Late-Breaking Abstract Session at Digestive Disease Week (DDW), held May 3 – 6, 2014 in Chicago. As previously presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, “The Liver Meeting”) in November 2013 and as updated at DDW, studies were performed in transgenic mice overexpressing the human Z-AAT protein. Subcutaneous administration of a GalNAc-siRNA targeting AAT led to rapid, potent, dose-dependent, and durable knockdown of AAT of greater than 95%, as well as a significant reduction in fibrosis and the incidence of liver tumors.

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