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Hereditary ATTR Amyloidosis with Cardiomyopathy (hATTR-CM)

ATTR amyloidosis is a progressive, life-threatening disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in multiple organs, but primarily in the peripheral nerves and heart. ATTR amyloidosis can lead to significant morbidity, disability, and mortality. TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein – one of the vehicles used to transport vitamin A around the body. Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils that typically contain both mutant and wild-type TTR that deposit in tissues such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.

Hereditary ATTR represents a major unmet medical need based on its significant morbidity and mortality. There are over 100 reported TTR mutations; the particular TTR mutation and the site of amyloid deposition determine the clinical manifestations of the disease, whether it is predominantly symptoms of neuropathy or cardiomyopathy.

Specifically, hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM), also referred to familial amyloidotic cardiomyopathy (FAC) is an inherited, progressive, life-threatening disease. It is due to a mutation in the transthyretin (TTR) gene, which causes misfolded TTR proteins to accumulate as amyloid fibrils primarily in the heart. Hereditary ATTR amyloidosis with cardiomyopathy can result in heart failure and death.

While the exact numbers are not known, it is estimated hATTR-CM, also known as FAC, affects at least 40,000 people worldwide. hATTR-CM is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. Wild-type ATTR amyloidosis, also known as senile systemic amyloidosis (SSA), is a nonhereditary, progressive, life-threatening disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in the heart. Wild-type ATTR amyloidosis can cause cardiomyopathy and result in heart failure and death. There are no approved therapies for the treatment of hATTR-CM or SSA hence there is a significant unmet need for novel therapeutics to treat these patients.

Our hereditary ATTR program is the lead effort in our Genetic Medicine Strategic Therapeutic Area (STAr) product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of rare diseases with high unmet medical need. We are developing revusiran (ALN-TTRsc), a subcutaneously administered RNAi therapeutic for the treatment of hATTR-CM.

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Revusiran for the Treatment of hATTR-CM

Alnylam is advancing revusiran targeting TTR for the treatment of patients with hATTR-CM. Revusiran employs an siRNA targeting wild-type and all mutant forms of TTR and utilizes our proprietary GalNAc-conjugate delivery platform which enables subcutaneous delivery of our RNAi therapeutics, primarily to the liver.

Please read the latest press releases and data presentations for revusiran here.

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ENDEAVOUR Phase 3 Trial

The ENDEAVOUR Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of revusiran in patients with hATTR-CM.

For more information about the ENDEAVOUR Phase 3 trial, please go to ENDEAVOURtrial.com.

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Updates from Patisiran and Revusiran, in Development for the Treatment of hATTR Amyloidosis

Updates from Patisiran and Revusiran, in Development for the Treatment of hATTR Amyloidosis

We reported new clinical data from our ongoing Phase 2 open-label extension (OLE) studies with patisiran and revusiran, investigational RNAi therapeutics targeting transthyretin (TTR) for the treatment of hereditary TTR-mediated amyloidosis (hATTR amyloidosis). These data were presented at the XV International Symposium on Amyloidosis held July 3 – 7, 2016 in Uppsala, Sweden.






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Pre-Clinical Data and Advancement of ALN-TTRsc02 for Transthyretin-Mediated Amyloidosis

Pre-Clinical Data and Advancement of ALN-TTRsc02 for Transthyretin-Mediated Amyloidosis

We presented pre-clinical data with ALN-TTRsc02, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis).  In pre-clinical studies, including those in non-human primates (NHPs), ALN-TTRsc02 achieved potent and highly durable knockdown of serum TTR of up to 99% with multi-month durability achieved after just a single dose, supportive of a potentially once quarterly dose regimen. Results from studies comparing TTR knockdown activity of ALN-TTRsc02 to that of revusiran showed that ALN-TTRsc02 has a markedly superior TTR knockdown profile.  Further, in initial rat toxicology studies, ALN-TTRsc02 was found to be generally well tolerated with no significant adverse events at doses as high as 100 mg/kg.



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