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Hereditary ATTR Amyloidosis with Polyneuropathy (hATTR-PN)

Hereditary 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. Hereditary 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 polyneuropathy (hATTR-PN), also referred to as familial amyloidotic polyneuropathy (FAP) is an inherited, progressive, life-threatening disease, which causes misfolded TTR proteins to accumulate as amyloid fibrils predominantly in peripheral nerves and other organs. Hereditary ATTR amyloidosis with polyneuropathy can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death.

It is estimated that hATTR-PN, also known as FAP, affects approximately 10,000 people worldwide. Patients have a life expectancy of five to 15 years from symptom onset, and the only treatment options for early stage disease are liver transplantation and TTR stabilizers such as tafamidis (approved in Europe) and diflunisal. Unfortunately liver transplantation has limitations, including limited organ availability as well as substantial morbidity and mortality. Furthermore, transplantation eliminates the production of mutant TTR but does not affect wild-type TTR, which can further deposit after transplantation, leading to cardiomyopathy and worsening of neuropathy. There is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

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 patisiran (ALN-TTR02), an intravenously administered RNAi therapeutic, to treat the hATTR-PN form of the disease.

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Patisiran for the Treatment of hATTR-PN

Our approach to the treatment of hereditary ATTR amyloidosis is to employ the RNAi mechanism to knockdown the disease-causing TTR protein, which is primarily synthesized in the liver. Investigational patisiran employs a TTR-targeting siRNA that knocks down both wild-type and all mutant forms of TTR in a lipid nanoparticle formulation that targets delivery to the liver; it is administered by intravenous infusion. The therapeutic hypothesis that lowering TTR can result in clinical benefit is supported by data from hATTR-PN patients receiving liver transplants, and from other systemic amyloidotic diseases, which show that as little as a 50% reduction of the disease-causing protein can result in disease improvement or stabilization.

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

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APOLLO Phase 3 Trial

The APOLLO Phase 3 trial, which completed patient enrollment in January 2016, is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in ATTR patients with hATTR-PN.

For more information about the APOLLO Phase 3 trial, please go to APOLLOtrial.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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Complete 18-Month Data from Ongoing Phase 2 OLE Study with Patisiran in Development for the Treatment of Hereditary TTR-Mediated Amyloidosis with Polyneuropathy (hATTR-PN)

Complete 18-Month Data from Ongoing Phase 2 OLE Study with Patisiran in Development for the Treatment of Hereditary TTR-Mediated Amyloidosis with Polyneuropathy (hATTR-PN)

We reported results from our ongoing Phase 2 open-label extension (OLE) study with patisiran at the 68th Annual Meeting of the American Academy of Neurology (AAN), held April 15 – 21, 2016 in Vancouver, British Columbia, Canada.  Complete 18-month data (N=27) from the study provided continued evidence that patisiran has the potential to halt neuropathy progression in patients with hATTR-PN (also known as familial amyloidotic polyneuropathy, or FAP), showing a mean 0.8-point decrease in mNIS+7, which compares favorably to an estimated increase in mNIS+7 of 22 to 26 points at 18 months based upon analysis of historical data sets in untreated hATTR-PN patients with similar baseline neurologic impairment. Patisiran administration was also associated with a statistically significant, approximately 77% median improvement in nerve fiber density as read histologically in a blinded manner from distal thigh sweat gland biopsy samples.

Further, in the first reported exploratory analysis of its kind, the degree of TTR knockdown observed in patients was shown to correlate with improvement in mNIS+7 scores, supporting the therapeutic hypothesis that reduction of mutant and wild-type TTR may be associated with potential halting of neuropathy progression in patients with hATTR-PN.

Importantly, patisiran was found to be generally well tolerated out to 25 months of treatment.  There were no drug-related severe adverse events (SAEs), and the majority of reported adverse events (AEs) were mild to moderate.  The most common drug-related or possibly drug-related AEs were flushing (22.2%) and infusion-related reactions, or “IRRs” (18.5%). All IRRs and drug-related flushing AEs were mild in severity and did not result in any discontinuations.  In addition, there were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematologic parameters, including platelets.



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