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.
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.
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.