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RNAi Roundtable: ALN-TTR

XII International Symposium on Amyloidosis

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Alnylam and Collaborators Demonstrate Regression of Pathogenic Transthyretin (TTR) Amyloid Deposits Following Treatment with an RNAi Therapeutic in an Animal Model of TTR-Mediated Amyloidosis (ATTR)

Alnylam Presents New Pre-Clinical Data on ALN-TTR, an RNAi Therapeutic for the Treatment of Transthyretin-Mediated Amyloidosis

TTR Amyloidosis

ALN-TTR: TTR Amyloidosis

We are developing ALN-TTR, a systemically delivered RNAi therapeutic that targets the transthyretin (TTR) gene, to treat TTR-mediated amyloidosis (ATTR).

ATTR is caused by mutations in the TTR gene, which is expressed predominantly in the liver, and results in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in multiple extra-hepatic tissues, including the peripheral nervous system, heart, and the gastrointestinal tract.

Pre-clinical studies in a mouse transgenic model have shown that treatment with ALN-TTR01 results in both prevention and regression of pathogenic TTR deposits in peripheral tissues including dorsal root ganglia, sciatic nerve, stomach, and intestines. Further, ALN-TTR01 administration in non-human primates was found to result in dose-dependent and durable, yet reversible silencing of the TTR gene and serum levels of TTR.For most patients with TTR amyloidosis, liver transplantation is the only treatment option. These data suggest that treatment of TTR amyloidosis with an RNAi therapeutic may represent a promising alternative medical strategy.

In July 2010, we initiated dosing in a Phase I human clinical study with ALN-TTR01. The study is aimed at evaluating the safety and tolerability of ALN-TTR01 in patients with ATTR, and is also designed to provide preliminary data on human proof of concept based on measurements of TTR serum levels.

ALN-TTR01 employs a first generation lipid nanoparticle formulation developed in collaboration with Tekmira Pharmaceuticals Corporation. In parallel, we are also advancing ALN-TTR02 utilizing second-generation lipid nanoparticles.

The Phase I trial is being conducted in Portugal, Sweden, and the U.K., and is a randomized, blinded, placebo-controlled dose escalation study designed to enroll approximately 28 ATTR patients. The primary objective is to evaluate the safety and tolerability of a single dose of intravenous ALN-TTR01, with patients being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.4 mg/kg. Secondary objectives include characterization of plasma and urine pharmacokinetics of ALN-TTR01 and assessment of pharmacodynamic activity based on measurements of circulating TTR serum levels.

Transthyretin-mediated amyloidosis (ATTR) is an orphan, or rare, hereditary disease caused by mutations in a protein made in the liver, known as transthyretin (TTR). This mutation results in the accumulation of toxic deposits of the protein in several tissues including nerves, heart, and gastrointestinal tract. ATTR affects approximately 50,000 people worldwide and leads to familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). In its severest form, ATTR represents a tremendous unmet medical need with significant morbidity and mortality. ATTR patients have a life expectancy of five to fifteen years from the onset of the disease. The only treatment option for FAP patients is liver transplantation, and only about one third of these patients are candidates for this invasive procedure.