Phase 2 Open-Label Extension (OLE) Study of Patisiran, an Investigational RNA interference (RNAi) Therapeutic for the Treatment of Hereditary ATTR Amyloidosis with Polyneuropathy (S27.004)

Objective: The primary objective is to evaluate the safety of patisiran, an investigational lipid nanoparticle-formulated RNAi therapeutic inhibiting hepatic transthyretin (TTR) protein production. Secondary objectives include assessment of serum TTR levels and clinical neuropathy measures, including the mNIS+7 composite neuropathy impairment score. Background: Hereditary ATTR (hATTR) amyloidosis is a rapidly progressive, life-threatening disease caused by a mutation in the TTR gene, resulting in misfolded TTR proteins accumulating as amyloid fibrils in multiple organs, including the nerves, heart, and gastrointestinal tract. The heterogeneous clinical presentation of hATTR amyloidosis includes sensory, motor and autonomic neuropathies, and cardiac dysfunction. The aggressive disease course can lead to significant morbidity, disability, and mortality. Design/Methods: This is a Phase 2 OLE (NCT01961921) study in patients with hATTR amyloidosis with polyneuropathy receiving patisiran (0.3mg/kg IV) every three weeks for two years. Results: Twenty-seven patients enrolled in the study. Patisiran was generally well tolerated. Six patients experienced serious adverse events unrelated to study drug, including one discontinuation for gastroesophageal cancer (eventually leading to death). Another unrelated death occurred from myocardial infarction after completing study dosing, but prior to the final visit. Flushing (25.9%) and infusion-related reactions (18.5%) were the most common related adverse events; all were mild in severity and didn’t result in discontinuations. Sustained mean serum TTR lowering of ~80% was achieved for u003e24months (mean maximal knockdown: 93%). Preliminary 24-month data suggest improvement in neuropathy with a mean 6.7-point decrease in mNIS+7 (n=24) and a significant increase in sweat gland nerve fiber density in the distal leg (n=17; p=0.007). Conclusions: Preliminary 24-month data demonstrate long-term administration of patisiran is generally well-tolerated, results in robust and sustained serum TTR lowering, and supports the therapeutic hypothesis that TTR knockdown can potentially halt or improve neuropathy progression. Final 24-month data, including serial assessment of amyloid burden in skin punch biopsies, will be presented. Study Supported by: This study is sponsored by Alnylam Pharmaceuticals. Disclosure: Dr. Adams has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Coelho has received research support from Alnylam Pharmaceuticals Dr. Conceicao has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Conceicao has received research support from Alnylam Pharmaceuticals. Dr. Waddington Cruz has received research support from Alnylam Pharmaceuticals. Dr. Schmidt has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Schmidt has received research support from Alnylam Pharmaceuticals Dr. Juan has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Juan has received research support from Alnylam Pharmaceuticals. Dr. Campistol has received research support from Alnylam Pharmaceuticals. Dr. Pouget has nothing to disclose. Dr. Berk has received research support from Alnylam Pharmaceuticals. Dr. Polydefkis has received personal compensation for activities with Pfizer and Alnylam as a consultant. Dr. Ziyadeh has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Partisano has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Chen has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Gollob has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Suhr has received research support from Alnylam Pharmaceuticals.