A Phase 2/3 Randomized Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy

Brief Description Of Study

Familial Amyloid Polyneuropathy (FAP) is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP. ISIS TTR Rx is an antisense drug that decreases the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression. The purpose of this study is to determine if ISIS TTR Rx can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP male and female patients ages 18-82. Patients will receive either ISIS TTR Rx or placebo subcutaneously 3 times on alternate days in the first week and then once-weekly for 64 weeks. Inclusion Criteria: Stage 1 and Stage 2 FAP patients with the following: a.NIS score greater than or equal to 10 and less than or equal to 100 b.Ability to walk unaided or with the use of no more than one stick/cane c.Documented transthyretin variant by genotyping d.Documented amyloid deposit by biopsy Willingness to take Vitamin A supplements Females of child-bearing potential must use appropriate contraception and must be non-pregnant and non-lactating. Males engaged in relations of child-bearing potential must use appropriate contraception Exclusion Criteria: Low Retinol level at screen Karnofsky performance status less than or equal to 50 Poor Renal function Presence of known type 1 or type 2 diabetes mellitus Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease) If previously treated with Vyndaqel®, must have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, must have discontinued treatment for 3 days prior to Study Day 1 Previous treatment with any oligonucleotide or siRNA within 6 months of screening Prior liver transplant or anticipated liver transplant within 1 yr of screening New York Heart Association (NYHA) functional classification of greater than or equal to 3 Acute Coronary Syndrome or major surgery within 3 months of screening Known Primary or Leptomeningeal Amyloidosis Anticipated survival less than 2 years Have any other conditions in the opinion of the investigator which could interfere with the patient participating in or completing the study

Clinical Study Identifier: 820456

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