Efficacy and Safety of Inotersen in 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.

Inotersen (also known as ISIS 420915) is an antisense drug that was designed to decrease the
amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount
of TTR protein would 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 inotersen can slow or stop the nerve damage
caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP
participants. Participants will receive either inotersen or placebo for 65 weeks.

Inclusion Criteria:

- Stage 1 and Stage 2 FAP participants with the following:

1. NIS score within protocol criteria

2. Documented transthyretin variant by genotyping

3. Documented amyloid deposit by biopsy

- Females of child-bearing potential must use appropriate contraception and be
non-pregnant and non-lactating. Males engaging in relations of child-bearing potential
are to use appropriate contraception

Exclusion Criteria:

- Low Retinol level at screen

- Karnofsky performance status ≤50

- Poor Renal function

- Known type 1 or type 2 diabetes mellitus

- Other causes of sensorimotor or autonomic neuropathy (for example, autoimmune disease)

- If previously treated with Vyndaqel®, will need to have discontinued treatment for 2
weeks prior to Study Day 1. If previously treated with Diflunisal, will need to have
discontinued treatment for 3 days prior to Study Day 1

- Previous treatment with any oligonucleotide or siRNA within 12 months of screening

- Prior liver transplant or anticipated liver transplant within 1 year of screening

- New York Heart Association (NYHA) functional classification of ≥3

- Acute Coronary Syndrome or major surgery within 3 months of screening

- Known Primary or Leptomeningeal Amyloidosis

- Anticipated survival less than 2 years

- Any other conditions in the opinion of the investigator which interfere with the
participant participating in or completing the study