To identify changes in the proteome associated with onset and progression of ATTRv amyloidosis, we performed an observational, case-controlled study which compared proteomes of patients with ATTRv amyloidosis and healthy controls.

Plasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in the APOLLO study and in healthy controls. The impact of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed using an orthogonal quantitative approach.

Levels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10⁻²⁰). Analysis of changes in protein levels demonstrated that the proteome of patisiran-treated patients trended toward healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 vs 69.4 pg/mL, effect: −53.1 pg/mL, 95% CI [–60.5 to −45.9]). NfL levels at 18 months increased with placebo (99.5 vs 63.2 pg/mL, 36.3 pg/mL, [16.5–56.1]) and decreased with patisiran treatment (48.8 vs 72.1 pg/mL, −23.3 pg/mL, [–33.4 to −13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 following patisiran significantly correlated with reduced NfL (R = 0.43, [0.29–0.55]).

Findings suggest NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, may enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.

This study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.

This supplementary data comprises:

Table e-1

A comprehensive list of all proteins that significantly changed between placebo- and patisiran-treated hereditary transthyretin (ATTRv) amyloidosis patients over time during the APOLLO study

Table e-2

Comparisons of levels of neurofilament light chain (NfL) between healthy controls and placebo- or patisiran-treated patients at baseline, 9 months, or 18 months

Table e-3

Comparisons of levels of NfL in baseline APOLLO patients at different polyneuropathy disability (PND) scores

Table e-4

Comparisons of levels of NfL in baseline APOLLO patients that were in the prespecified cardiac subpopulation or not to healthy controls

Table e-5

Comparisons of levels of NfL in healthy controls and placebo- or patisiran-treated patients at baseline or 18 months between groups.