Increase in Polyneuropathy Disability Stage Does Not Predict Neuropathic Progression in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy Receiving Inotersen: Results from the NEURO-TTR Study
Aaron Yarlas1, Montserrat Vera Llonch2, Duncan Brown2, Andrew Lovley1, Sami Khella3, Chafic Karam3
1QualityMetric, 2Global Health Economics & Outcomes Research, Akcea Therapeutics, 3Clinical Neurology, University of Pennsylvania
Objective:
To examine whether increased polyneuropathy disability (PND) stage corresponds with worsening in clinician- and patient-reported neuropathic measures (the modified Neuropathy Impairment Score +7 [mNIS+7] and Norfolk-Quality of Life-Diabetic Neuropathy [Norfolk-QOL-DN], respectively) in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) receiving inotersen.  
Background:
PND staging broadly classifies neurologic health and ambulation for patients with hATTR-PN. PND ranges from stage 0 (no neurological/ambulatory impairment) to 4 (confined to wheelchair/bedridden). Patients in later PND stages exhibit worse neuropathy and QOL than patients in earlier stages.  
Design/Methods:
mNIS+7 and Norfolk-QOL-DN were administered at baseline and following 65 weeks of treatment to adult patients with hATTR-PN randomized to receive inotersen or placebo in the NEURO-TTR trial (ClinicalTrials.gov ID: NCT01737398). Patients were classified into two subgroups: “PND worse” (PND stage increased from baseline to week 65) or “PND same/better” (PND stage unchanged/decreased). Analysis of variance tested main effects and the interaction of treatment and PND subgroup on mean changes in mNIS+7 and Norfolk-QOL-DN.
Results:
Twenty of 84 patients receiving inotersen, and 13/52 patients receiving placebo, were classified as “PND worse.” For mNIS+7, main and interaction effects were statistically significant (ps<0.001), reflecting substantially larger differences in mean change between “PND worse” and “PND same/better” for placebo (46.7 vs. 16.3) than for inotersen (6.3 vs. 3.6). For Norfolk-QOL-DN, main effects were statistically significant (ps<0.05) although not the interaction effect (p=0.19). Larger differences in Norfolk-QOL-DN mean change were observed between “PND worse” and “PND same/better” for placebo (21.6 vs. 7.2) than for inotersen (2.7 vs. -1.2).
Conclusions:
Preliminary results suggest that increasing PND stage was not associated with worsening on granular measures of neuropathy for patients with hATTR-PN receiving inotersen. This dissociation suggests that factors other than neuropathy progression may affect PND stage and that PND may not be a reliable outcome for neuropathy progression in patients with systemic disorders.