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Clinical Trial
. 2023 Mar 17;23(1):108.
doi: 10.1186/s12883-023-03116-7.

The impact of inotersen on Neuropathy Impairment Score in patients with hereditary transthyretin amyloidosis with polyneuropathy

Aaron Yarlas  1 , Andrew Lovley  2 , Duncan Brown  3 , Montserrat Vera-Llonch  3 , Sami Khella  4 , Chafic Karam  4
Affiliations
Clinical Trial

The impact of inotersen on Neuropathy Impairment Score in patients with hereditary transthyretin amyloidosis with polyneuropathy

Aaron Yarlas et al. BMC Neurol. .

Abstract

Background: Patients with hereditary transthyretin amyloidosis (ATTRv) frequently experience symptoms of polyneuropathy (PN) that worsen over time and impair daily functioning. Previous analyses supported efficacy of inotersen, an antisense oligonucleotide, to slow neuropathic progression in patients with ATTRv-PN, as indicated by larger mean changes, relative to placebo, in total score and several subscales of the Neuropathy Impairment Score (NIS), and for the subset of NIS items specific to lower limbs (NIS-LL) for the overall study sample. A key objective of the current study was to evaluate efficacy of inotersen for slowing neuropathic progression in NIS/NIS-LL within key clinical subgroups of patients with ATTRv-PN. Additionally, for this study, responder definition (RD) thresholds were estimated for NIS/NIS-LL total and subscale scores, for the purpose of evaluating clinically meaningful benefit of inotersen at the individual patient-level.

Methods: Post hoc analyses used data from the NEURO-TTR phase 3 trial of inotersen in patients with ATTRv-PN (NCT01737398). Treatment differences in mean changes on NIS/NIS-LL total and subscale scores from baseline to week 65 were examined within patient subgroups defined by clinical characteristics. Anchor- and distribution-based approaches estimated RDs for NIS/NIS-LL scores, with responders defined as patients who did not experience clinically meaningful neuropathic progression. Responder analyses compared the proportion of patients classified as responders for each NIS/NIS-LL score between treatment arms.

Results: Within each patient subgroup, mean increases in NIS/NIS-LL total and muscle weakness subscales were significantly smaller after 65 weeks of treatment with inotersen compared to placebo. Similar patterns were observed for some, but not all, subgroups on NIS/NIS-LL reflex subscale scores. Recommended RDs were 8.1 points for NIS total and 4.7 points for NIS-LL total. Patients receiving inotersen for 65 weeks were significantly less likely than those receiving placebo to exhibit clinically meaningful increases on NIS/NIS-LL total, muscle weakness, and sensation subscales.

Conclusions: This study supports previous evidence for efficacy of inotersen in this patient population and provides interpretation guidelines for clinically meaningful changes in NIS/NIS-LL scores.

Keywords: Hereditary transthyretin amyloidosis; Inotersen; Neuropathic progression; Neuropathy.

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Conflict of interest statement

At the time of this research, AY was an employee of QualityMetric, which received payment from Ionis Pharmaceuticals Inc., to conduct these analyses and develop this manuscript; AY is currently an employee of and owns stock in Ionis Pharmaceuticals Inc. AL is an employee of QualityMetric. DB and MVL are employees of and own stock in Ionis Pharmaceuticals Inc. SK has received consulting honoraria from Ionis Pharmaceuticals, Akcea Therapeutics, Alnylam, Pfizer, and Eidos. CK has received consulting honoraria from Ionis Pharmaceuticals, Akcea Therapeutics, Argenx, CSL Behring, Alnylam, Biogen, and Sanofi.

Figures

Fig. 1
Fig. 1
Treatment Differences in NIS (a) and NIS-LL (b) Total Mean Change Scores from Baseline to Week 65. Note: Means in purple ink are statistically significantly different from 0 (p < 0.05). Abbreviations: CI, confidence interval; CM, cardiomyopathy; FAP, familial amyloid polyneuropathy; FAS, full analysis set; LS, least-squares; NIS, Neuropathy Impairment Score; NIS-LL, Neuropathy Impairment Score – Lower Limb
Fig. 2
Fig. 2
Treatment Differences in NIS (a) and NIS-LL (b) Muscle Weakness Domain Change Scores from Baseline to Week 65. Note: Means in purple ink are statistically significantly different from 0 (p < 0.05). Abbreviations: CI, confidence interval; CM, cardiomyopathy; FAP, familial amyloid polyneuropathy; FAS, full analysis set; LS, least-squares; NIS, Neuropathy Impairment Score; NIS-LL, Neuropathy Impairment Score – Lower Limb
Fig. 3
Fig. 3
Treatment Differences in NIS (a) and NIS-LL (b) Sensation Domain Change Scores from Baseline to Week 65. Note: Means in purple ink are statistically significantly different from 0 (p < 0.05). Abbreviations: CI, confidence interval; CM, cardiomyopathy; FAP, familial amyloid polyneuropathy; FAS, full analysis set; LS, least-squares; NIS, Neuropathy Impairment Score; NIS-LL, Neuropathy Impairment Score – Lower Limb
Fig. 4
Fig. 4
Treatment Differences in NIS (a) and NIS-LL (b) Reflexes Domain Change Scores from Baseline to Week 65. Note: Means in purple ink are statistically significantly different from 0 (p < 0.05). Abbreviations: CI, confidence interval; CM, cardiomyopathy; FAP, familial amyloid polyneuropathy; FAS, full analysis set; LS, least-squares; NIS, Neuropathy Impairment Score; NIS-LL, Neuropathy Impairment Score – Lower Limb
Fig. 5
Fig. 5
Proportion of Responders at Week 65 by Treatment Arm for NIS Total and Subscale Scores. Abbreviations: CI, confidence interval; NIS, Neuropathy Impairment Score; OR, odds ratio
Fig. 6
Fig. 6
Proportion of Responders at Week 65 by Treatment Arm for NIS-LL Total and Subscale Scores. Abbreviations: CI, confidence interval; NIS-LL, Neuropathy Impairment Score – Lower Limb; OR, odds ratio
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References

    1. Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T, Cruz M, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol. 2015;66(21):2451–2466. doi: 10.1016/j.jacc.2015.09.075. - DOI - PubMed
    1. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon B-G, Ikeda S, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8(1):1–18. doi: 10.1186/1750-1172-8-31. - DOI - PMC - PubMed
    1. Lin X, Yarlas A, Vera-Llonch M, Baranwal N, Biber J, Brown D, et al. Rate of neuropathic progression in hereditary transthyretin amyloidosis with polyneuropathy and other peripheral neuropathies: a systematic review and meta-analysis. BMC Neurol. 2021;21(1):70. doi: 10.1186/s12883-021-02094-y. - DOI - PMC - PubMed
    1. Lovley A, Raymond K, Guthrie SD, Pollock M, Sanchorawala V, White MK. Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being. J Patient Rep Outcomes. 2021;5(1):3. doi: 10.1186/s41687-020-00273-y. - DOI - PMC - PubMed
    1. Yarlas A, Gertz MA, Dasgupta NR, Obici L, Pollock M, Ackermann EJ, et al. Burden of hereditary transthyretin amyloidosis on quality of life. Muscle Nerve. 2019;60(2):169–175. doi: 10.1002/mus.26515. - DOI - PMC - PubMed

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