Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial

T H Brannagan, A K Wang, T Coelho, M Waddington Cruz, M J Polydefkis, P J Dyck, V Plante-Bordeneuve, J L Berk, F Barroso, G Merlini, I Conceição, S G Hughes, J Kwoh, S W Jung, S Guthrie, M Pollock, M D Benson, M Gertz, NEURO-TTR open-label extension investigators, Brian Drachman, Peter Gorevic, Stephen Heitner, Morton Scheinberg, Hartmut Schmidt, Carol Whelan, David Adams, Josep Maria Campistol Plana, Josep Gamez, Edward Gane, Arnt Kristen, Laura Obici, Fabrizio Salvi, Acary Souza Bulle Oliveira, Giuseppe Vita, T H Brannagan, A K Wang, T Coelho, M Waddington Cruz, M J Polydefkis, P J Dyck, V Plante-Bordeneuve, J L Berk, F Barroso, G Merlini, I Conceição, S G Hughes, J Kwoh, S W Jung, S Guthrie, M Pollock, M D Benson, M Gertz, NEURO-TTR open-label extension investigators, Brian Drachman, Peter Gorevic, Stephen Heitner, Morton Scheinberg, Hartmut Schmidt, Carol Whelan, David Adams, Josep Maria Campistol Plana, Josep Gamez, Edward Gane, Arnt Kristen, Laura Obici, Fabrizio Salvi, Acary Souza Bulle Oliveira, Giuseppe Vita

Abstract

Background and purpose: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study.

Methods: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed.

Results: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure.

Conclusion: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Keywords: genetic and inherited disorders; peripheral neuropathies; polyneuropathy.

Conflict of interest statement

Thomas Brannagan: Advisory boards for Akcea Therapeutics, Pfizer and Alnylam Pharmaceuticals; study investigator for Ionis Pharmaceuticals Inc. and Alnylam Pharmaceuticals; speaker for Alnylam Pharmaceuticals; received honoraria for speaking for Akcea Therapeutics. Annabel K. Wang: Study investigator, consultant and speaker for Ionis Pharmaceuticals Inc. Teresa Coelho: Financial support to attend scientific meetings from Pfizer, Alnylam and Biogen. Márcia Waddington Cruz: Consulting and travel honoraria from NHI, Prothena, FoldRx, Ionis, Pfizer, Alnylam, PTC; principal investigator for Ionis Pharmaceuticals Inc. Michael J. Polydefkis: Honoraria from Pfizer and Alnylam Pharmaceuticals Inc. Peter J. Dyck: Training and consulting honoraria from Ionis Pharmaceuticals Inc. and Alnylam Pharmaceuticals. Violaine Plante‐Bordeneuve: Consulting honoraria from Alnylam Pharmaceuticals, Ionis and Pfizer and travel honoraria from Ionis. John L. Berk: Honoraria from Ionis Pharmaceuticals Inc. and Alnylam Pharmaceuticals; study investigator for Ionis Pharmaceuticals Inc., Alnylam Pharmaceuticals and Pfizer. Fabio Barroso: Honoraria for conducting clinical research from Ionis Pharmaceuticals. Giampaolo Merlini: Advisory committee for Pfizer and Janssen. Isabel Conceição: Consultancy for Alnylam and Pfizer; honoraria from Alnylam, Pfizer and Sanofi; speakers bureau for Alnylam, Pfizer and Sanofi. Steven G. Hughes: Consultant for Ionis Pharmaceuticals and Akcea Therapeutics. Jesse Kwoh and Shiangtung Jung: Employed by Ionis Pharmaceuticals. Spencer Guthrie: (formerly) Employed by Akcea Therapeutics. Michael Pollock: Employed by Akcea Therapeutics. Merrill D. Benson: Study investigator for Ionis Pharmaceuticals Inc. Morie Gertz: Consulting honoraria from Ionis, AbbVie, Alnylam, Amgen, Annexon, Appellis, Celgene, Janssen, Medscape, Physicians Education Resource, Prothena, Research to Practice, Teva and Spectrum, and grants from Spectrum.

© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Figures

Figure 1
Figure 1
Patient disposition. NEURO‐TTR disposition data from Benson et al. [12]. AE, adverse event; OLE, open‐label extension; SAE, serious adverse event. aOne patient was randomly assigned in error and did not begin the trial regimen. bPrimary reason for early treatment discontinuation.
Figure 2
Figure 2
Open‐label extension (OLE) median serum transthyretin (TTR) levels relative to the NEURO‐TTR baseline. Data shown are for all enrolled patients who received ≥1 dose of inotersen in the OLE and had ≥1 post‐baseline efficacy assessment (full analysis set). Median percentage change from the NEURO‐TTR baseline is indicated using green squares for the inotersen‐inotersen group and red circles for the placebo‐inotersen group. The dashed line represents the OLE baseline (OLE week 0).
Figure 3
Figure 3
Change from the NEURO‐TTR baseline to week 66 in mNIS + 7 and Norfolk QOL‐DN for the NEURO‐TTR safety set. Least‐squares mean (LSM) ± SE change from the NEURO‐TTR baseline in (a) the Modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7) and (b) the Norfolk Quality of Life – Diabetic Neuropathy (QOL‐DN) questionnaire total score. Data shown are for all patients who received ≥1 dose of study drug in NEURO‐TTR (safety set).
Figure 4
Figure 4
Mean change from the NEURO‐TTR baseline to open‐label extension (OLE) week 104 in efficacy measures. Mean (± SE) change from the NEURO‐TTR baseline in (a) the Modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7); (b) the Norfolk Quality of Life – Diabetic Neuropathy (QOL‐DN) questionnaire total score; (c) the 36‐item Short‐Form Health Survey, version 2 (SF‐36) Physical Component Summary (PCS) score. Data shown are for all enrolled patients who received ≥1 dose of inotersen in the OLE and had ≥1 post‐baseline efficacy assessment (full analysis set). Green squares indicate results for the inotersen‐inotersen group and red circles indicate results for the placebo‐inotersen group. The vertical dashed line represents the OLE baseline (OLE week 0). Sample sizes for each time point and treatment group are indicated under the figure.

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