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

doi:10.1111/ene.14285

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

Eur J Neurol. 2020 Aug;27(8):1374-1381. doi: 10.1111/ene.14285. Epub 2020 May 29.

Authors

T H Brannagan¹, A K Wang², T Coelho³, M Waddington Cruz⁴, M J Polydefkis⁵, P J Dyck⁶, V Plante-Bordeneuve⁷, J L Berk⁸, F Barroso⁹, G Merlini¹⁰, I Conceição¹¹, S G Hughes¹², J Kwoh¹², S W Jung¹², S Guthrie¹³, M Pollock¹⁴, M D Benson¹⁵, M Gertz⁶; NEURO-TTR open-label extension investigators

Collaborators

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

Affiliations

¹ Columbia University Medical Center, New York, NY, USA.
² University of California, Irvine, Orange, CA, USA.
³ Centro Hospitalar do Porto, Porto, Portugal.
⁴ CEPARM, Amyloidosis Referral Center, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁵ Johns Hopkins University, Baltimore, MD, USA.
⁶ Mayo Clinic, Rochester, MN, USA.
⁷ CHU Henri Mondor, Creteil, France.
⁸ Boston University, Boston, MA, USA.
⁹ FLENI, Buenos Aires, Argentina.
¹⁰ Amyloidosis Center, IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
¹¹ CHULN, Hospital Santa Maria and Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
¹² Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
¹³ Aurora Bio, San Francisco, CA, USA.
¹⁴ Akcea Therapeutics, Inc., Boston, MA, USA.
¹⁵ Indiana University School of Medicine, Indianapolis, IN, USA.

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.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Neuropathies, Familial* / drug therapy
Amyloid Neuropathies, Familial* / genetics
Female
Humans
Male
Middle Aged
Oligonucleotides
Prealbumin
Quality of Life*

Substances

Oligonucleotides
Prealbumin
Inotersen

Supplementary concepts

Amyloidosis, Hereditary, Transthyretin-Related

Associated data