Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update.

Autor: Brannagan TH; Department of Neurology, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA. tb2325@cumc.columbia.edu., Coelho T; Centro Hospitalar Universitário do Porto, Porto, Portugal., Wang AK; Neuromuscular Diagnostic Laboratory, University of California, Irvine, Orange, CA, USA., Polydefkis MJ; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA., Dyck PJ; Neurology and General Internal Medicine, Mayo Clinic, Rochester, MN, USA., Berk JL; Amyloid Clinic, Boston University, Boston, MA, USA., Drachman B; Cardiovascular Medicine, Penn Presbyterian Medical Center, Philadelphia, PA, USA., Gorevic P; Department of Rheumatology, Mount Sinai Medical Center, New York, NY, USA., Whelan C; Cardiology, National Amyloidosis Centre, Royal Free Hospital, London, UK., Conceição I; Department of Neurology, CHULN, Hospital Santa Maria and Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Plante-Bordeneuve V; CHU Henri Mondor, Creteil, France., Merlini G; Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San Matteo, University of Pavia, Pavia, Italy., Obici L; Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San Matteo, University of Pavia, Pavia, Italy., Plana JMC; Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain., Gamez J; Neurology Department, GMA Clinic, Autonomous University of Barcelona and European Reference Network on Rare Neuromuscular Diseases (ERN EURO-NMD), Barcelona, Spain., Kristen AV; Amyloidosis Center, Heidelberg University Hospital, Heidelberg, Germany., Mazzeo A; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Gentile L; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Narayana A; Akcea Therapeutics, Boston, MA, USA., Olugemo K; Akcea Therapeutics, Boston, MA, USA., Aquino P; Akcea Therapeutics, Boston, MA, USA., Benson MD; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., Gertz M; Neurology and General Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Jazyk: angličtina
Zdroj: Journal of neurology [J Neurol] 2022 Dec; Vol. 269 (12), pp. 6416-6427. Date of Electronic Publication: 2022 Jul 31.
DOI: 10.1007/s00415-022-11276-8
Abstrakt: Background: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years.
Methods: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.
Results: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.
Conclusion: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.
(© 2022. The Author(s).)
Databáze: MEDLINE
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