Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro

Abstract

Background Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype.

Objective To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN).

Methods Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1–first dose of inotersen). Disease progression was evaluated by standard measures.

Results Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted.

Conclusion The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

Resumo

Antecedentes Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo.

Objetivo Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN).

Métodos Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1–primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas.

Resultados Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança.

Conclusão O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.

Keywords

Amyloidosis - Peripheral Nervous System Diseases - Amyloid Neuropathies, Familial - Mutation, Missense - Amyloidosis, Hereditary, Transthyretin-Related - Inotersen

Palavras-chave

Amiloidose - Doenças do Sistema Nervoso Periférico - Neuropatias Amiloides Familiares - Mutação de Sentido Incorreto - Amiloidose Neuropática Hereditária - Inotersena

Authors' Contributions

MD, LFP, MVP, RG, PA, GA, MG, CPG, RCP: writing – review and editing; MWC: conceptualization, data curation, formal analysis, funding acquisition, validation, writing of he original draft, and writing – review and editing.

Support

The present study received support from PTC Farmacêutica do Brasil LTDA and Ionis Pharmaceuticals, which kindly provided the drug to enable the study. None of the companies interfered in the content of the manuscript.

Publication History

Received: 05 October 2023

Accepted: 03 January 2024

Article published online:
05 April 2024

• References

• 1 Pinto MV, Barreira AA, Bulle AS. et al. Brazilian consensus for diagnosis, management and treatment of transthyretin familial amyloid polyneuropathy. Arq Neuropsiquiatr 2018; 76 (09) 609-621
• 2 Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci 2022; 43 (Suppl. 02) 595-604
• 3 Ihne S, Morbach C, Sommer C, Geier A, Knop S, Störk S. Amyloidosis-the diagnosis and treatment of an underdiagnosed disease. Dtsch Arztebl Int 2020; 117 (10) 159-166
• 4 Dohrn MF, Ihne S, Hegenbart U. et al. Targeting transthyretin - Mechanism-based treatment approaches and future perspectives in hereditary amyloidosis. J Neurochem 2021; 156 (06) 802-818
• 5 Gertz MA, Scheinberg M, Waddington-Cruz M. et al. Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. Expert Rev Clin Pharmacol 2019; 12 (08) 701-711
• 6 Tegsedi™ (Inotersena) PTC FARMACÊUTICA DO BRASIL LTDA. Solução Injetável 284 mg/1,5mL. Available from https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=tegsedi
• 7 Ackermann EJ, Guo S, Benson MD. et al. Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides. Amyloid 2016; 23 (03) 148-157
• 8 Benson MD, Waddington-Cruz M, Berk JL. et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018; 379 (01) 22-31
• 9 Brannagan TH, Wang AK, Coelho T. et al; NEURO-TTR open-label extension investigators. 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; 27 (08) 1374-1381
• 10 Brannagan TH, Coelho T, Wang AK. et al; NEURO-T. T. R. Open-Label Extension Investigators. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update. J Neurol 2022; 269 (12) 6416-6427
• 11 Luigetti M, Antonini G, Di Paolantonio A. et al. Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: Data from an early-access program in Italy. Eur J Neurol 2022; 29 (07) 2148-2155