This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

Amyloidosis Conferences



Long-term efficacy and safety of an antisense oligonucleotide inhibitor in hATTR amyloidosis with polyneuropathy

Take-home messages
  • Benefits of inotersen in patients with hATTR amyloidosis with neuropathy are sustained for up to 5 years of treatment
  • Early treatment is important for improved outcomes in hATTR amyloidosis
  • Enhanced monitoring may help reduce risks of severe thrombocytopenia and acute glomerulonephritis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive and fatal disease in which mutations in the transthyretin (TTR) gene destabilise the resulting protein, causing aggregation of TTR monomers as amyloid fibrils throughout the body.1,2 This manifests as multisystem dysfunction, including peripheral sensorimotor neuropathy, autonomic neuropathy, cardiomyopathy, nephropathy and gastrointestinal dysfunction.2,3

Inotersen, an antisense oligonucleotide inhibitor of the hepatic production of TTR, showed positive results in the treatment of hATTR amyloidosis in the NEURO-TTR phase III, multicentre, double-blind, placebo-controlled study. Patients with stage 1 or stage 2 hATTR amyloidosis with polyneuropathy were randomised to receive 300 mg once-weekly subcutaneous inotersen (n=112) or placebo (n=60). Inotersen showed greater efficacy than placebo for the co-primary efficacy analyses of difference from baseline to Week 66 in mNIS+7 and the Norfolk QOL-DN, irrespective of disease stage, mutation or the presence of cardiomyopathy.2

To assess the long-term efficacy and safety of inotersen, participants who successfully completed the NEURO-TTR trial were invited to enrol in a 3-year open-label extension (OLE), in which all were treated with inotersen. Dr Teresa Coelho presented results from the NEURO-TTR OLE at the 7th Congress of the European Academy of Neurology (EAN) – Virtual 2021.

The efficacy analysis, conducted in patients from Europe and North America only (70 patients from the NEURO-TTR inotersen group (inotersen-inotersen) and 39 patients from the placebo group (placebo-inotersen)), supported the long-term use of inotersen for hATTR amyloidosis with polyneuropathy:

  • Placebo-inotersen patients demonstrated sustained improvement in neuropathy progression (as measured by change in mNIS+7 score from baseline) during the OLE versus the predicted worsening based on placebo data from NEURO-TTR
  • In the inotersen-inotersen group, the benefit of inotersen from NEURO-TTR was sustained with up to 3 more years of treatment and was greater than that of the placebo-inotersen group (change from baseline in mNIS+7 at Year 3: 17.2 vs 40.6)
  • Norfolk QOL-DN scores, used to assess patients’ objective perceptions of their symptoms, demonstrated a stabilisation of neuropathy-related quality of life in the placebo-inotersen group but remained consistently worse (higher) than those of the inotersen-inotersen group. At Year 3, there was a 7.5-point difference in Norfolk QOL-DN change from baseline between inotersen-inotersen and placebo-inotersen (9.8 vs 17.3)
  • Serum TTR reductions from NEURO-TTR were sustained up to 3 years in the inotersen-inotersen group and rapid, sustained decreases in the placebo-inotersen group were observed during the OLE

In the long-term safety analysis of inotersen, which included patients from Europe, North America, Latin America and Australasia (N=135), 97.8% of patients experienced at least one treatment-emergent adverse event (TEAE). Fatal TEAEs occurred in 11.9% of patients but none were considered treatment related. 22.2% of patients permanently discontinued inotersen due to a TEAE. The most common (≥10%) TEAEs across all patients were thrombocytopenia, diarrhoea, nausea, urinary tract infection, fall, fatigue, vomiting, chills, peripheral oedema, injection site pain, injection site erythema, constipation, syncope, dyspnoea, headache, pyrexia and anaemia.

There were no cases of Grade 4 platelet count decrease or acute glomerulonephritis; transient decreases in platelet count were observed but improved on drug interruption, suggesting the implementation of platelet and renal monitoring during the OLE study was effective.

These long-term results support the use of inotersen for the slowing of disease progression in patients with hATTR amyloidosis with polyneuropathy, and further highlight the importance of early treatment; patients in the inotersen-inotersen group (who initiated inotersen earlier) showed consistently favourable outcomes with respect to neuropathic impairment and quality of life compared with the placebo-inotersen group (who were switched to inotersen after 1 year of placebo).

mNIS+7: modified neuropathy impairment score +7 neurophysiologic tests composite score; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy.

Based on: Coelho T, Whelan C et al. Efficacy and safety with >3 years of inotersen treatment for the polyneuropathy of hereditary transthyretin amyloidosis. Oral presentation 015 presented at the 7th Congress of the European Academy of Neurology – Virtual 2021, 19-22 June 2021

  1. Ando Y, Coelho T et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013;8:31
  2. Benson M D, Waddington-Cruz M et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31
  3. Conceicao I, Gonzalez-Duarte A et al. "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst 2016;21(1):5-9

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