Open Label Extension Trial Depicts Long-Term Efficacy and Safety of Inotersen for Hereditary Transthyretin Amyloidosis

A syringe with injectable drugs.
Long-term treatment with inotersen is effective for polyneuropathy secondary to hATTR amyloidosis with a promising long-term safety profile.

Long-term treatment with inotersen is effective for polyneuropathy secondary to hereditary transthyretin (hATTR) amyloidosis with a promising long-term safety profile, according to study results published in European Journal of Neurology.

Deposition of misfolded transthyretin (TTR) protein is the cause for hATTR amyloidosis, a rare autosomal dominant disease that can involve multiple systems, including peripheral neuropathy, cardiomyopathy, autonomic dysfunction, ocular abnormalities, and carpal tunnel syndrome.  Inotersen, which can prevent production of TTR protein, was shown to stabilize neuropathy and quality of life in the pivotal NEURO-TTR trial in adults with hATTR amyloidosis with polyneuropathy.

The goal of the current study was to assess the efficacy and safety of extended treatment with inotersen for up to 5 years in the open-label extension of the NEURO-TTR study ( Identifier: NCT01737398).

The ongoing open-label extension study included patients who completed the randomized NEURO-TTR study. Here participants received 300 mg inotersen once weekly, for up to 5 years. The efficacy of inotersen was assessed using the modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life-Diabetic Neuropathy questionnaire total score (Norfolk QOL-DN), and the Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score.

Of the 139 patients who completed the NEURO-TTR study, 135 patients enrolled in the open-label extension, including 85 patients who continued to receive inotersen (inotersen-inotersen) and 50 that switched from placebo to inotersen (placebo-inotersen). The current interim analysis included 93 (69%) patients receiving ongoing treatment in the open-label extension, and 59 (44%) patients that had completed week 104.

In the extension study, patients who continued treatment with inotersen demonstrated sustained benefit (mean [SE] change from baseline to week 104) in mNIS+7 (11.18±3.347), Norfolk QOL-DN (5.22±3.321), and health-related quality of life according to SF-36 PCS (0.08±1.397). Patients who switched from placebo to inotersen in the open label arm showed improvement or stabilization (mean [SE] change from baseline to week 104) in mNIS+7 (5.08±4.159) Norfolk QOL-DN (2.26±3.997), and SF-36 PCS (-1.15±1.367) over time, compared to predicted worsening with placebo.

The long-term safety of inotersen is promising, with no additional safety concerns or increased toxicity observed after exposure of up to 5 years. The most common adverse events across both groups were nausea/vomiting, diarrhea, urinary tract infection, fatigue, chills, peripheral edema, injection-site pain or edema, thrombocytopenia, sarcopenia, headache, muscular weakness and myalgia.

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Treatment-emergent adverse events leading to treatment interruption occurred in 66 patients (48.9%), including thrombocytopenia (17.8%) and renal urinary disorders (3.7%). Serious treatment-emergent adverse events were more common in the inotersen-inotersen group (33.8% vs 28%) and included thrombocytopenia (2 patients), nausea (1 patient), chills (1 patient) and hypertension (1 patient). Fatal adverse events were reported in 9 patients, however, only 3 of the 9 deaths occurred on treatment and none were considered related to treatment.

There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure.

The study had several limitations, including the interim nature, open-label design, limited sample size, lack of statistical analyses and only reporting only qualitative results.

“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,” concluded the researchers.

Disclosure: This clinical trial was supported by Ionis Pharmaceuticals, Inc. Please see the original reference for a full list of authors’ disclosures.


Brannagan TH 3rd, Wang AK, Coelho T, et al. 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 [published online ahead of print, 2020 Apr 28]. Eur J Neurol. doi:10.1111/ene.14285