Dataset Information

MNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis.

ABSTRACT:

Introduction

Inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR-mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test.

Methods

Adults with hATTR in the NEURO-TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks.

Results

All major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS-reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects.

Discussion

The results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

SUBMITTER: Dyck PJB

PROVIDER: S-EPMC7540053 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

mNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis.

Dyck P James B PJB Kincaid John C JC Wiesman Janice F JF Polydefkis Michael M Litchy William J WJ Mauermann Michelle L ML Ackermann Elizabeth J EJ Guthrie Spencer S Pollock Michael M Jung Shiangtung W SW Baker Brenda F BF Dyck Peter J PJ

Muscle & nerve 20200813 4

<h4>Introduction</h4>Inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR-mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test.<h4>Methods</h4>Adults with hATTR in the NEURO-TTR trial (NCT01737 ...[more]

PMID: 32654212

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Project description:BackgroundHereditary 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.MethodsPatients 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.ResultsIn 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.ConclusionInotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Project description:Background and purposeHereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult-onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene-silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early-access program was opened in Italy, and in this article, we present the long-term outcome of a cohort of Italian ATTRv patients who received inotersen within this program.MethodsThis is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early-access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life-Diabetic Neuropathy, troponin, N-terminal pro-brain natriuretic peptide, interventricular septum thickness, and body mass index.ResultsIn total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug-related hypotension, and amyloid-negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow-up available.ConclusionsThe long-term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.

Project description:ObjectiveTo identify changes in the proteome associated with onset and progression of hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, we performed an observational, case-controlled study that compared proteomes of patients with ATTRv amyloidosis and healthy controls.MethodsPlasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in a Phase 3 study of patisiran (APOLLO), and in healthy controls. The effect of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed with an orthogonal quantitative approach.ResultsLevels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10-20). Analysis of changes in protein levels demonstrated that the proteome of patients treated with patisiran trended toward that of healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 pg/mL vs 69.4 pg/mL, effect -53.1 pg/mL [95% confidence interval -60.5 to -45.9]). NfL levels at 18 months increased with placebo (99.5 pg/mL vs 63.2 pg/mL, effect 36.3 pg/mL [16.5-56.1]) and decreased with patisiran treatment (48.8 pg/mL vs 72.1 pg/mL, effect -23.3 pg/mL [-33.4 to -13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 score after patisiran treatment significantly correlated with reduced NfL (R = 0.43 [0.29-0.55]).ConclusionsFindings suggest that NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.Classification of evidenceThis study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.