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A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.

ABSTRACT: BACKGROUND:Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18?months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3?mg/kg intravenously every 3?weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score?+7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup. RESULTS:Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~?82%), and sustained reduction of mean transthyretin levels over 24?months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24?months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24?months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24?months. CONCLUSIONS:Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis. TRIAL REGISTRATION:The study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.

SUBMITTER: Coelho T

PROVIDER: S-EPMC7341568 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.

Coelho Teresa T Adams David D Conceição Isabel I Waddington-Cruz Márcia M Schmidt Hartmut H HH Buades Juan J Campistol Josep J Berk John L JL Polydefkis Michael M Wang Jing Jing JJ Chen Jihong J Sweetser Marianne T MT Gollob Jared J Suhr Ole B OB

Orphanet journal of rare diseases 20200708 1

<h4>Background</h4>Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical ...[more]

PMID: 32641071

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Project description:IntroductionPatients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study.MethodsOne-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively.ResultsFor both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning.ConclusionLong-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients.Trial registrationClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE study INFOGRAPHIC.

Dataset Information

A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.

Publications

A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.

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