Journal Article

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

Sweetser, Marianne T., Waddington-Cruz, Márcia, Chen, Jihong, Coelho, Teresa, Gollob, Jared, Campistol, Josep, Buades, Juan, Conceição, Isabel, Suhr, Ole B., Adams, David, Schmidt, Hartmut H., Berk, John L., Polydefkis, Michael, Wang, Jing Jing

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Amyloidosis / Analysis / ATTR amyloidosis / Autonomic nervous system / Biomarkers / Biopsy / Cardiac patients / Cardiomyopathy / Care and treatment / Complications and side effects / Coronary artery disease / Diflunisal / Heart diseases / Human Genetics / Hypertension / Labels / Liver / Medical laboratories / Medical prognosis / Medical research / Medicine / Medicine & Public Health / Mortality / Mutation / Neuropathy / Nutritional status / Pathophysiology / Patients / Patisiran / Pharmacology/Toxicology / Polyneuropathy / Proteins / Quality of life / Questionnaires / Rare diseases / Rare neurological diseases / RNA / RNA interference / RNA-mediated interference / Tafamidis / Transthyretin / Ultrasonic imaging / Vital signs / Vitamin A