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.

Keywords: ATTR amyloidosis; Cardiomyopathy; Patisiran; Polyneuropathy; RNA interference.

Conflict of interest statement

TC reports compensation for training from Pfizer Pharmaceuticals and Alnylam Pharmaceuticals Inc., and compensation for travel from Pfizer Pharmaceuticals, Alnylam Pharmaceuticals Inc., and IONIS Pharmaceuticals. DA reports grants from Alnylam Pharmaceuticals Inc., and personal fees from Pfizer Pharmaceuticals and Alnylam Pharmaceuticals Inc. outside the submitted work. IC acknowledges financial support as a primary investigator for FoldRx Pharmaceuticals/Pfizer Inc., Alnylam Pharmaceuticals Inc., and IONIS Pharmaceuticals, and serves on the Transthyretin Amyloidosis Outcome Survey (THAOS) scientific advisory board. MWC received honorarium from NHI, Prothena, FoldRx, Akcea Therapeutics, Pfizer Pharmaceuticals, Alnylam Pharmaceuticals Inc., PTC, and Genzyme for travel expenses related to presentations at medical meetings, and for acting as a consultant and as a principal investigator in clinical trials. HHS reports grants and consulting fees from Alnylam Pharmaceuticals Inc. outside the submitted work. JBu reports personal fees from Alnylam Pharmaceuticals Inc. during the conduct of the study for serving as a principal investigator. JCo has nothing to disclose. JBe reports serving as a study investigator for IONIS Pharmaceuticals and Pfizer Pharmaceuticals, and consultant for Intellia Therapeutics Inc. and Corino Therapeutics Inc. outside the submitted work. MP reports grants from Alnylam Pharmaceuticals Inc. during the conduct of the study and honorarium following completion of the study. JJW, JCh, MTS, and JG are all Alnylam employees. OBS reports personal fees from Alnylam Pharmaceuticals Inc. during the conduct of the study, personal fees and non-financial support from Pfizer Pharmaceuticals, and personal fees from Prothena Pharmaceuticals and Intellia Therapeutics, Inc. outside the submitted work.

Figures

Fig. 1

Serum TTR reduction. Percentage change in serum TTR from baseline over time. Pre- and post-dose (0.3 mg/kg Q3W patisiran) values are indicated on the graph with an x. BSL, baseline; ELISA, enzyme-linked immunosorbent assay; Q3W, every 3 weeks; TTR, transthyretin

Fig. 2

Mean change from baseline (SEM) in mNIS+7 in the all-treated population over 24 months. Error bars represent the SEM. mNIS+7, modified Neuropathy Impairment Score +7; SEM, standard error of the mean

Fig. 3

Change in sweat gland nerve-fiber density and dermal amyloid burden of the lower limb. a Change in sweat gland nerve-fiber density in distal thigh and distal leg to 24 months. b Distal thigh sweat gland innervation at baseline and at Month 24 in an individual patient, with nerve fibers immunostained for PGP 9·5 (green), blood vessels immunostained for CD31 (red), and cell nuclei labeled with DAPI (blue). c Change from baseline to 24 months in amyloid burden for the lower limb. The statistical significance (performed as a post hoc analysis) of the change from baseline is shown for each time-point where: *p = 0.01–0.05, **p = 0.001–0.01. BSL, baseline; CD31, cluster of differentiation 31 protein (or platelet endothelial cell adhesion molecule [PECAM1]); DAPI, 4′,6-diamidino-2-phenylindole; PGP, protein gene product