Journal Article

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis

Sweetser, Marianne T., Chen, Jihong, Hung, Rebecca R., Simões, Marcus, Fernandes, Fábio, Solomon, Scott D., Yureneva, Elena, Di Carli, Marcelo, Damy, Thibaud, Berk, John L., Tang, W.H. Wilson, Poulsen, Steen Hvitfeldt, Kubanek, Milos, Gustafsson, Finn, Gottlieb, Robert L., Taylor, Mark S., González-Duarte, Alejandra, Diemberger, Igor, Maurer, Mathew S., Sekijima, Yoshiki, Obici, Laura, Tahara, Nobuhiro, Yu, Wen-Chung, Kale, Parag, Tsujita, Kenichi, Perfetto, Federico, Sarswat, Nitasha, Jay, Patrick Y., Vest, John, Donal, Erwan, Palecek, Tomas, White, Matthew T., Fontana, Marianna, Grogan, Martha, Badri, Prajakta, Garg, Pushkal P., Gillmore, Julian D.

2023

Overview

Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

• Publisher: Massachusetts Medical Society
• Subject: Amyloid / Amyloidosis / Amyloidosis - complications / Amyloidosis - drug therapy / Amyloidosis - genetics / Amyloidosis, Familial / Amyloidosis, Familial - complications / Amyloidosis, Familial - drug therapy / Amyloidosis, Familial - genetics / Arthralgia / Body weight / Cardiology / Cardiology and cardiovascular system / Cardiology General / Cardiomyopathies / Cardiomyopathies - drug therapy / Cardiomyopathies - etiology / Cardiomyopathies - genetics / Cardiomyopathies - metabolism / Cardiomyopathy / Congestive heart failure / Coronaviruses / COVID-19 / Double-Blind Method / Genetics / Genetics General / Heart failure / Human health and pathology / Humans / Hypotheses / Hypothesis testing / Investigations / Life Sciences / Liver / Liver - metabolism / Myocarditis / Neurology / Neurosurgery / Neurosurgery General / Pericarditis / Pharmacodynamics / Placebos / Prealbumin / Prealbumin - genetics / Prealbumin - metabolism / Proteins / Quality of life / RNA Therapeutics / RNA, Small Interfering / RNA, Small Interfering - therapeutic use / RNA-mediated interference / Statistical analysis / Transthyretin