Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR)

Daniel P Judge, Arnt V Kristen, Martha Grogan, Mathew S Maurer, Rodney H Falk, Mazen Hanna, Julian Gillmore, Pushkal Garg, Akshay K Vaishnaw, Jamie Harrop, Christine Powell, Verena Karsten, Xiaoping Zhang, Marianne T Sweetser, John Vest, Philip N Hawkins, Daniel P Judge, Arnt V Kristen, Martha Grogan, Mathew S Maurer, Rodney H Falk, Mazen Hanna, Julian Gillmore, Pushkal Garg, Akshay K Vaishnaw, Jamie Harrop, Christine Powell, Verena Karsten, Xiaoping Zhang, Marianne T Sweetser, John Vest, Philip N Hawkins

Abstract

Purpose: The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis.

Methods: Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction.

Results: Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events.

Conclusions: Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded.

Clinical trial registration: NCT02319005.

Keywords: ATTR amyloidosis; Cardiomyopathy; RNA interference; Revusiran.

Conflict of interest statement

Daniel P. Judge received support for clinical trial participation, scientific consultation, and writing from Alnylam Pharmaceuticals, Inc. and support for scientific consultation from GlaxoSmithKline plc and Pfizer. Arnt V. Kristen received a research grant, support for scientific consultation, and symposia honoraria from Alnylam Pharmaceuticals, Inc. Martha Grogan received support for clinical trial participation from Alnylam Pharmaceuticals, Inc., Eidos Therapeutics, Inc., Pfizer, and Prothena Corporation plc. Matthew S. Maurer received support for clinical research from Alnylam Pharmaceuticals, Inc., Eidos Therapeutics, Inc., Pfizer, and Prothena Corporation plc; support for Data and Safety Monitoring Board participation from Prothena Corporation plc; and support for steering committee participation from Pfizer. Rodney H. Falk received support for consultancy and research from Akcea Therapeutics, Inc. Eidos Therapeutics, Inc., and Alnylam Pharmaceuticals, Inc. Mazen Hanna received support for advisory board participation from Alnylam Pharmaceuticals, Inc., Akcea Therapeutics, Inc, Eidos Therapeutics, Inc., and Pfizer. Julian Gillmore received support for clinical trial and advisory board participation from Alnylam Pharmaceuticals, Inc. Pushkal Garg, Akshay K. Vaishnaw, Jamie Harrop, Christine Powell, Verena Karsten, Marianne Sweetser, John Vest, and Xiaoping Zhang are employees of, and own stock in, Alnylam Pharmaceuticals, Inc.

Figures

Fig. 1
Fig. 1
All-cause and cardiovascular mortality (modified intent-to-treat population). (a) Time to all-cause mortality. (b) Time to cardiovascular mortality. CI = confidence interval; HR = hazard ratio
Fig. 2
Fig. 2
Time to all-cause, cardiovascular, and heart failure hospitalization (modified intent-to-treat population). (a) Time to first cardiovascular hospitalization. (b) Time to first heart failure hospitalization. CI = confidence interval; HR = hazard ratio

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