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

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.

Single‐Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N‐acetylgalactosamine–Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects

“…4,5 Indeed, the chemical characteristics of vutrisiran, a second-generation ESC compound, differ substantially from those of revusiran, a discontinued first-generation standard template chemistry GalNAc conjugate that is prone to rapid in vivo nuclease-mediated degradation. 42,47 As a result of the enhanced chemical stabilization, the proposed dose of vutrisiran (25 mg once every 3 months; 100 mg annually) is 280-fold lower than the dose of revusiran used in the ENDEAVOUR phase III study (500 mg daily for 5 days then 500 mg weekly; 28,000 mg annually) 48 to achieve a similar degree of TTR reduction.…”

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data

“…This trial was halted early, however, due to an unfavourable imbalance in mortality rate between the revusiran and placebo arms 33 . Further to this outcome, treatment‐emergent peripheral neuropathy and severe hepatic events were only reported in the revusiran arm, and four revusiran‐treated patients had elevations in liver transaminase accompanied by increases in total bilirubin 34 . Consequently, the revusiran development program was terminated.…”

Role of Lipid-Based and Polymer-Based Non-Viral Vectors in Nucleic Acid Delivery for Next-Generation Gene Therapy

“…Givosiran (Givlaari TM ), the second siRNA drug approved by the FDA for the treatment of acute intermittent porphyria (AIP) developed by Alnylam Pharmaceuticals contains three GalNAc residues covalently linked to the siRNA targeting delta-aminolevulinic acid synthetase 1 [ 117 ]. A number of GalNAc-conjugated siRNA drug candidates—Cemdisiran [ 118 , 119 ], Lumisiran [ 120 ], Revusiran [ 121 ], Fitusiran [ 122 , 123 ] and Inclisiran [ 124 , 125 , 126 ]—have entered in clinical trials. Similarly, IONIS-ANGPTL3-LRx [ 127 ], GSK3389404/IONIS-HBV-LRx [ 128 ], IONIS-FB-LRx [ 129 ], and IONIS-PKK-LRx [ 130 ] are GalNAc-conjugated antisense oligonucleotides currently in clinical trials.…”