Transthyretin amyloidosis is a rare disease, caused by deposits of insoluble fibrillar protein in tissues, particularly in cardiac tissue – where this accumulation of fibrils leads to a progressive impairment of the functioning of the myocardium. As the National Academy of Medicine points out, the identification of this pathology appears « capital » to the extent that the diagnosis must lead to a “special cardiological care”: “conventional treatments for heart failure can be harmful”et “alone (of the) specific treatments can slow or stop the infiltrative process,” insists the authority (1).
However, these specific, etiological treatments for transthyretin cardiac amyloidosis remain few in number. In fact, until now, only tafamidis, a specific transthyretin stabilizer, had shown its ability to improve patient survival in the Attract study.
Five treatment candidates in the pipeline
But other molecules are in the pipeline. Trials are underway in amyloid cardiomyopathy, in order to evaluate the benefit of patisiran — small interfering RNA specifically targeting the transthyretin gene, capable of reducing its expression and thus limiting hepatic production of fibrils, explains the Academy of Medicine (1). The instance also evokes the inotersen, “antisense oligonucleotide (…) which would block (Also) abnormal protein synthesis. » And nexiguran-ziclumeran (nex-z), derived from the Crispr-Cas 9 method, showed encouraging results in a phase 1 trial presented at the 2024 American Heart Association meeting: a single infusion of the drug candidate would have led, biologically, to a lasting drop of 90% in plasma transthyretin levels and, clinically, to a stabilization of the ejection fraction.
Two candidate treatments appear more advanced. Like acoramidis, which gave results in phase 3 last year. And another candidate treatment was particularly talked about at the end of 2024: vutrisiran, an interfering RNA also designed to inhibit hepatic production of transthyretin. Indeed, this product intended for subcutaneous administration every 3 to 6 months was the subject of a phase 3 clinical trial — Helios-B — described in an article in the New England Journal of Medicine (2).
35% lower death rate with vutrisiran
More precisely, this trial was conducted double-blind in 655 patients suffering from transthyretin cardiac amyloidosis, randomized to receive, every 12 weeks for more than 36 months, a subcutaneous injection of either 25 mg of vutrisiran or of a placebo. Note that not only patients who were not receiving tafamidis when they were included were recruited, but also people who were already receiving this treatment.
As specified in the publication, the primary endpoint concerned a composite endpoint including all-cause mortality and recurrent cardiovascular events. Performance on the six-minute walk test (6MWT) and quality of life estimated by the KCCQ-OS score were also assessed.
-Result: compared to placebo, vutrisiran did help reduce the risk of death from all causes and the risk of cardiovascular events — with an overall HR of 0.72, and even 0.67 in patients also treated with tafamidis . Taken in isolation, the risk of death from all causes was also significantly lower at 42 months in participants taking vultrisiran (HR = 0.65).
In addition, the treatment seems to be able to preserve functional capacities (with better performance on the walking test in the vutrisiran group) and quality of life (with on average a difference of six points between the two groups in the KCCQ-OS score). . And this in all participants — already treated or not with tafamidis.
All for a similar tolerance profile in both groups. Note, however, a high overall prevalence of serious adverse events – recorded in 62% of participants in the intervention arm, and in 67% of participants in the placebo group.
(1) Damy T, et al. Transthyretin cardiac amyloidosis, a disease of the 21st centurye century: from diagnosis to treatment. Bulletin of the National Academy of Medicine. 2023 May(207)5:576-82
(2) Fontana M, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med 2025;392:33-44
