https://orcid.org/0000-0002-7880-2316
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ABSTRACT
Introduction
Hereditary transthyretin (ATTRv) amyloidosis is a progressive, fatal disorder caused by mutations in the transthyretin (TTR) gene leading to deposition of the misfolded protein in amyloid fibrils. The main phenotypes are peripheral neuropathy (PN) and cardiomyopathy (CM).
Areas covered
Gene silencing therapy, by dramatically reducing liver production of TTR, has transformed ATTRv-PN patient care in the last decade. In this drug discovery case history, the authors discuss the treatment history of ATTRv-PN and focus on the latest siRNA therapy: vutrisiran. Vutrisiran is chemically enhanced and N-acetylgalactosamin-conjugated, allowing increased stability and specific liver delivery. HELIOS-A, a phase III, multicenter randomized study, tested vutrisiran in ATTRv-PN and showed significant improvement in neuropathy impairment, disability, quality of life (QoL), gait speed, and nutritional status. Tolerance was acceptable, no safety signals were raised.
Expert opinion
Vutrisiran offers a new treatment option for patients with ATTRv-PN. Vutrisian’s easier delivery and administration route, at a quarterly frequency, as well as the absence of premedication, are major improvements to reduce patients’ disease burden and improve their QoL. Its place in the therapeutic strategy is to be determined, considering affordability.
Article highlights
Progress in ATTRv-PN treatments has transformed the course of this life-threatening disease in the past 20 years.
Liver transplantation (LT) then TTR stabilizers were the first available treatments, however, complications following LT and inconsistent efficacy with tafamidis are strong limitations to their use.
2018 was a pivotal year with the development of two silencing mRNA therapies for ATTRv-PN: patisiran and inotersen.
In 2022, vutrisiran, a new chemically enhanced, GalNAc-conjugated siRNA, was approved for the treatment of ATTRv-PN stage 1 and 2 in the U.S.A. and the EU as a subcutaneous injection every 3 months.
Vutrisiran was shown to improve neuropathy impairment and quality of life.
Its place in treatment strategy is to be determined considering its quarterly SC administration, the absence of premedication and affordability.
Abbreviation
| AE | = | adverse effect |
| AGO2 | = | argonaute-2 |
| AGPR | = | asialoglycoprotein receptor |
| ASO | = | antisens oligonucleotide |
| ATTRv | = | hereditary transthyretin-mediated amyloidosis |
| BMI | = | body mass index |
| CM | = | cardiomyopathy |
| CNS | = | central nervous system |
| DN | = | diabetic neuropathy |
| EMA | = | European Medicines Agency |
| FDA | = | Food and Drug Administration |
| GalNAc | = | N-acetylgalactosamin |
| IRR | = | infusion related reaction |
| IU | = | international unit |
| IV | = | intravenous |
| kDa | = | kilo Dalton |
| LNP | = | lipidic nanoparticles |
| LV | = | left ventricle |
| mNIS | = | modified neuropathy impairment score |
| mRNA | = | messenger RNA |
| OLE | = | open-label extension |
| PN | = | polyneuropathy |
| PS | = | phosphorothioate |
| Norfolk QOL-DN | = | Norfolk Quality Of Life – Diabetic Neuropathy |
| QoL | = | quality of life |
| RISC | = | RNA-induced silencing complex |
| R-ODS | = | rasch-built overall disability scale |
| RNA | = | ribonucleic acid |
| RNase | = | ribonuclease |
| SC | = | subcutaneous |
| siRNA | = | small interfering RNA |
| TTR | = | transthyretin |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One referee is the inventor of, and receives royalty payments for, a competitor drug that is in competition with vutrisiran while another referee has received a travel grant to attend scientific congresses from Alnylam (the originator company of vutrisiran). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.