Vutrisiran

Vutrisiran belongs to the substance group of siRNA therapeutics (small interfering RNA), also known as RNAi therapeutics (RNA interference) or gene silencers, and works by inhibiting transthyretin (TTR) mRNA, which leads to a reduction in TTR protein production. It is used to treat ATTR neuropathy and ATTR cardiomyopathy.

In contrast to patisiran, the first siRNA approved for the treatment of ATTR neuropathy, vutrisiran is administered s.c. and only every 3 months.

Vutrisiran belongs to the substance group of siRNA therapeutics (small interfering RNA), also known as RNAi therapeutics or gene silencers, and works by inhibiting transthyretin (TTR) mRNA and translation, leading to a reduction in TTR protein production.

Vutrisiran is a chemically stabilized double-stranded small interfering ribonucleic acid (siRNA) that specifically targets variants of transthyretin (TTR) messenger RNA (mRNA) and/or its wild type.

It is covalently bound to a ligand consisting of three N-acetylgalactosamine (GalNAc) residues to enable uptake of the siRNA into the hepatocytes.

Through so-called RNA interference (RNAi), vutrisiran causes the catalytic degradation of TTR mRNA in the liver, which leads to a reduction in serum levels of variant and amyloidogenic wild-type TTR proteins in the serum, and thus to a reduction in the deposition of TTR amyloid in the tissue.

RNAi is a cellular mechanism that regulates gene expression in the cell by preventing the translation of mRNA into proteins. RNAi is triggered by double-stranded RNA.

A reduction of the TTR level in the serum by approx. 75% can be achieved after just 6 weeks. After 9 months of treatment, an average reduction in TTR of approx. 85% can be achieved (Helios A study)(Adams D etal 2023). With a reduction in TTR, there is a decrease in serum vitamin A levels of approx. 60-70%.

Cardiac biomarkers (NT-proBNP and troponin I) showed relative stability compared to an increase in biomarkers as a sign of deterioration with placebo (Helios B study)(Fontana M et al 2025). The echocardiogram showed a decrease in left ventricular wall thickness and longitudinal strain with vutrisiran treatment.

Treatment with vutrisiran resulted in a reduction in the risk of mortality and cardiovascular events by approx. 30% compared to placebo (approx. 20% reduction in the risk of mortality in patients with tafamidis background therapy).

There was a statistically significant improvement in functional tests and quality of life scores in favor of treatment with vutrisiran.

Vutrisiran was non-inferior to patisiran, a previously approved siRNA for the intravenous treatment of hATTR-PN.

Absorption: occurs rapidly from the injection site; _Cmax in about 2-6 hours; plasma protein binding is high, but concentration-dependent with lower binding at high concentrations.

Metabolism: Vutrisiran is metabolized in the liver by endo- and exonucleases into short nucleotide fragments of various sizes. In humans, essentially no circulating metabolites have been found. In vitro studies indicate that vutrisiran is not metabolized by CYP450 enzymes.

Distribution: Predominantly in the liver.

Elimination: Elimination half-life approx. 2.5-6.5 hours; 15-25% of vutrisiran is excreted unchanged via the kidney.

Do not use during pregnancy and breastfeeding.

Women of childbearing age: Treatment with Vutrisiran reduces serum vitamin A levels. If vitamin A levels are too high or too low, there is an increased risk of fetal malformations! Therefore, pregnancy must be ruled out before initiating therapy and women of childbearing age must use a reliable method of contraception. If pregnancy is planned, Vutrisiran and vitamin A substitution should be discontinued and vitamin A levels monitored; vitamin A levels should have normalized and remain stable before pregnancy occurs. Vitamin A levels may be reduced for more than 12 months after the last dose of Vutrisiran.

In the case of an unplanned pregnancy, Vutrisiran should be discontinued. There is no clear recommendation as to whether vitamin A supplementation should be continued or discontinued in the first trimester of an unplanned pregnancy (check serum vitamin A levels if necessary). If vitamin A supplementation is continued, the dose should not exceed 3,000 IU per day. In the second and third trimester, supplementation with 2,500 IU to 3,000 IU vitamin A should be resumed if vitamin A levels have not normalized by then in order to avoid the risk of vitamin A deficiency.

Exceeding the dose of 3000 IU vitamin A per day can have harmful effects on the fetus and the pregnant woman.

As a precautionary measure, vitamin A and TSH levels should be measured early during pregnancy. The fetus must be closely monitored, especially in the first trimester.

It is not known whether vutrisiran passes into breast milk. It must be considered whether breastfeeding should be interrupted or whether treatment with Vutrisiran should be discontinued. Both the benefit of breastfeeding for the child and the benefit of the therapy for the woman must be considered.

For further information, see the expert information.

for advice embryotox Charité

Vitrisiran is generally well tolerated and based on the data from the phase III clinical trials (Helios A and Helios B) only the following adverse reactions were listed:

frequent:

minor and reversible irritation at the injection site.

slight reversible increases in serum teansaminases (ALT) (up to ≤3 times normal) without other clinical signs.

slight increase in alkaline phosphatase (AP).

In rare cases, patients developed anti-drug antibodies (ADA). This was only minor, reversible and without clinical symptoms or impact on the efficacy and safety of treatment with vutrisiran.

Vutrisiran is subject to increased pharmacovigilaz. Adverse reaction reporting of side effects Bund.

Hypersensitivity (e.g. anaphylaxis) to the active substance or one of the other ingredients.

Contraindicated during pregnancy and breastfeeding (see there and the information for healthcare professionals).

In severe hepatic insufficiency and severe renal insufficiency, use only with great caution and only if the expected clinical benefit exceeds the potential risk (no studies are available!).

Precautions:

Vitamin A deficiency: By reducing serum transthyretin (TTR) protein, treatment leads to a reduction in serum vitamin A (retinol) levels. Before initiating therapy, vitamin A levels should be determined and, if necessary, corrected if too low or borderline, and ocular symptoms or signs of disease due to vitamin A deficiency should be investigated, assessed and treated.

Concomitant vitamin A supplementation at a dose of approximately 2,500 IU to 3,000 IU per day (but no more) should always be given alongside therapy to reduce the potential risk of ocular symptoms due to vitamin A deficiency. Ophthalmologic evaluation of ocular symptoms is always recommended, especially in cases of decreased night vision or night blindness, persistent dry eyes, ocular inflammation, corneal inflammation or ulceration, corneal thickening or perforation.