Vutrisiran, sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA; also called RNA interference or RNAi therapeutic) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years. Vutrisiran was approved for medical use in the United States in June 2022, in the European Union in September 2022, and in Australia in June 2024.
Medical uses Vutrisiran is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. In 2025, the medication was approved by the United States Food and Drug Administration to treat familial amyloid cardiomyopathy in the U.S.
Adverse effects Vutrisiran is generally well tolerated but side effects can include injection site reactions, fatigue, arthralgia, dyspnea, diarrhea and musculoskeletal pains. Vutrisiran treatment leads to decreased Vitamin A levels and supplementation at the recommended daily allowance of vitamin A is advised. Patients should be referred to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness) develop.
Pharmacokinetics Plasma concentration profiles of vutrisiran showed rapid absorption and elimination from systemic circulation. There was a dose-proportional increase in peak plasma concentrations Cmax and a slightly greater than dose-proportional increase in AUC∞ inf and AUC last after a single subcutaneous dose across the dose range studied in the phase I trial in healthy volunteers. However, accumulation was not evident after repeated administration of vutrisiran 25 mg every 3 months in patients with hATTR amyloidosis. Plasma concentrations of vutrisiran were detectable at 10 minutes after SC administration and peak plasma concentrations were seen at a median 4 h after SC administration of a 25 mg single dose in healthy volunteers. Plasma half-life was (4.2–7.5 hours). The apparent volume of distribution of vutrisiran is estimated to be 10.1 L. Vutrisiran is 80% plasma protein bound; however, plasma protein binding is concentration dependent and decreases with increasing concentrations. Vutrisiran distributes mainly to the liver after subcutaneous administration. The plasma clearance of siRNA is primarily influenced by ASGPR-facilitated uptake into the liver where the siRNAs are gradually metabolized by endonucleases and exonucleases to short nucleotide fragments of varying sizes. After a 25 mg single dose SC vutrisiran in healthy volunteers, the median elimination half-life was 5.2 h and the median apparent clearance was 21.4 L/h. The primary pathway for excretion of vutrisiran is via the kidneys, although the fraction of renal clearance to total clearance was 15.5–27.5% after a single 5–300 mg subcutaneous dose in healthy volunteers, indicating that renal excretion is a minor route of elimination. Across the dose levels tested, mean renal CLR of vutrisiran ranged from 4.45 to 5.74 L/hour (mean, 5 L/hour) after a single subcutaneous dose in healthy volunteers and the percentage of vutrisiran dose excreted unchanged in urine through 24 hours ranged between 15 and 25% and increased slightly with increasing dose, with a majority excreted within the first 12 hours after administration. Age, sex, bodyweight, race, and mild or moderate kidney impairment or mild hepatic impairment do not have clinically significant effects on vutrisiran pharmacokinetics. In vitro, vutrisiran was neither a substrate nor inhibitor of cytochrome P450 enzymes and is not expected to cause drug- drug interaction by inducing CYP enzymes. Vutrisiran is not expected to modulate drug transporter activities.
Mechanism of action Vutrisiran is a gene silencing double-stranded siRNA-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through RNA interference by binding and silencing messenger RNA (mRNA) encoding for disease causing protein (Transthyretin), which results in a reduction of serum TTR protein and TTR protein deposits in tissues. Vutrisiran utilises a GalNAc conjugate delivery platform which is an enhanced stabilisation chemistry. This allows subcutaneous administration of smaller doses with longer dosing intervals.
History The U.S. Food and Drug Administration (FDA) granted the application for vutrisiran orphan drug designation.
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