Vutrisiran

Introduction Overview

Generic Name

vutrisiran

Brand Name

Amvuttra

Dosage Form

single-dose prefilled syringe (25 mg/0.5 mL), subcutaneous injection

Drug Class

Miscellaneous metabolic agents

Pharmacokinetics

Absorption

Vutrisiran is administered via subcutaneous injection and demonstrates efficient absorption into the systemic circulation through the subcutaneous tissue. Injection sites include the abdomen (excluding the area within two inches of the umbilicus), upper thighs, and posterior upper arms. Pharmacokinetic studies indicate a gradual absorption profile appropriate for the drug's extended dosing interval, with sufficient bioavailability to exert therapeutic effects. Absorption is not significantly affected by food intake, allowing flexibility in administration timing relative to meals.

Distribution

Upon absorption, vutrisiran is preferentially targeted to hepatocytes in the liver due to conjugation with N-acetylgalactosamine (GalNAc) moieties, which facilitate high-affinity binding to the asialoglycoprotein receptor abundantly expressed on hepatic cells. This targeted delivery results in efficient hepatic uptake, the primary site for transthyretin (TTR) synthesis. The volume of distribution is limited predominantly to liver tissue with minimal systemic distribution elsewhere. Plasma protein binding is moderate, facilitating hepatic targeting while limiting peripheral exposure. Tissue distribution studies confirm high liver concentrations with low accumulation in other organs, which reduces off-target effects.

Metabolism

Vutrisiran is an siRNA therapeutic and undergoes metabolism primarily by endogenous nucleases throughout the body. The drug is cleaved into shorter oligonucleotide fragments and nucleotides, which are further degraded and recycled via normal nucleic acid metabolism pathways. Unlike small molecules, it is not metabolized by the cytochrome P450 enzyme system or other phase I/II hepatic enzymes, reducing the potential for typical drug-drug interactions. The siRNA backbone modification confers stability against rapid degradation, allowing for sustained action over several months.

Elimination

Elimination of vutrisiran and its metabolites occurs mainly through renal excretion of nucleic acid fragments after metabolic breakdown. The intact drug is not excreted unchanged in urine. The elimination half-life supports a dosing schedule of once every three months. There is no accumulation with repeated doses administered according to recommended intervals. Hepatic or renal impairment has not been shown to significantly affect elimination, though clinical data in severely impaired patients remain limited. No significant biliary excretion or fecal elimination of intact drug has been reported.

Dosage Forms

Adults

Amvuttra is administered as a subcutaneous injection of 25 mg vutrisiran once every three months (quarterly). Injection sites include the abdomen (avoiding a 2-inch radius around the navel), upper thighs, or upper arms. The dosing regimen is consistent across adult patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) or amyloid cardiomyopathy (ATTR-CM). Vitamin A supplementation is recommended concomitantly due to drug-associated reductions in vitamin A levels.

Adolescents

Safety and efficacy of Amvuttra have not been established in pediatric populations; hence, it is not recommended for use in children and adolescents under 18 years of age. Clinical trials have been conducted only in adult patients, and there is a lack of dosing guidelines for younger age groups.

Special Populations

In patients with hepatic or renal impairment, no dose adjustments are currently recommended due to the drug’s targeted hepatic delivery and metabolic pathway via nucleases. However, limited data are available in severe impairment cases. Amvuttra is not recommended in pregnancy due to potential harm to the unborn baby from vitamin A depletion, and women of childbearing potential should use effective contraception. Breastfeeding safety is unknown; therefore, caution is advised. Elderly patients tolerate the drug comparably to younger adults without dose adjustment requirements. The drug should be administered under healthcare provider supervision for all populations.

Mechanism Of Action

Amvuttra (vutrisiran) is a small interfering RNA (siRNA) therapeutic designed to specifically target and degrade transthyretin (TTR) messenger RNA (mRNA) in hepatocytes, the liver cells responsible for producing the majority of circulating TTR protein. The drug is conjugated to N-acetylgalactosamine (GalNAc) ligands that facilitate high-affinity binding to asialoglycoprotein receptors on hepatocytes, enabling precise delivery and uptake via receptor-mediated endocytosis. Once inside the cells, vutrisiran engages the RNA-induced silencing complex (RISC) which recognizes and cleaves TTR mRNA, leading to decreased translation into TTR protein. This reduction in synthesis lowers both normal and mutated TTR protein levels in plasma, mitigating the formation of amyloid fibrils that deposit in peripheral nerves, heart, and other tissues, thereby slowing or reversing disease progression in hereditary transthyretin-mediated amyloidosis (hATTR) and wild-type ATTR amyloidosis. By selectively degrading TTR mRNA, vutrisiran differs mechanistically from TTR stabilizers such as tafamidis, which prevent tetramer dissociation but do not reduce TTR protein production. Clinical evidence demonstrates that sustained suppression of TTR translation improves neuropathy measures, quality of life, and cardiac outcomes in affected patients. The siRNA mechanism confers high specificity and durable effects with infrequent dosing intervals, representing an advanced modality in RNA interference therapeutics for systemic amyloid diseases.

Pharmacological Actions

Selective RNA interference-mediated silencing of transthyretin (TTR) gene expression in hepatocytes
Reduction of both mutant and wild-type soluble TTR protein levels in plasma
Prevention of amyloid fibril formation by lowering circulating precursor TTR
Improvement in peripheral nerve function and reduction in polyneuropathy progression
Decrease in amyloid deposition in cardiac tissue leading to improved cardiac function
Long-acting suppression of TTR synthesis allowing once every three months administration
Targeted delivery to the liver via GalNAc conjugation minimizing systemic exposure
Minimal off-target effects due to high specificity of siRNA mechanism

Therapeutic Clinical Uses

Treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults
Reduction of cardiovascular mortality and morbidity in wild-type or hereditary transthyretin-mediated amyloid cardiomyopathy (ATTR-CM)
Slowing progression and improving neurological function in hATTR amyloidosis patients
Improvement in functional capacity, quality of life, and nutritional status in amyloid patients
Reduction of hospitalization and urgent heart failure visits in cardiac amyloidosis
Use as a novel RNAi therapeutic targeting a genetic cause of systemic amyloidosis
Potential to improve walking speed and activities of daily living in affected patients
Adjunct therapy with vitamin A supplementation to prevent deficiency-related complications

Side Or Adverse Effects

Injection site reactions including pain, swelling, redness
Peripheral neuropathic pain in hands and feet
Joint pain (arthralgia)
Shortness of breath (dyspnea)
Decreased plasma vitamin A levels leading to potential deficiency
Rare vision disturbances related to vitamin A deficiency such as night blindness
Potential hypersensitivity or allergic reactions to drug components
Fatigue or malaise reported in some patients
Occasional mild gastrointestinal discomfort
Possible transient elevation in liver enzymes not clinically significant
No significant renal toxicity reported with standard dosing
Serious adverse effects reported are rare but include low vitamin A-related complications

Precautions

Monitor vitamin A levels during therapy and ensure appropriate supplementation
Advise patients to report visual symptoms such as difficulty seeing at night immediately
Use caution in pregnant women due to risk of fetal harm secondary to vitamin A deficiency
Advise women of childbearing potential to use effective contraception during treatment
Monitor for injection site reactions and manage accordingly
Regularly assess neurological and cardiac function to evaluate therapeutic response
Caution in patients with known allergies to drug components or excipients
Educate patients about the importance of adherence to quarterly dosing to maintain efficacy
Consider monitoring liver function tests periodically
Avoid concomitant use of vitamin A supplements exceeding prescribed amounts to prevent toxicity
Inform patients regarding the potential for respiratory symptoms and assess if they develop shortness of breath
Ensure patients are informed about storage requirements to maintain drug stability

Warnings

Amvuttra lowers circulating vitamin A levels which may lead to severe vitamin A deficiency if untreated
Vitamin A deficiency can cause serious adverse effects including night blindness and other vision problems
Pregnancy is contraindicated without stringent vitamin A management due to risk of harm to fetus
Drug is indicated only for adult use; safety in pediatric patients is unknown
Potential risk of serious hypersensitivity reactions; monitor during and after injection
Patients should be advised to seek immediate medical attention for any signs of vision impairment
Injection site reactions are common but generally mild; severe reactions are rare
Lack of long-term safety data beyond clinical trial durations limits understanding of prolonged use consequences
Risk of worsening of symptoms if doses are missed and therapy interrupted
No significant drug-drug interactions known but clinical vigilance recommended
Use with caution in patients with preexisting sensory neuropathies or cardiac dysfunction
Storage outside recommended temperatures may compromise drug effectiveness

Contraindications

Known hypersensitivity to vutrisiran or any component of the formulation
Pregnancy unless under strict vitamin A supplementation and medical supervision due to potential fetal harm
Pediatric patients under 18 years of age due to absence of safety and efficacy data
Patients with untreated vitamin A deficiency at baseline
Use in breastfeeding mothers unless benefits outweigh risks and under medical guidance
Known hypersensitivity or severe allergic reactions to RNA interference therapies
Patients unable to adhere to regular dosing schedules and vitamin supplementation
Concurrent use of high-dose vitamin A supplements exceeding prescribed amounts
Severe hepatic impairment pending further clinical data
Patients with active infection or uncontrolled comorbid conditions contraindicating immunomodulatory effects

Drug Interactions

No clinically significant drug-drug interactions identified to date
Does not interact with cytochrome P450 enzymatic pathways reducing interaction potential
No observed interactions with common cardiovascular or neuropathy medications
Concurrent use of vitamin A supplements required; avoidance of excess dosing necessary to prevent toxicity
No formal studies on interactions with herbal or over-the-counter supplements; caution advised
Potential for additive effects with other hepatically targeted therapies not established
No known interactions with anticoagulants or antiplatelet drugs
Lacks interaction with drugs metabolized via renal pathways
Potential interaction with immunosuppressants is not reported
No evidence of interactions affecting plasma protein binding
Drug transporters appear unaffected by vutrisiran
Caution with concurrent use of other RNAi or antisense oligonucleotides due to theoretical overlapping toxicities

Preparations Of The Drug

Prefilled single-dose syringe containing 25 mg of vutrisiran in 0.5 mL solution
Stable aqueous solution containing active ingredient and inactive excipients (water, sodium hydroxide, phosphoric acid, sodium phosphate monobasic and dibasic dihydrates, sodium chloride)
Supplied in original carton to protect from moisture and light
Intended for subcutaneous injection administered by a healthcare provider
Stored at controlled temperature 2°C to 30°C (36°F to 86°F), do not freeze
No generic formulations available as of current approvals
No oral, intravenous, or alternative dosage forms developed yet
Packaging designed to facilitate once-every-three-month administration schedule
Comes with patient information leaflet specifying injection sites and vitamin A supplementation instructions