Vutrisiran for transthyretin amyloidosis

Background:
Hereditary transthyretin amyloidosis (hATTR, also known as ATTRv) is a rare, autosomal dominant, multisystem condition caused by mutations or variants in the transthyretin (TTR) gene. TTR is a protein predominantly produced in the liver that transports thyroxine and retinol-binding proteins, so affects serum vitamin A concentration. Genetic variants in the TTR gene result in misfolding of the TTR protein, destabilising the structure, and ultimately resulting in the formation of abnormal, insoluble amyloid fibrils. These amyloid fibrils deposit throughout the body, predominantly in extracellular tissue, leading to multisystem disease, debilitating morbidity and high mortality.^1,2 Whilst the peripheral nervous system and heart are most commonly affected, organ involvement may include the kidney, eyes, central nervous and gastrointestinal systems; hence, clinical presentation is widely variable.^1,2

The current approval is only for adults with polyneuropathy due to hATTR and a proven genetic variant; either stage 1 (unimpaired ambulation; mild sensory, motor and autonomic lower limb neuropathy) or stage 2 (assistance with ambulation required; moderate impairment of the lower limbs, upper limbs and trunk).² Patisiran was approved in 2022 for the same indication as vutrisiran and is in the same class of drugs.³ Vutrisiran acts via a similar mechanism of action to patisiran but has increased stability and tolerability, and therefore requires smaller doses with a longer dosing interval.

Mechanism of action:
Vutrisiran is a TTR gene silencer; one of a group of drugs that acts via small RNA-interfering agents to reduce production of the TTR protein in the liver, and therefore amyloid fibril production and disease progression.^2,4

Clinical trials:
Vutrisiran was approved for treatment of hATTR in adults with stage 1 or stage 2 polyneuropathy based on outcomes from the HELIOS-A trial – a global, open-label, randomised study comparing vutrisiran to patisiran and an external placebo group (77 patients from the APOLLO phase 3 double-blind, randomised trial that compared patisiran with placebo in a similar population of patients with hATTR polyneuropathy).⁵ Patients were randomised 3:1 to receive 25 mg of vutrisiran (n=122) subcutaneously every 3 months, or 0.3 mg/kg of patisiran (n=42) intravenously every 3 weeks over 18 months. All patients received vitamin A supplementation of 2500 international units daily. Ninety-seven percent of participants completed 18 months of treatment. The median patient age at baseline of those who received vutrisiran was 60 years (range 34 to 80 years), 38% were 65 years or older, and 65% of patients were male.

The primary endpoint was a change from baseline to month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is a composite measure of motor, sensory and autonomic neuropathy that includes motor strength, reflexes, quantitative sensory testing, nerve conduction studies and postural blood pressure, with the score ranging from 0 to 304 points, where an increasing score indicates worsening impairment.

Secondary endpoints included change from baseline to month 18 in the Norfolk Quality of Life-Diabetic Neuropathy (QoL‑DN) total score, gait speed (10-meter walk test [10‑MWT]), nutritional status (modified BMI), and patient-reported ability to perform activities of daily living and social participation (Rasch-built Overall Disability Scale [R‑ODS]). The range of endpoints reflect the wide-ranging disease burden of hATTR. Serum TTR concentrations were reduced in less than 3 weeks and sustained at 18 months, with 87.6% and 81% reduction in vutrisiran and patisiran groups respectively.

Vutrisiran was assessed as noninferior to patisiran. Compared with placebo, treatment with vutrisiran demonstrated statistically significant improvement from baseline to month 9 (mNIS+7, QoL‑DN and 10‑MWT) and month 18 (all endpoints) (Table 1). In addition, approximately half of patients demonstrated reversal in some manifestations of disease.⁶

Table 1 Percentage of patients with improvement in mNIS+7 and QoL‑DN after 9 months and after 18 months of vutrisiran treatment compared with placebo⁶

	Duration of treatment
	9 months		18 months
	Placebo	Vutrisiran	Placebo	Vutrisiran
mNIS+7	18.2%	50.4%	3.9%	48.3%
QoL‑DN	23.4%	53.4%	10.4%	56.8%
mNIS+7 = modified Neuropathy Impairment Score +7; QoL‑DN = Norfolk Quality of Life-Diabetic Neuropathy score

Adverse effects:
Although most patients (97.5%) in the vutrisiran group reported adverse events, the majority were mild or moderate in severity, and most were consistent with the underlying disease. Adverse events occurring in 10% or more of patients were falls, pain in extremity, diarrhoea, peripheral oedema, urinary tract infection, arthralgia and dizziness, with all except pain in extremity and arthralgia occurring at a similar or lower rate than in the external placebo group. Five patients (4.1%) reported mild and transient reactions at the injection site. There were 2 deaths in the vutrisiran group and 3 in the patisiran group, with none being considered drug-related.⁶

Dosage and administration:
The dosage of vutrisiran is 25 mg administered via subcutaneous injection every 3 months by a health professional.⁷ Premedication is not required. Vutrisiran must be prescribed by, or in consultation with, an amyloid expert. Delivery is typically initially at an amyloid specialist service but, once established on therapy, may be performed by a general practitioner or local health service.

No dose adjustment is required for patients aged 65 years or older, with mild hepatic impairment, or with moderate renal impairment (estimated glomerular filtration rate over 30 mL/min/1.73 m²).

There are no data for use in patients younger than 18 years.⁷

Precautions:
Vutrisiran use can lead to vitamin A deficiency, due to reduced circulating concentration of TTR, reducing serum retinol. Vitamin A deficiency should be corrected prior to starting vutrisiran, and vitamin A supplements are required while on treatment.⁷ Serum monitoring of vitamin A is not accurate while on vutrisiran as alternative transport and storage mechanisms can occur in the absence of retinol-binding TTR.⁷ Ophthalmological assessment at baseline and yearly is recommended.

Vutrisiran has not been studied in the context of hepatic or renal impairment,⁷ although no ocular, hepatic or renal safety concerns have been reported in pooled safety data.⁸

Use in pregnancy and breastfeeding:
Vutrisiran is classified as Therapeutic Goods Administration pregnancy category D and should not be used in pregnancy, mainly because of known teratogenicity of vitamin A levels that are either too high or too low. Pregnancy should be excluded prior to starting vutrisiran and avoided while on treatment. If pregnancy is planned, vutrisiran and vitamin A supplementation should be stopped. Vitamin A should be monitored and confirmed as normal prior to conception.

It is not known whether vutrisiran is excreted in human milk and breastfeeding is not recommended.⁷

Place in therapy:
Vutrisiran is effective in preventing progression of disease in patients with polyneuropathy due to hATTR. Vutrisiran is first-line therapy for patients with hATTR and evidence of polyneuropathy with or without concurrent cardiomyopathy. Vutrisiran will replace patisiran, as it was demonstrated in trial to be noninferior, and has better tolerability and a more favourable dosing regimen. Patisiran will be withdrawn from the Australian market and patients currently treated with partisiran will transition to vutrisiran.

Practice points:
Treatment with vutrisiran should be started and monitored by an hATTR specialist service and vitamin A supplementation is required while on treatment.

This new drug comment was finalised on 13 January 2026. It was prepared by Mary Belfrage, Clinical Editor, Australian Prescriber, and reviewed by Natasha Gorrie, Cardiologist, St Vincent's Hospital Sydney and PhD candidate, Victor Chang Cardiac Research Institute, Sydney.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

This article is peer reviewed.

 

References

1. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care. Ther Clin Risk Manag 2020;16:109-23.
2. Therapeutic Goods Administration. Australian Public Assessment Report for Amvuttra. Department of Health, Disability and Ageing; 2024. [cited 2026 Jan 13]
3. Therapeutic Goods Administration. Australian Product Information - ONPATTRO patisiran concentrated injection for infusion vial. Department of Health, Disability and Ageing; 2022. [cited 2025 Jan 13]
4. Patel AGM, Li P, Badrish N, Kesari A, Shah KB. Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies. Curr Cardiol Rep 2025;27:33.
5. Maurer MS, Kale P, Fontana M, Berk JL, Grogan M, Gustafsson F, et al. Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis. N Engl J Med 2023;389:1553-65.
6. Adams D, Tournev IL, Taylor MS, Coelho T, Plante-Bordeneuve V, Berk JL, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 2023;30:1-9.
7. Therapeutic Goods Administration. Australian Product Information - AMVUTTRA vutrisiran (as sodium) solution for injection pre-filled syringe. Department of Health, Disability and Ageing; 2024. [cited 2025 Jan 13]
8. Witteles RM, Garcia-Pavia P, Morbach C, Gillmore JD, Taylor MS, Conceicao I, et al. Vutrisiran in Transthyretin Amyloidosis: A Pooled Safety Analysis of HELIOS-A and HELIOS-B. JACC Adv 2025;4:102066.

 

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