The Scottish Medicines Consortium (SMC) has accepted vutrisiran sodium (Amvuttra, Alnylam UK Ltd) for restricted use in NHS Scotland as monotherapy in adults with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

The advice applies only under an approved patient access scheme (PAS) that delivers the cost-effectiveness results on which the decision was based, or at a PAS or list price that is equivalent or lower.

New Option for ATTR-CM 

ATTR-CM is a rare, fatal condition in which transthyretin (TTR) amyloid deposits stiffen the heart and lead to heart failure. TTR is produced in the liver, and amyloid can also accumulate in the peripheral nerves and gastrointestinal tract.

Wild-type ATTR-CM arises when TTR becomes structurally unstable with age. Hereditary ATTR-CM is caused by one of more than 120 TTR gene mutations. 

Tafamidis, an oral TTR stabiliser, is the only therapy currently accepted for use in Scotland for wild-type and hereditary ATTR-CM. Other management approaches include diuretics for congestive symptoms and treatments for arrhythmias and conduction abnormalities. Cardiac or liver transplantation may be considered in selected patients, but advanced age and comorbidities mean transplantation is rarely an option.

Vutrisiran is a small interfering RNA therapy that targets and suppresses hepatic synthesis of both wild-type and variant TTR protein via RNA interference. By lowering circulating TTR levels, it reduces tissue TTR amyloid deposition. 

Trial Evidence on Survival and Function 

The decision draws on HELIOS-B, a phase 3 trial of 655 patients with ATTR-CM and a history of heart failure. Participants were randomised to receive vutrisiran 25 mg or placebo via subcutaneous injection every 12 weeks for up to 36 months. 

The co-primary endpoints were a composite of all-cause mortality and recurrent cardiovascular events, defined as cardiovascular hospitalisations and urgent visits for heart failure, assessed in the overall population and in the vutrisiran monotherapy subgroup. The monotherapy subgroup comprised patients not receiving tafamidis at baseline; this is the population covered by the SMC restriction.

Vutrisiran significantly reduced the risk for the composite outcome versus placebo in both the overall population (hazard ratio [HR], 0.72; 95% CI, 0.56-0.93) and the monotherapy subgroup (HR, 0.67; 95% CI, 0.49-0.93).

All-cause mortality at 42 months was 18% with vutrisiran vs 26% with placebo in the overall population (HR, 0.65; 95% CI, 0.46-0.90) and 22% vs 29% in the monotherapy subgroup (HR, 0.66; 95% CI, 0.44-0.97). 

At 30 months, in the overall population, vutrisiran also slowed the decline in 6-minute walk distance (least-squares mean change -45.4 m vs -71.9 m; difference, 26.5 m; 95% CI, 13.4-39.6) and in health status measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score (-9.7 vs -15.5 points; difference, 5.8 points; 95% CI, 2.4-9.2).

Safety and Prescribing Information 

The safety profile of vutrisiran was consistent with that already known, with no new safety concerns identified. At the primary analysis, adverse events occurred in 99% of patients receiving vutrisiran and 98% of those receiving placebo. Serious adverse events were reported in 62% and 67%, respectively, and adverse events led to treatment discontinuation in 3.1% and 4.0%.

The most frequently reported serious adverse events in either group were cardiac failure (12% vs 17%), atrial fibrillation (8.0% vs 6.1%) and acute cardiac failure (4.0% vs 5.5%).

The recommended dose is 25 mg by subcutaneous injection once every 3 months. Patients should take vitamin A supplements providing approximately 2500-3000 IU daily, and ophthalmologic assessment is advised if ocular symptoms suggestive of vitamin A deficiency develop. Treatment should be started as early as possible in the disease course to prevent accumulating disability.

SMC chair Dr Rob Peel said in a statement: "Vutrisiran offers another treatment option for patients with ATTR-CM, that is administered in a different way from the currently available option and may suit some patients better."

Uncertainties Flagged by the SMC 

The SMC noted that data are limited for indirect comparisons between vutrisiran and tafamidis. A post hoc in-study comparison of the two monotherapies found no evidence of a difference in the composite outcome (HR, 0.83; 95% CI, 0.54-1.29), but it was not pre-specified and may be biased because patients in the tafamidis group were probably already benefiting at baseline.

HELIOS-B was not designed to establish the benefit of adding vutrisiran to tafamidis. The SMC also noted uncertainty over efficacy in hereditary ATTR-CM, which made up only 12% of participants. Subgroup analysis suggested possibly lower benefit than in wild-type disease, but the subgroup was small and results should be interpreted with caution.

Clinical experts consulted by the SMC considered vutrisiran a therapeutic advance because of its novel mechanism of action, and an effective alternative to tafamidis.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.