Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The evidence indicates that vutrisiran has comparable efficacy to tafamidis, meeting non-inferiority but lacking a clear edge. The committee concluded that vutrisiran is likely to work as well as tafamidis, but the lack of direct head-to-head trials and the uncertainties in indirect comparisons limit the strength of the evidence.
Cost effectiveness
The cost-minimisation analysis suggests that vutrisiran is likely to be cost-effective compared to tafamidis, with costs being similar or lower. The committee concluded that the economic model supports the use of vutrisiran within the NHS.
Quality of life
While the evidence suggests some potential benefits in HRQoL, the data is not robust, and the committee noted that the impact on carer quality of life was not fully evidenced. The lack of significant improvements in validated HRQoL measures leads to a cautious rating.
Supporting Domains
Safety and Adverse Effects
The safety profile of vutrisiran appears acceptable, with serious adverse events being comparable to tafamidis. The committee noted that while some adverse events were higher in the vutrisiran group, the overall tolerability is considered good.
Comparator Selection
The primary comparator, tafamidis, was appropriate; however, the lack of direct comparison and reliance on indirect evidence introduces uncertainty. The committee acknowledged that the evidence for best supportive care as a comparator was not fully explored.
Patient Population and Subgroups
The trial population is generally representative of the intended patient population with ATTR-CM. However, there are some limitations in subgroup analyses, particularly regarding hereditary versus wild-type forms.
Care Pathway Integration
Vutrisiran can be integrated into existing care pathways with minor adjustments, such as home administration. The committee noted that the treatment initiation may shift to home settings in the future, which supports its integration.
Resource Use and Cost Implications
The budget impact is manageable, and the analysis indicates that the resource use associated with vutrisiran is justifiable given the expected outcomes. The committee concluded that the economic implications are reasonable.
Evidence Quality and Robustness
While the HELIOS-B trial provides robust evidence, the uncertainties in the indirect comparisons and the non-randomised nature of some analyses raise concerns about the overall robustness of the evidence.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties regarding the clinical effectiveness and economic modelling, particularly concerning the assumptions made in the analyses. The committee noted these uncertainties but did not find them sufficient to reject the treatment.
