Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Inclisiran shows comparable efficacy to existing options, as it significantly reduces LDL-C levels based on the results from the ORION trials. However, there is no direct comparison with other lipid-lowering therapies like ezetimibe, alirocumab, or evolocumab, and the long-term impact on cardiovascular events remains uncertain. Thus, it meets non-inferiority but lacks a clear edge over existing treatments.
Cost effectiveness
Inclisiran is considered cost-effective for secondary prevention populations with a history of cardiovascular events, with ICERs below £20,000 per QALY gained. However, for primary prevention populations, the cost-effectiveness estimates are highly uncertain and likely above acceptable thresholds, which affects the overall rating.
Quality of life
While inclisiran is expected to improve adherence due to its twice-yearly dosing schedule, there is no substantial evidence presented that demonstrates significant improvements in quality of life metrics compared to standard care. The committee concluded that any potential benefits are likely captured in the QALY calculations.
Supporting Domains
Safety and Adverse Effects
Inclisiran has an acceptable safety profile, with adverse events similar to placebo, except for a higher incidence of injection site reactions. The overall tolerability appears good, with manageable adverse events.
Comparator Selection
The committee concluded that the appropriate comparators include ezetimibe, alirocumab, evolocumab, and maximum tolerated statins. However, the company did not consider ezetimibe as a relevant comparator initially, which raises concerns about the robustness of the evidence.
Patient Population and Subgroups
The populations included in the submission are clinically relevant, although they are narrower than inclisiran’s marketing authorization. The committee noted that the populations are well-defined and relevant to the intended use of the therapy.
Care Pathway Integration
Inclisiran is likely to be integrated into primary care settings with manageable adjustments needed. The committee noted that there are plans to support its implementation, indicating a good fit within existing healthcare pathways.
Resource Use and Cost Implications
While inclisiran is expected to be cost-effective in certain populations, the overall budget impact is high, particularly in primary prevention populations. This raises concerns about the resource burden on the healthcare system.
Evidence Quality and Robustness
The evidence is based on three randomized controlled trials, which provide a solid foundation. However, the lack of long-term data on cardiovascular outcomes and uncertainties in the indirect treatment comparisons introduce some concerns about the robustness of the evidence.
Uncertainty, Sensitivity, and Broader Impacts
There is significant uncertainty regarding the long-term effectiveness of inclisiran on cardiovascular outcomes, which is a major driver of cost-effectiveness results. The committee noted that ongoing trials may address these uncertainties, but they currently limit the confidence in the appraisal.
