Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The pivotal phase 3 MYR301 trial demonstrated moderate clinical effectiveness with a combined primary endpoint achieved in 45% to 48% of patients receiving bulevirtide compared to 2% in the control group. While these results indicate a significant improvement over delayed treatment, the reliance on surrogate endpoints rather than direct clinical outcomes limits the strength of the evidence.
Cost effectiveness
Cost-effectiveness estimates vary significantly across jurisdictions, with NICE suggesting acceptable ICERs around £27,000 per QALY, while NCPE found the ICER to be unacceptably high at Û193,273 per QALY. This divergence indicates a lack of stability in the economic evaluation, warranting a rating of low cost-effectiveness.
Quality of life
The exploratory analysis indicated some improvements in HRQoL measures, particularly on the EQ-5D-3L visual analogue scale. However, the absence of robust, validated utility values specific to bulevirtide limits the ability to quantify these benefits definitively, leading to a rating of questionable benefit.
Supporting Domains
Safety and Adverse Effects
Bulevirtide has a favorable safety profile with manageable adverse effects, primarily injection-site reactions and mild to moderate symptoms. The absence of serious adverse events in the phase 3 trial supports a strong safety rating, although there are significant concerns regarding exacerbation of hepatitis after discontinuation.
Comparator Selection
The phase 3 trial compared bulevirtide to delayed treatment, which is considered best supportive care. However, the lack of direct comparison with active treatments like peginterferon limits the robustness of the evidence, leading to a rating of suboptimal comparator selection.
Patient Population and Subgroups
The trial population included adults without cirrhosis or with compensated cirrhosis, which is relevant for the intended use. However, the limited representation of older patients and those with decompensated cirrhosis introduces some concerns about generalizability, justifying a moderate rating.
Care Pathway Integration
Bulevirtide can be integrated into existing care pathways for hepatitis management, although it requires daily self-injection and monitoring. The operational feasibility in specialized centers supports a strong rating for integration.
Resource Use and Cost Implications
The evidence indicates a substantial cost burden due to the high price of bulevirtide and additional healthcare resource use for monitoring and administration. However, the lack of detailed cost analyses limits the ability to assess the overall economic impact accurately.
Evidence Quality and Robustness
The evidence base is primarily supported by a randomized phase 3 trial with long-term follow-up data. However, the reliance on surrogate endpoints and the variability in economic evaluations across HTA bodies introduce some concerns about the robustness of the evidence.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties regarding the long-term clinical benefits and cost-effectiveness of bulevirtide, particularly due to the reliance on surrogate endpoints and variable economic models. This uncertainty warrants a rating of high concern.
