Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Cenobamate shows moderate benefit in reducing seizure frequency, with 40.2% to 64.2% of patients achieving at least a 50% reduction in seizures across different doses in clinical trials. However, the evidence is limited to short-term studies and lacks direct comparisons with other treatments, leading to a modest margin of benefit.
Cost effectiveness
Cenobamate is considered cost-effective, with an ICER of £20,522 per QALY gained, which is within acceptable thresholds for Healthcare resources. The committee concluded that cenobamate dominates other treatments, being both more effective and less costly in certain scenarios.
Quality of life
While cenobamate may improve seizure control, the evidence regarding its impact on HRQoL is limited and mixed. The clinical experts noted that a 50% reduction in seizures may not significantly enhance daily functioning or independence, indicating minimal or uncertain impact on quality of life.
Supporting Domains
Safety and Adverse Effects
Cenobamate has an acceptable safety profile, with adverse events primarily being mild to moderate. However, there are concerns about the potential for higher rates of treatment-emergent adverse events compared to some comparators, which necessitates cautious use.
Comparator Selection
The comparators selected for the network meta-analysis were primarily ‘third generation’ medicines, which may not fully represent the range of available treatments. The committee noted that older treatments were not adequately considered, leading to potential gaps in the evidence base.
Patient Population and Subgroups
The patient population in the trials is broadly representative of those likely to receive cenobamate in clinical practice, with high baseline seizure rates. However, the exclusion of individuals with psychiatric comorbidities may limit generalizability.
Care Pathway Integration
Cenobamate can be integrated into existing care pathways with minor adjustments, as it is administered once daily, which is more convenient than many other antiseizure medications. This ease of integration supports its use in clinical practice.
Resource Use and Cost Implications
The resource use estimates provided by the company were based on clinical opinion and may overestimate costs. The committee expressed concerns about the validity of these estimates, indicating a moderate risk in resource implications.
Evidence Quality and Robustness
The evidence base includes two randomized controlled trials, which provide a strong foundation for the assessment. However, the reliance on short-term data and the absence of long-term comparative evidence introduce some methodological concerns.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties regarding the long-term effectiveness and safety of cenobamate, particularly due to the potential for attrition bias in the open-label studies. This uncertainty may restrict its use until more data is available.
