Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The pivotal phase 3 trial (KONFIDENT) demonstrated that sebetralstat provided faster symptom relief compared to placebo, with significant improvements in primary and secondary endpoints. However, the lack of direct comparisons against active standard treatments limits the ability to claim superiority over existing therapies, which is crucial for a higher rating.
Cost effectiveness
The cost-effectiveness analysis is hampered by confidentiality around ICERs and the lack of direct comparative data. NICE indicated that the ICER was considerably higher than the acceptable threshold, which raises concerns about the therapy’s economic viability.
Quality of life
The pivotal trial did not collect HRQoL data, which is a significant gap for evaluating the treatment’s impact on patients’ overall well-being. The absence of this data leads to uncertainty in assessing the therapy’s value in terms of quality of life improvements.
Supporting Domains
Safety and Adverse Effects
The safety profile from the KONFIDENT trial showed that adverse events were comparable to placebo, with low rates of serious adverse events. This suggests a favorable safety profile, although long-term safety data are still needed.
Comparator Selection
The pivotal trial used placebo as a comparator, which is acceptable for establishing efficacy but does not provide the necessary evidence for comparative effectiveness against active treatments like icatibant or C1-INH, which are the standard of care.
Patient Population and Subgroups
The trial included a diverse population across multiple regions, and subgroup analyses were conducted. However, the lack of representation for patients with normal C1-INH limits generalizability.
Care Pathway Integration
Sebetralstat’s oral administration offers a significant advantage over parenteral therapies, suggesting a seamless integration into existing care pathways with minimal adjustments required.
Resource Use and Cost Implications
The economic implications are uncertain due to the lack of publicly available cost data and the high level of uncertainty in the economic model. This raises concerns about the therapy’s affordability and budget impact.
Evidence Quality and Robustness
The evidence base is primarily supported by a well-conducted phase 3 RCT, but the absence of head-to-head trials against active comparators introduces limitations in the robustness of the conclusions.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties regarding the economic model and the lack of direct comparative data, which could impact decision-making. However, the therapy addresses an unmet need in HAE management.
