Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical evidence from the APeX-2 trial indicates that berotralstat significantly reduces the mean monthly attack rate by 44% compared to placebo, which is a moderate benefit. However, the evidence on attack severity is less robust, as the subjective measures of severity were not included in the analysis due to credibility concerns. Thus, while there is a clear benefit in terms of attack frequency, the lack of data on severity limits the overall effectiveness rating.
Cost effectiveness
The cost-effectiveness analysis indicates that berotralstat is within the range typically considered acceptable by NICE, with an ICER estimated to be between £20,000 and £30,000 per QALY gained. This suggests that the treatment is clearly cost-effective under common thresholds, especially given the commercial arrangement that provides a discount.
Quality of life
The committee acknowledged that while the treatment reduces attack rates, the impact on quality of life is not fully captured due to the limitations in the utility values used. The patient experts indicated that a reduction in attack frequency could significantly improve quality of life, but the analysis did not adequately reflect the severity of attacks. Therefore, while there are positive indications, the evidence is moderate.
Supporting Domains
Safety and Adverse Effects
The safety profile of berotralstat is considered very good, with mostly mild to moderate adverse events reported. The committee noted that the treatment does not introduce significant new risks compared to existing therapies, which supports a strong tolerability rating.
Comparator Selection
The company compared berotralstat against standard care, which includes C1-IHealthcare and other treatments. The committee agreed that this was an appropriate comparator, although it noted that the comparison was narrower than initially specified. Overall, the choice of comparators is acceptable.
Patient Population and Subgroups
The trial population included patients with hereditary angioedema aged 12 years and older, but the subgroup analysis focused on those with at least 2 attacks per month, which narrows the generalizability. While the committee recognized the rationale for this focus, it also highlighted concerns about the representativeness of the population.
Care Pathway Integration
Berotralstat is positioned as an oral prophylactic treatment, which is a significant improvement over existing injectable options. The committee noted that this could facilitate easier integration into current care pathways, although some adjustments may be necessary for implementation.
Resource Use and Cost Implications
The economic model indicates that berotralstat is likely to reduce overall healthcare costs associated with managing acute attacks due to its prophylactic nature. The committee concluded that the resource implications are manageable and justifiable given the treatment’s benefits.
Evidence Quality and Robustness
The evidence is primarily derived from a Phase 3 RCT (APeX-2), which is a strong design. However, concerns about the small sample size and the subjective measures of attack severity introduce some limitations. Overall, the evidence is credible but has some methodological concerns.
Uncertainty, Sensitivity, and Broader Impacts
While there are uncertainties regarding the long-term effects and the impact of the continuation rule, the committee noted that these are manageable within the context of the unmet need for effective treatments for hereditary angioedema. The societal context supports the use of berotralstat.
