Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical trials APPOINT-PNH and APPLY-PNH provide strong evidence of iptacopan’s effectiveness in increasing hemoglobin levels and reducing the need for blood transfusions. In APPOINT-PNH, 92.2% of participants achieved a haematological response at 24 weeks, and 97.4% at 48 weeks. In APPLY-PNH, iptacopan showed a significant increase in hemoglobin compared to C5 inhibitors, with 82.3% achieving an increase of 2 g/dl or more at 24 weeks. However, the indirect comparisons with C5 inhibitors introduce some uncertainty, preventing a higher rating.
Cost effectiveness
The cost-effectiveness estimates for iptacopan are within the range that NICE considers acceptable for Healthcare resources. The committee concluded that the ICERs presented were defensible, although they noted high uncertainty regarding the relative effects compared to C5 inhibitors and pegcetacoplan. The economic model was consistent with previous evaluations, supporting its cost-effectiveness.
Quality of life
The evidence suggests that iptacopan improves health-related quality of life due to its oral administration and better haematological response, leading to less fatigue. Patient experts noted that the oral treatment allows for greater independence and fewer hospital visits, which positively impacts daily life. However, the data on HRQoL improvements is based on treatment-dependent utility values, which introduces some uncertainty.
Supporting Domains
Safety and Adverse Effects
Iptacopan has a favorable safety profile, with adverse effects primarily being mild to moderate. The committee noted that the oral administration reduces the risks associated with intravenous or subcutaneous treatments. There were no significant safety concerns raised in the trials, supporting a very good tolerability rating.
Comparator Selection
The committee identified ravulizumab and pegcetacoplan as the most relevant comparators for iptacopan. The evidence includes direct comparisons with these treatments, and the committee concluded that the selected comparators were appropriate for evaluating iptacopan’s effectiveness.
Patient Population and Subgroups
The trials included a representative population of adults with PNH, and the committee noted that the evidence is broadly generalizable. However, there were some limitations in subgroup analyses, particularly regarding those who had previously received C5 inhibitors.
Care Pathway Integration
Iptacopan can be integrated into existing care pathways with minimal disruption, as it is an oral treatment that does not require new infrastructure or extensive training. The committee noted that this ease of integration is a significant advantage over current intravenous or subcutaneous therapies.
Resource Use and Cost Implications
The economic model indicates that iptacopan is resource-efficient, with a manageable budget impact. The committee concluded that the overall resource use associated with iptacopan is justifiable given the benefits it provides, although there are concerns about the high costs associated with its use.
Evidence Quality and Robustness
The evidence base is supported by robust Phase 3 trials, although there are some methodological concerns regarding the indirect comparisons. The committee noted that while the evidence is strong, the uncertainties in the indirect treatment comparisons introduce some limitations.
Uncertainty, Sensitivity, and Broader Impacts
The committee acknowledged some uncertainties in the evidence, particularly regarding the indirect comparisons and the assumptions made in the economic model. However, the overall context of unmet need and the potential benefits of iptacopan mitigate some of these concerns.
