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Introduction <p>Prompt and effective on-demand treatment is critical in hereditary angioedema (HAE). Although multiple on-demand therapies are available, including recombinant human C1 esterase inhibitor (rhC1-INH) and sebetralstat, no head-to-head efficacy trials exist.</p> Methods <p>A series of indirect treatment comparisons evaluated the relative efficacy of US Food and Drug Administration-approved doses of intravenous rhC1-INH (50&#xa0;U/kg for patients weighing &lt; 84&#xa0;kg; 4200&#xa0;U otherwise) vs oral sebetralstat (600&#xa0;mg) for the on-demand treatment of HAE attacks. Patient-level data from rhC1-INH trials (C1&#xa0;1310, C1&#xa0;1205, and C1&#xa0;1304 [placebo only]) were reweighted to match aggregate baseline characteristics (i.e., prophylaxis use, pooled attack location) from the sebetralstat KONFIDENT trial; matching variables were identified from a validated, clinician-informed study of treatment effect modifiers. In the primary analysis, time to complete resolution (TTCR) and redosing were compared using unanchored matching-adjusted indirect comparisons. TTCR subgroup analyses were performed for variables not matched for in the primary analysis due to population differences (i.e., attack severity, time to treatment). Scenario and sensitivity analyses were performed to support TTCR results; a scenario analysis was performed to support redosing results. Hazard ratios (HRs) and odds ratios (ORs), with 95% confidence intervals (CIs), were estimated using a weighted Cox proportional hazards model and a weighted logistic regression model, respectively.</p> Results <p>In the primary analysis, rhC1-INH was associated with a statistically significant 4.5-fold increased likelihood of achieving complete resolution (HR 4.52; 95%&#xa0;CI 2.84–7.18) and a significant 82% reduction in redosing (OR 0.18; 95%&#xa0;CI 0.06–0.53) vs sebetralstat. Similar results for TTCR were observed in subgroup analyses of patients with severe/very severe baseline attacks and patients receiving earlier treatment (within the median time to treatment). Scenario and sensitivity analyses confirmed the robustness of these findings.</p> Conclusions <p>rhC1-INH provides significantly faster symptom resolution and lower redosing rates vs sebetralstat.</p>

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Comparative Efficacy of Recombinant C1 Inhibitor Versus Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks: A Matching-Adjusted Indirect Treatment Comparison

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月2日

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  • John Anderson,
  • Nihal Narsipur,
  • Douglas Jones,
  • Andrew Smith,
  • Anurag Relan,
  • Emily Aiello,
  • Neil Roskell,
  • Adam Gough,
  • Sakshi Jindal,
  • Ketsia Habimana,
  • Hannah Kilvert,
  • H. Henry Li,
  • Amanda Harrington

摘要

Introduction

Prompt and effective on-demand treatment is critical in hereditary angioedema (HAE). Although multiple on-demand therapies are available, including recombinant human C1 esterase inhibitor (rhC1-INH) and sebetralstat, no head-to-head efficacy trials exist.

Methods

A series of indirect treatment comparisons evaluated the relative efficacy of US Food and Drug Administration-approved doses of intravenous rhC1-INH (50 U/kg for patients weighing < 84 kg; 4200 U otherwise) vs oral sebetralstat (600 mg) for the on-demand treatment of HAE attacks. Patient-level data from rhC1-INH trials (C1 1310, C1 1205, and C1 1304 [placebo only]) were reweighted to match aggregate baseline characteristics (i.e., prophylaxis use, pooled attack location) from the sebetralstat KONFIDENT trial; matching variables were identified from a validated, clinician-informed study of treatment effect modifiers. In the primary analysis, time to complete resolution (TTCR) and redosing were compared using unanchored matching-adjusted indirect comparisons. TTCR subgroup analyses were performed for variables not matched for in the primary analysis due to population differences (i.e., attack severity, time to treatment). Scenario and sensitivity analyses were performed to support TTCR results; a scenario analysis was performed to support redosing results. Hazard ratios (HRs) and odds ratios (ORs), with 95% confidence intervals (CIs), were estimated using a weighted Cox proportional hazards model and a weighted logistic regression model, respectively.

Results

In the primary analysis, rhC1-INH was associated with a statistically significant 4.5-fold increased likelihood of achieving complete resolution (HR 4.52; 95% CI 2.84–7.18) and a significant 82% reduction in redosing (OR 0.18; 95% CI 0.06–0.53) vs sebetralstat. Similar results for TTCR were observed in subgroup analyses of patients with severe/very severe baseline attacks and patients receiving earlier treatment (within the median time to treatment). Scenario and sensitivity analyses confirmed the robustness of these findings.

Conclusions

rhC1-INH provides significantly faster symptom resolution and lower redosing rates vs sebetralstat.