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

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

doi:10.1007/s12325-026-03605-4

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

Adv Ther. 2026 May 2. doi: 10.1007/s12325-026-03605-4. Online ahead of print.

Authors

John Anderson^{1

2

3}, Nihal Narsipur⁴, Douglas Jones⁵, Andrew Smith⁶, Anurag Relan⁷, Emily Aiello⁸, Neil Roskell⁹, Adam Gough⁹, Sakshi Jindal¹⁰, Ketsia Habimana⁹, Hannah Kilvert⁹, H Henry Li¹¹, Amanda Harrington⁷

Affiliations

¹ AllerVie Health, Birmingham, AL, USA.
² University of Alabama at Birmingham, Birmingham, AL, USA.
³ Birmingham VA Medical Center, Birmingham, AL, USA.
⁴ Pharming Healthcare, Inc., Warren, NJ, 07059, USA. N.Narsipur@pharming.com.
⁵ Rocky Mountain Allergy, Asthma, and Immunology, Salt Lake City, UT, USA.
⁶ Allergy Associates of Utah, Sandy, UT, USA.
⁷ Pharming Healthcare, Inc., Warren, NJ, 07059, USA.
⁸ Lumanity, Toronto, ON, Canada.
⁹ Lumanity, Sheffield, England, UK.
¹⁰ Lumanity, Gurugram, Haryana, India.
¹¹ Institute for Asthma & Allergy, Wheaton, MD, USA.

PMID: 42068479
DOI: 10.1007/s12325-026-03605-4

Abstract

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.

Keywords: Hereditary angioedema; Indirect treatment comparison; On-demand therapies; Redosing; Sebetralstat; Time to complete resolution; rhC1-INH.