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.
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.
unanchored MAIC with unmatched severity and treatment timing, plus a non-significant anchored scenario
Supportive analyses provided similar results, with 100% favoring rhC1-INH and 75% achieving statistical significance.
one anchored scenario crossed the null despite prose calling it statistically significant
Derived from the full evaluation — not a separate score.
Strengths
The analysis compares FDA-approved doses and focuses on complete resolution and redosing, outcomes presented as more decision-relevant than onset of symptom relief.
↳ Introduction, final paragraph; Discussion, paragraph 3
Tables 2 and 3 identify major differences in treatment setting, attack severity, treatment timing, and redosing protocols rather than treating the source trials as directly interchangeable.
↳ Results, Feasibility Assessment; Tables 2–3
The Discussion directly addresses a 2025 ITC and specifies differences in endpoint mapping, anchoring, matching variables, and sebetralstat dose.
↳ Discussion, paragraph addressing the 2025 ITC
Limitations
The Scenario Analyses prose states that both intervention-permissive comparisons were statistically significant, while Table 4 gives confidence intervals crossing the null for TTCR and redosing. This undermines the reported consistency of supportive analyses.
↳ Results, Scenario Analyses; Table 4
The unanchored MAIC could not match attack severity or treatment timing because the trial populations had minimal overlap. Subgroup analyses explore these differences but do not remove the underlying cross-trial confounding.
↳ Results, Feasibility Assessment and Subgroup Analyses; Table 3
No formal risk-of-bias tool or GRADE-equivalent certainty assessment is reported for the included trials, yet the Conclusions characterize the findings as robust and decision-relevant.
↳ Methods and Results; Conclusions
The contribution score reflects a focused comparison of approved doses using TTCR and redosing, but the work remains an indirect reanalysis of heterogeneous trials. Tables 2 and 3 transparently document major differences in severity, treatment timing, setting, and redosing rules, while the primary unanchored MAIC cannot fully adjust for two central modifiers. Table 4 also conflicts with the Scenario Analyses prose because both intervention-permissive confidence intervals cross the null despite being called statistically significant. The absent formal risk-of-bias assessment and the final robustness language therefore weigh heavily against otherwise structured methods and substantive engagement with prior evidence.
Nabu’s assessment, alongside the field’s view.
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Limited2.7
Confidence mediumThe study addresses an unresolved comparison between FDA-approved doses using TTCR and redosing, extending a prior TOSR-focused ITC. The advance remains incremental because it reanalyzes existing trials rather than providing direct comparative evidence.
“The objective of this study was to evaluate the relative TTCR and redosing of rhC1-INH versus sebetralstat.”
The Cope feasibility framework, MAIC weighting, and scenario, subgroup, and sensitivity analyses provide a structured synthesis. Methodological Rigour is constrained by absent formal risk-of-bias assessment and conclusions that overstate robustness despite non-significant anchored estimates.
“These findings were consistent across multiple analyses... and remained robust in sensitivity and scenario analyses.”
The manuscript is organized around a traceable sequence from evidence search through primary and supportive analyses, with estimates displayed in tables and figures. Reporting is reduced by prose that labels null-crossing scenario estimates statistically significant and then uses them to support robustness.
“The scenario analyses for both TTCR and redosing... demonstrated statistical significance.”
The Discussion directly engages a conflicting 2025 ITC and explains differences in dose, endpoints, matching variables, and anchoring. However, the acknowledged sensitivity to placebo-comparator choice is not reflected proportionately in the final claim of robust results.
“The variability observed in the effect estimates across anchoring scenarios indicates that the results are sensitive to the choice of placebo comparator.”
Concerns4 of 4 checks
The statistical-significance characterization of the intervention-permissive scenario conflicts with the confidence intervals reported in Table 4. This directly affects the paper's claims that supportive analyses were statistically consistent and robust.
Ethics requirements and the approvals and consent for the underlying trials are described, but no conflict-of-interest disclosure appears in the supplied article text. No data- or code-availability claim is made.
Flags: 1 declared / 5 total
22 of 22 checkable references verified
28 references in manuscript 6 are books, websites or datasets — counted, but not index-checkable
References not verified automatically are resolved manually within 24 hours.
No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Both therapies are already in clinical use, so comparative findings could enter decisions without a long development pathway. The indirect, modeled analysis and sensitivity to anchoring mean it can inform rather than determine treatment selection.
“As with all indirect comparisons, this analysis is subject to several assumptions and limitations.”
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Other papers Nabu has evaluated blind, starting with the same field.
Riedl, Farkas, Aygören-Pürsün, et al. · 2024 · Clinical medicine
Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo.
Well-supportedRiedl, Tachdjian, Lumry, et al. · 2024 · Clinical medicine
Donidalorsen at a dose of 80 mg administered subcutaneously every 4 or 8 weeks significantly reduced the hereditary angioedema attack rate
SupportedCohn, Gurugama, Magerl, et al. · 2024 · Clinical medicine
NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema.
Tentative