INDIRECT TREATMENT COMPARISON OF ORAL SEBETRALSTAT AND INTRAVENOUS RHC1-INH AS ON-DEMAND TREATMENTS FOR HEREDITARY ANGIOEDEMA

Introduction

Substantial heterogeneity in hereditary angioedema (HAE) on-demand trial designs and endpoints make indirect treatment comparison (ITC) challenging. Sebetralstat, an investigational oral on-demand plasma kallikrein inhibitor, demonstrated efficacy and safety in a phase 3 randomized placebo-controlled trial, in which the primary endpoint of time to beginning of symptom relief was measured by the Patient Global Impression of Change scale. Based on a systematic literature review, among published phase 3 HAE on-demand trials, only one, the pivotal trial for intravenous recombinant human C1 esterase inhibitor (IV-rhC1-INH), reported relevant data for a comparable primary endpoint to enable an ITC with sebetralstat.

Methods

Based on available data, a Bayesian fixed-effects network meta-analysis (NMA) was conducted to indirectly compare the efficacy and safety outcomes of sebetralstat (NCT05259917) and IV-rhC1-INH (NCT01188564, NCT00225147, NCT00262301). Sensitivity analyses were examined with random effects models. Matching-adjusted indirect comparison (MAIC) of efficacy outcome was also performed, adjusting for differences in baseline clinical and demographic characteristics.

Results

The NMA fixed effects model found no significant differences in time to beginning of symptom relief between sebetralstat 300 mg and IV-rhC1-INH 50 IU/kg (HR [95% CI] 0.96 [0.42-2.15] to 1.19 [0.58-2.45]). After adjusting for baseline attack severity, MAIC showed numerically favorable results with sebetralstat vs IV-rhC1-INH, regardless of whether baseline demographics variables were matched. NMA found no significant differences in treatment-related adverse events. All sensitivity analyses returned consistent results.

Conclusions

This ITC study found no significant differences in time to beginning of symptom relief and overall treatment-related adverse events between sebetralstat and IV-rhC1-INH.