D1.322 - Clinical Cardiovascular Safety Assessment of Oral Deucrictibant

Hereditary angioedema (HAE) attacks are caused by excess bradykinin activating bradykinin B2 receptors. Deucrictibant is a selective, orally administered, bradykinin B2 receptor antagonist under development for prophylaxis and on-demand treatment (ODT) of bradykinin-mediated angioedema attacks. We report cardiovascular (CV) safety data from deucrictibant clinical studies to-date.

In two single- and one multiple-ascending dose (SAD/MAD) Phase 1 studies, electrocardiograms (ECG) were collected to perform a concentration QTc (C-QTc) analysis and assess CV safety. Healthy participants were exposed to placebo (N=28) or to a range of deucrictibant doses (1-50 mg; N=117) with the highest dose resulting in substantially higher plasma concentration than the concentration estimated to provide 85% maximal response (EC₈₅: 13.8 ng/mL). Phase 2 studies of deucrictibant for prophylaxis (CHAPTER-1) and ODT (RAPIDe-1) of HAE attacks also assessed CV outcomes, including diastolic and systolic blood pressure (DBP; SBP), heart rate (HR), ECG, and vital signs. CHAPTER-1 randomized 34 participants with HAE to deucrictibant 20 mg/day (n=11), 40 mg/day (n=12), or placebo (n=11) for 12 weeks; 30 participants entered the subsequent open-label extension. RAPIDe-1 randomized 74 participants with HAE to deucrictibant 10 mg (n=24), 20 mg (n=25), or 30 mg (n=25) and placebo to treat HAE attacks in a crossover design.

A metanalysis of pooled data from the Phase 1 studies showed no evidence of prolongation of QT interval nor effects on HR by deucrictibant. The HR-corrected concentration-QT (C-QTcF) model estimated a slope of -0.00453 ms/(ng/mL) between deucrictibant plasma concentration and QTcF, which was statistically and clinically non-significant. The placebo-corrected mean change from baseline in QT interval at the highest estimated clinical exposure scenario (840.6 ng/mL) was -2.55 ms (upper 90% CI: +2.29 ms), below the 10 ms threshold set by regulatory agencies for a clinically meaningful change. Across SAD/MAD, CHAPTER-1, and RAPIDe-1 studies, there were no safety signals in vital signs or ECG identified, nor reports of treatment-related CV adverse events. No treatment-, dose-, or time-dependent changes in DBP, SBP, or in HR were observed with single or repeated daily deucrictibant dosing.

These findings provide evidence on CV safety of deucrictibant treatment with no evidence of QTc prolongation observed and no CV safety signals identified.