D2.378 - Evaluations of Safety Margins and Response to Deucrictibant Extended-Release (XR) Tablet in Combination with Deucrictibant Immediate-Release (IR) Capsule

Deucrictibant is a selective, orally administered, bradykinin B2 receptor antagonist under development as an extended-release (XR) tablet and an immediate-release (IR) capsule for long-term prophylaxis (LTP) and on-demand treatment (ODT) of bradykinin-mediated angioedema attacks, respectively. Combined use of deucrictibant XR and IR may occur, upon regulatory approval of each formulation, if IR is used in the event of an attack occurring during prophylaxis with XR. We assessed safety margins of deucrictibant XR and IR, and efficacy of bradykinin B2 receptor antagonists for both LTP and ODT in combination.

Safety margins were calculated using human exposure simulations performed with a population pharmacokinetic model combining XR (40 mg, at steady state) and IR (20 mg) and systemic exposure at the no observed adverse effect level (NOAEL) in different animal toxicity studies. A post-hoc analysis of CHAPTER-1 - a two-part, Phase 2 study evaluating deucrictibant for prophylaxis against hereditary angioedema attacks - assessed response to use of bradykinin B2 receptor antagonism for both LTP and ODT by measuring mean duration (onset to resolution) of attacks in the placebo group (part 1) and combined deucrictibant 20/40 mg group (across parts 1 and 2) that were treated once with another bradykinin B2 receptor antagonist, icatibant, as ODT.

If 1 IR capsule was taken after 1 XR tablet (total dose 60 mg), the anticipated human C_max (281 ng/mL) had an associated margin of >8-fold to the non-clinical NOAEL. Total area under the curve from 0–24 hours (AUC_0-24h) in humans was estimated at 1923 ng*h/mL with a margin of 2.5- to 10-fold to the AUC_0-24h at the NOAELs. Estimated exposure remained below the exposure in humans (steady-state C_max of 693 ng/mL, 2xAUC_0-12h of 9716 ng*h/mL) following daily deucrictibant 100 mg (50 mg BID) - a dose not associated with adverse reactions in a Phase 1 study and the highest tested in a clinical setting. In CHAPTER-1, mean attack duration was comparable for the placebo-icatibant (n=25) and deucrictibant-icatibant (n=20) groups (1.12 and 1.05 days, respectively).

Nonclinical safety data and maximum steady-state exposure recorded in ascending-dose clinical studies provide safety coverage for combined use of deucrictibant XR and IR, subject to approval by regulatory authorities. In a Phase 2 trial, there was no evidence that use of bradykinin B2 receptor antagonism for combined LTP and ODT was associated with different attack durations.