Combined use of deucrictibant formulations in HAE expected to be safe
Drug being developed as extended-release tablet, immediate-release capsule
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Using a daily extended-release tablet of deucrictibant — an oral small molecule being developed by Pharvaris — together with deucrictibant in its immediate-release formulation as an on-demand treatment for acute attacks of hereditary angioedema (HAE) is expected to be safe based on computer data.
A presentation on these data, titled “Evaluating Safety Margins of the Use of Deucrictibant Extended-Release Tablet in Combination with Deucrictibant Immediate-Release Capsule,” was made earlier this month at the Consortium of Independent Immunology Clinics Spring 2026 Conference in Arlington, Texas. It followed a post-hoc analysis of the Phase 2 clinical study CHAPTER-1 (NCT05047185) in which on-demand treatment with Firazyr (icatibant) was effective regardless of whether patients were already taking deucrictibant as a prophylactic (preventive) treatment. Firazyr is an approved medication that works similarly to deucrictibant.
“These safety data, combined with the post-hoc efficacy analyses of mechanism-on-mechanism treatment of breakthrough attacks, provide evidence for the potential of the combined use of deucrictibant as a prophylactic treatment and as an on-demand medication,” Peng Lu, MD, PhD, chief medical officer of Pharvaris, said in a company press release.
Deucrictibant aims to prevent bradykinin from causing blood vessel leaks
Angioedema occurs when fluid builds up under the skin or mucous membranes, leading to repeated attacks of swelling that can occur anywhere in the body. In HAE, this is caused by genetic mutations that result in an excess of a small protein called bradykinin. Excess bradykinin widens blood vessels and causes fluid to leak from blood vessels into tissues.
Deucrictibant is a bradykinin B2 receptor antagonist, meaning it blocks the bradykinin B2 receptor and prevents bradykinin from causing blood vessels to leak. It is being developed both as an extended-release tablet that slowly releases deucrictibant into the bloodstream to keep its level stable and as an immediate-release capsule that rapidly releases deucrictibant to stop symptoms during an attack.
“Bradykinin-mediated angioedema can be prevented by administering a bradykinin B2 receptor antagonist that exceeds the therapeutic threshold to compete with bradykinin,” Lu said. A breakthrough attack can occur if treatment is below this threshold, in which case “an on-demand treatment using the same mechanism could be a compelling treatment approach.”
Researchers have now tested whether it is safe to combine these two formulations using computer-based simulations of the amount of decrictibant present in the body, along with earlier clinical trial data and animal safety studies. They looked at “safety margins,” which refer to the extent to which human exposure exceeds levels that did not cause harm in animal studies. A higher safety margin suggests lower risk.
The combined use … in the event of an attack occurring during prophylactic treatment with [the extended-release] tablet is supported by adequate safety margins.
They tested two main real-world scenarios. In the first, a patient takes a 40 mg extended-release tablet daily and adds one 20 mg immediate-release capsule during an attack. In the second, they take two 20 mg immediate-release capsules four hours apart while still on the extended-release tablet. These scenarios assume the medication peaks in the blood at the same time, which creates the highest possible exposure.
In the first scenario, the peak blood level of deucrictibant was well below harmful levels seen in animals. In the second scenario, levels were higher than in the first scenario but remained within safe margins. Importantly, even these higher exposures were lower than doses previously tested in humans, which did not cause serious side effects.
While this combination would still require regulatory approval of each formulation before use in practice, these data suggest it may be safe.
“The combined use … in the event of an attack occurring during prophylactic treatment with [the extended-release] tablet is supported by adequate safety margins,” the researchers wrote.
