Deucrictibant shows promise for treating acquired angioedema

HAE drug candidate tested in small trial for on-demand, preventive use

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Deucrictibant, an experimental treatment for hereditary angioedema (HAE), now has shown promising efficacy as an on-demand and prophylactic, or preventive, treatment in three patients with acquired angioedema.

The findings, from a small clinical trial, suggest that “deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency,” the researchers wrote.  In people with acquired angioedema, a lack of the C1-inhibitor protein, called C1-INH, leads to swelling episodes.

According to the researchers, “the reported findings warrant further exploration [of deucrictiban] in a larger cohort of patients with angioedema due to acquired C1-inhibitor deficiency.”

The results of the small trial were reported in a study titled “Deucrictibant for angioedema due to acquired C1-inhibitor deficiency: A randomized-controlled trial,” published in The Journal of Allergy and Clinical Immunology.

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Acquired angioedema can be treated with off-label use of HAE therapies

Testing the safety, efficacy of deucrictibant in acquired angioedema

Angioedema refers to swelling that happens due to a buildup of fluid in the deeper layers of the skin or the mucosal lining of the digestive and respiratory tract.

In acquired angioedema, attacks arise due to a C1-INH protein deficiency. In the absence of C1-INH, the levels of a signaling molecule called bradykinin increase, triggering a swelling attack.

Unlike HAE, acquired angioedema is not caused by genetic mutations. The most typical causes are an underlying condition, usually a cancer or an autoimmune disease.

Deucrictibant is a small molecule that’s being developed by Pharvaris both as an on-demand and prophylactic treatment for HAE swelling attacks. The medication works by binding to the bradykinin B2 receptor, effectively preventing bradykinin from interacting with it and activating the signaling cascade that would prompt an HAE attack.

The therapy is available in three formulations: as an oral suspension, as an immediate-release capsule called PHVS416, or as an extended-release tablet called PHVS719.

Here, researchers in the Netherlands conducted a clinical trial, partially funded by Pharvaris Netherlands, to test the safety and efficacy of deucrictibant as an on-demand and prophylactic treatment in three male patients with acquired angioedema. The trial was conducted from October 2021 to March 2023.

In part one, the participants were randomly assigned to receive three oral doses of deucrictibant — 10, 20, or 30 mg — or a placebo as an on-demand treatment for four angioedema attacks.

In part two, the patients were randomly assigned to receive a capsule formulation containing 20 mg of deucrictibant, or a placebo, both given twice daily for eight weeks, or about two months, as a preventive treatment. For the following eight weeks, those given deucrictibant switched over to the placebo and vice-versa.

Altogether, one patient completed both parts of the study; the remaining two participants completed only part two.

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Deucrictibant reduces rate of HAE swelling attacks in Phase 2 trial

Reductions in attack severity seen with deucrictibant used on-demand

In the first part of the study, a combined attack that affected the abdomen and skin was treated with 10 mg of deucrictibant, while a skin attack was treated with the 20 mg dose. The highest dose of 30 mg was used to treat an attack involving the face. The placebo was administered to treat a combined attack affecting the skin and face.

A clinical response was defined by a reduction in attack severity occurring within four hours after treatment, as assessed by a mean change in a three-symptom visual analogue scale (VAS-3). In this scale, scores ranged from 0 to 100, with 100 indicating the worst possible manifestations.

A reduction in attack severity was observed in all attacks treated with deucrictibant, while an increase in severity was seen with the placebo, as assessed by the VAS-3. Specifically, mean VAS-3 decreased by 16.4 points with the 10 mg dose, by 3.3 points with the 20 mg dose, and by 9.0 points with the 30 mg dose. With the placebo, mean VAS-3 scores increased by 11.3 points.

The placebo-treated attack was the only one that required rescue treatment, which was administered six hours after the initial treatment.

These findings are in agreement with data from the Phase 2 RAPIDe-1 trial (NCT04618211), which assessed the efficacy of on-demand treatment with deucrictibant to treat attacks in adults with HAE.

In part two, mean monthly attack rates ranged from 0.6 to two attacks per month while the patients were on the placebo. None of the three patients experienced any attack in the eight weeks of treatment with deucrictibant.

Adverse events were observed in the second part of the study: seven with deucrictibant and six with the placebo. Abdominal pain after ingestion of capsules without water was the only adverse event linked to deucrictibant; this was resolved by reinstructing the patient to use water for capsule ingestion. No serious adverse events were reported.

Overall, these findings suggest that deucrictibant may “effectively [control acquired] angioedema … indicating that this condition shares mechanistic features with hereditary angioedema,” the researchers wrote.