Oral Hereditary Angioedema Treatment Provides Effective Bradykinin-Inhibiting Concentrations

A single dose of PHA-022121, an oral beta-2 antagonist, was associated with effective bradykinin-inhibiting concentrations within 15 minutes of administration in patients with hereditary angioedema, with concentrations maintained for up to 10 hours. These findings were presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) Virtual Annual Meeting held February 26 to March 1, 2021.

The study was an analysis of 2 double-blind placebo-controlled single ascending dose studies of orally administered PHA-022121, ranging from 1 mg to 50 mg. These studies included pharmacokinetic (PK) assessments and safety. The researcher also assessed the inhibition of bradykinin-induced-cardiovascular effects in patients treated with 12 mg and 22 mg PHA-022121. A nonlinear mixed-effect PK/pharmacodynamic (PD) model was used to evaluate PHA-022121-induced changes in bradykinin responses compared with historical icatibant treatment data.

The PK of PHA-022121 was dose proportional with rapid absorption in the fed or fasted state. Overall, PHA-022121 doses of up to 50 mg were well-tolerated. The treatment’s adverse event profile, laboratory safety, vital signs, and electrocardiogram parameters were considered comparable with placebo groups. Additionally, analysis of PK/PD found significant inhibition of cardiovascular changes induced by bradykinin with a mean composite EC₈₅ value of 13.8 ng/mL. Approximately 15 minutes following the 12 mg dose, plasma levels of the treatment reached 60.3 ng/mL.

Single oral doses of the study drug at 10 mg and above, according to quantitative modeling, were associated with maintenance of the drug levels of the identified clinical therapeutic threshold for 10 or more hours. In comparison, the maintenance duration of subcutaneous 30 mg icatibant drug levels was 6 hours in the historical dataset.

The investigator concluded that the long-term maintenance of the study drug concentrations makes oral PHA-022121 “ideally suited for single oral dose treatment of acute [hereditary angioedema] attacks.”

Reference

Crabbé R. PHA-022121: a novel and potent bradykinin 2 receptor antagonist for oral treatment of hereditary angioedema. Presented at: the American Academy of Allergy, Asthma & Immunology Virtual Annual Meeting; February 26-March 1, 2021. Abstract L23.