DEVELOPMENT OF PHVS719: AN ORAL EXTENDED-RELEASE BRADYKININ B2 RECEPTOR ANTAGONIST TO PREVENT HEREDITARY ANGIOEDEMA ATTACKS

Abstract

<h3>Introduction</h3> Hereditary angioedema (HAE) is managed by either of two treatment paradigms: on demand or prophylaxis. PHA121, an orally active bradykinin B2 receptor antagonist, is being developed as two drug products to optimize patient choice. PHVS416, the softgel capsule providing quick absorption for fast onset of symptom relief, is currently in clinical trials for treatment of acute attacks; PHVS719, an extended-release tablet, is being developed for use in prophylaxis. <h3>Methods</h3> To develop a daily oral pill for the prevention of attacks, we developed a PHA121 formulation (PHVS719) providing 24 h plasma exposure. Our strategy relied upon a combination of an optimally designed extended-release formulation and the ability of PHA121 to be absorbed throughout the full gastrointestinal tract. <h3>Results</h3> PHA121 is absorbed following intracolonic administration in rats. A human mass balance study showed only 3% PHA121 excreted in feces and oral bioavailability of 57%. An in vitro dissolution experiment conducted with PHVS719 in conditions mimicking fasted and fed gastrointestinal environments showed a linear dissolution of PHA121 over time. Using PHVS719, a PK study in healthy volunteers demonstrated that a single 40 mg dose provides 24 h plasma exposure above the anticipated therapeutic level. Together these data provide evidence that PHVS719 is optimally suited to serve as a once-daily oral pill. <h3>Conclusion</h3> The active ingredient PHA121 is under clinical investigation in the form of two therapeutic treatment modalities: PHVS416 softgel capsule providing quick absorption for fast symptom relief and PHVS719 once-daily extended-release tablet providing 24 hours coverage to prevent attacks from occurring.