MODELING AND SIMULATION PREDICTS ROBUST HAE ATTACK SUPPRESSION WITH EVERY 3 MONTH DOSING OF STAR-0215

Abstract

<h3>Introduction</h3> Inhibition of plasma kallikrein is a validated mechanism for prevention of hereditary angioedema (HAE) attacks. STAR-0215 is a long-acting monoclonal antibody inhibitor of plasma kallikrein. We sought to generate a mechanistic quantitative systems pharmacology (QSP) model to explore the potential for reduction of HAE attacks with different dosing regimens of STAR-0215. <h3>Methods</h3> A simplified QSP model was established based on published reaction parameters for the plasma kallikrein-kininogen pathway in the vascular space and adjacent to the endothelial surface. The pharmacokinetic (PK) parameters of STAR-0215 were derived from cynomolgus monkey PK studies and scaled to estimate human PK parameters. Variability in PK parameters was simulated using a standard deviation of 50% and a Poisson distribution was applied to randomly determine the timing of trigger events with an average attack frequency of 3 per month. <h3>Results</h3> A long circulating half-life of STAR-0215 in humans (108 days) was predicted from empirically obtained PK parameters in cynomolgus monkeys. The QSP model predicted long-term robust HAE attack suppression following a single subcutaneous administration of STAR-0215 at dose levels of ≥300 mg. The QSP model simulations also showed subcutaneously administered STAR-0215 could provide a potential prolonged HAE attack suppression with a once every 3 months maintenance dose regimen. <h3>Conclusions</h3> STAR-0215 is a novel, potent and selective long-acting monoclonal antibody plasma kallikrein inhibitor for the potential treatment of HAE. Results from the QSP model support STAR-0215 dosing once every 3 months or longer for robust suppression of HAE attacks.