Inhibition of plasma kallikrein activity is a validated mechanism for prevention of hereditary angioedema (HAE) attacks. High potency and long duration of action are key drivers of prophylactic efficacy of plasma kallikrein inhibitors. We are developing STAR-0215 as a novel, potent and selective long-acting monoclonal antibody plasma kallikrein inhibitor to incorporate both attributes. We tested target engagement and functional inhibition of activated plasma kallikrein in cynomolgus monkeys subcutaneously dosed with STAR-0215 by measuring cleavage of HMWK, the endogenous substrate of plasma kallikrein.

Cynomolgus monkeys were administered subcutaneous injections of either control, or 10, 30, or 100 mg/kg STAR-0215 (n=6-10 per dose) every 15 days. Pre- and post-dose plasma samples were collected for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. STAR-0215 concentrations were determined by ELISA with an anti-human detection antibody. For PD assessment, contact activated plasma samples were used. Contact activation was achieved by ex vivo addition of 10 nM FXIIa for 10 min at room temperature, and percentage of cleaved HMWK (cHMWK) was determined by Western blotting.

STAR-0215 plasma concentrations peaked at around 72 hours post-dose and reached average maximal levels (Cmax) of 114, 245, and 1131 μg/mL, respectively, for the 10, 30, and 100 mg/kg dose groups. At 1d post-dose, average STAR-0215 levels were 7, 23, and 45 μg/ml, while at 43d they were 212, 462, and 1439 μg/mL. Compared to pre-dose samples (67% cHMWK), STAR-0215 inhibited cHMWK in all dosed animals and at all post-dose time points (17, 10, and 6% cHMWK average post-dose for the three respective dose groups). In contrast, no inhibition of HMWK cleavage was seen in control dosed animals at any time point (63% cHMWK average for all post-dose time points). Inhibition was rapid after dose administration (22, 15 and 9% cHMWK 1d after dosing) and was sustained through the end of the 43-day study (15, 8, and 6% cHMWK).

STAR-0215, a long-acting monoclonal antibody plasma kallikrein inhibitor, demonstrated rapid and sustained inhibition of plasma kallikrein as measured by inhibition of HMWK cleavage from subcutaneously dosed cynomolgus monkeys. These data demonstrate that STAR-0215 engages its target plasma kallikrein in vivo and functionally inhibits plasma kallikrein enzymatic activity, thereby advancing STAR-0215 into clinical development. STAR-0215 is planned to enter clinical trials in 2022.