L15:
A Randomized, Double-Blind, Placebo-Controlled, Ascending Dose Phase 1 Study of AK002, a Novel Siglec-8 Selective Monoclonal Antibody, in Healthy Subjects
Monday, March 5, 2018
South Hall A2 (Convention Center)
Henrik S Rasmussen, MD, PhD, Alan T Chang, Nenad Tomasevic, PhD, Christopher Bebbington, PhD
Rationale: Eosinophils and mast cells play a significant role in chronic allergic and inflammatory diseases such as eosinophilic gastrointestinal diseases, urticaria, mastocytosis, allergic conjunctivitis, atopic dermatitis, and asthma. The Siglec-8 receptor is selectively present on eosinophils, mast cells, and basophils. Animal and in-vitro experiments have demonstrated that anti-Siglec-8 antibodies directly deplete eosinophils and inhibit mast cells. This study evaluated AK002, a novel humanized non-fucosylated IgG1 monoclonal antibody to Siglec-8, in healthy subjects – the first completed AK002 study in humans.

Methods: This study was a Phase 1, randomized, double-blind, placebo-controlled, single and multiple-dose study. 51 healthy subjects were randomized (4 AK002 to 2 placebo) in 7 AK002 dose level cohorts (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg given intravenously). Pharmacokinetics (PK), pharmacodynamics (PD), and safety were assessed.

Results: All AK002 dose groups recorded complete depletion of blood eosinophils by the first post-dosing timepoint (1 hr). Duration of eosinophil depletion increased with dose level and was sustained up to 84 days after a single dose of 1.0 mg/kg. Eosinophil levels were not significantly changed on placebo. AK002 had an 18-day half-life at 1.0 mg/kg. Mild to moderate infusion reactions occurred and resolved quickly; 1 serious adverse event occurred and resolved without sequelae within 1 day.

Conclusions: AK002 rapidly depleted blood eosinophils after a single dose. AK002’s PK, PD, and tolerability suggest an acceptable profile for chronic administration with monthly to quarterly dosing. These results suggest that AK002 should be evaluated as acute and chronic treatment in eosinophil and mast cell driven diseases.