QGE031 high affinity anti-IgE: Tolerability, safety, pharmacokinetics and pharmacodynamics in atopic subjects

QGE031, a human anti-IgE with higher affinity than omalizumab (OMA), was evaluated in atopic subjects (18-55 years) in single escalating intravenous (IV) and multiple ascending subcutaneous (SC) dose trials. Subjects in the IV trial received 0.1-10 mg/kg QGE031 (n=36), placebo (PB, n=29) or SC OMA (n=8). Subjects in the SC trial received 2-4 doses of 0.2-4 mg/kg QGE031 (n=70), PB (n=28) or OMA (n=12). Outcomes included safety, tolerability, PK, free and total IgE, expression of FceRI and IgE and, in the SC study, skin prick testing (SPT). No deaths or serious adverse events occurred. In the IV trial, subject discontinuation rate was 17.8% (unrelated to adverse events, AEs). Urticaria occurred in 4/73 subjects; 3 at the higher IV doses and 1 on PB. For the SC trial, 2 subjects receiving 2 mg/kg QGE031 withdrew (due to symptoms considered unrelated to drug). Four urticarial events (1 in the 0.6 mg/kg and 3 in PB group) occurred in 3 subjects. PK analyses of both IV and SC dosing showed minimal IgE mediated drug disposition, rapid capture of IgE and a biexponential distribution/elimination. QGE031 reduced free IgE below the quantification level for all doses and elicited dose-and time-dependent suppression of basophil FceRI, surface IgE expression and SPT responses. QGE031 showed 9-fold increase in PKPD potency (95% CI 6.1-14 fold) than OMA. The extent and duration of PD effects were dependent upon baseline IgE, but robust PD responses were observed in all groups including those with high baseline IgE. QGE031 was well tolerated with no serious AEs and reduced free circulating IgE, FceRI, surface IgE, and SPT responses significantly greater and for a longer duration than OMA.