Abstract
Aim: QGE031, a humanised anti-IgE, was assessed in atopic subjects (sbts). PD endpoints were drug-IgE complexation, free IgE, basophil FcεRI & cell surface IgE suppression & allergen induced skin prick wheal & flare inhibition.
Methods: Sbts received 2-wkly s.c. doses of QGE031 on 2 (0.2mg/kg,N=8) to 4 occasions (0.6, 2 & 4mg/kg,N=8, 46 & 8 respectively); placebo (N=28) & omalizumab (OMA,N=12). Allergen skin prick tests were run at baseline, 4, 8, 12 & 22 weeks (wks) after the first dose. PKPD & skin response data was fitted with a mathematical model to predict steady-state dose-responses & simulate 0-6 month responses of ∼1000 sbts, each receiving QGE031 0-1200mg & OMA per 4 wks.
Results: QGE031 was well tolerated with no SAEs. All PD endpoints were dose & baseline IgE dependent, with ≥2mg/kg QGE031 doses inhibiting more &/or for longer durations than OMA. OMA did not suppress wheal & flare responses, but QGE031 completely suppressed responses in most sbts. The model fitted with estimated parameters including drug-IgE binding constant (0.32nM;95%CI 0.19-0.45) & EC50 for IgE modulating basophil FcεR expression (3.0nM,2.1-5.7). QGE031 was 8.9X (6.1-14) more potent at binding IgE in vivo than OMA. For baseline IgE≤250IU/mL, QGE031 120mg/injection/4wks would be need for greater inhibition of local skin allergen-induced wheal & flare responses than OMA 600mg at 4-wk intervals. For IgE>250IU/mL, 240mg (2 injections/4wks) may be needed to match OMA 1200mg/4wks.
Conclusion: QGE031 was more effective than OMA in inhibiting skin allergen responses. The mathematical model allows better dose/regimen selection for future trials.
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