822
Modeling and Analyses to Identify Potential Dosing Regimens of DX-2930 for the Long-Term Prophylaxis of Hereditary Angioedema
Monday, March 7, 2016
South Exhibit Hall H (Convention Center)
H. James Wedner, MD FAAAAI, Paula J. Busse, MD FAAAAI, Aleena Banerji, MD, Mustafa Shennak, William R. Lumry, MD FAAAAI, Mark A. Davis-Lorton, MD FAAAAI, Joshua S. Jacobs, MD, James W. Baker, MD FAAAAI, Jonathan A. Bernstein, MD FAAAAI, Richard F. Lockey, MD, H. Henry Li, MD PhD, Timothy J. Craig, Marco Cicardi, Marc A. Riedl, MD MS, Ahmad Al-Ghazawi, Carolyn Soo, Ryan Iarrobino, Daniel Sexton, Christopher TenHoor, Ryan Faucette, Joseph C. Biedenkapp, Yung H. Chyung, Burt Adelman
Rationale: DX-2930 is a human monoclonal antibody inhibitor of plasma kallikrein in development for the prevention of hereditary angioedema (HAE) attacks. Data from Phase 1 studies of DX-2930 were modeled and analyzed to identify potential dosing regimens.

Methods: Pharmacokinetic, pharmacodynamic and efficacy data from Phase 1 clinical studies were examined. The incidence of HAE attacks was evaluated in relation to plasma drug concentrations to estimate steady-state trough drug levels necessary to prevent attacks. 

Results: Pharmacokinetic modeling predicts that dosing regimens of 300 mg DX-2930 every 2 (q2) or 4 (q4) weeks, and 150 mg q4 weeks will result in steady-state trough plasma concentrations of 27,000, 9,500, and 4,750 ng/mL, respectively. In the Phase 1b study, at 27,000 ng/mL (corresponding to approximate drug levels at Day 22 for 300 mg DX-2930), 2-chain high-molecular-weight kininogen was suppressed to a level approximating that observed in healthy subjects. The 300 mg q2 weeks regimen is therefore predicted to normalize the instability of HAE plasma at steady state. As successful HAE prophylaxis may not require such a high level of pharmacodynamic effect, we also conducted an analysis of clinical effect in relation to plasma drug concentrations. In the Phase 1b study following DX-2930 treatment, 24/25 attacks (96%), 21/25 (84%), and 18/25 attacks (72%) occurred below plasma concentrations of 27,000, 9,500, and 4,750 ng/mL respectively, suggesting a meaningful range of clinical response is associated with this range of drug exposure. 

Conclusions: Viable dosing regimens of DX-2930 were identified for further clinical investigation.