Pharmacodynamic Effect of DX-2930 on Plasma Kallikrein in Hereditary Angioedema Patients
Monday, March 7, 2016
South Exhibit Hall H (Convention Center)
Mark A. Davis-Lorton, MD FAAAAI, Paula J. Busse, MD FAAAAI, Aleena Banerji, MD, Mustafa Shennak, William R. Lumry, MD FAAAAI, H. James Wedner, 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: Hereditary angioedema (HAE) attacks result from uncontrolled contact system activation which generates a burst of plasma kallikrein (pKal) that cleaves high-molecular-weight kininogen (HMWK) to produce 2-chain HMWK and the edema-inducing peptide, bradykinin. DX-2930 is a human monoclonal antibody inhibitor of pKal in development for preventation of HAE attacks. The pharmacodynamic bioactivity of DX-2930 was assessed in subjects with HAE.

Methods: This phase 1b multi-center, double-blind study randomized subjects with Type 1 or 2 HAE to receive 2 subcutaneous doses of DX-2930 on Days 1 and 15 in dose groups of 30, 100, 300 or 400 mg (n=4, 4, 5, 11) or placebo (n=13). Blood samples were obtained prior to and following study drug administration (Days 1, 8, 22, 64, 92, 120). The ability of DX-2930 to inhibit pKal in FXIIa-activated citrated plasma was assessed using Western blot for 2-chain HMWK. 

Results: In FXIIa-activated samples mean 2-chain HMWK levels were significantly reduced and essentially normalized in the 300 and 400 mg dose groups on Days 8 and 22, and on Days 8, 22 and 50, respectively, when compared to placebo-treated subjects. Treatment with 300 or 400 mg DX-2930 also attenuated 2-chain generation to levels at or below that observed in healthy individuals. Levels of 2-chain HMWK did not differ from pre-dose plasma samples in samples collected on Days 64, 92 or 120 following DX-2930, which correspond to periods of low drug exposure.

Conclusions: DX-2930 inhibits pKal in a dose and time-dependent manner in HAE patients.