Abstract Number: PB0246
Meeting: ISTH 2020 Congress
Background: Plasma kallikrein (PKa) is a critical disease mediator in hereditary angioedema caused by C1 esterase inhibitor deficiency (C1INH-HAE). This disorder is characterized by dangerous attacks of bradykinin-mediated tissue swelling. PKa cleaves high-molecular-weight kininogen (HK) into a cleaved form (cHK), which liberates bradykinin. The oral PKa inhibitor ATN-249 is under clinical development for treatment of C1INH-HAE, and was investigated in a phase I randomized, double-blind, placebo-controlled single ascending dose study (ACTRN12618000430235).
Aims: To monitor the biological activity of ATN-249 in plasma.
Methods: Blood samples were collected from 48 healthy male participants at predose, 2, 4, 9, 12 and 24 hours after intake of a single dose ATN-249 (50-800 mg). Each dose cohort consisted of 6 subjects receiving active compound and two subjects receiving placebo. Contact activation was triggered with ellagic acid in subject plasma samples. We monitored PKa activity with a fluorogenic substrate, and cHK generation by ELISA.
Results: Consecutive samples (collected over 24 hours) of placebo-treated subjects developed comparable levels of PKa activity and cHK after ex vivo stimulation. However, we found a surprisingly large inter-individual variation (coefficient of variation of 41.7% for PKa activity, and 27.4% for cHK generation) between study subjects. We subsequently normalized data to predose levels to facilitate grouped comparisons. ATN-249 dose-dependently attenuated triggered PKa activity and -cHK generation. Two hours after intake, 800 mg ATN-249 inhibited triggered PKa activity by 92.5% and -cHK generation by 41% (Fig.1). Statistically significant effects were detectable until 24 hours and 9 hours after intake, respectively.
Conclusions: The considerable inter-individual variability in triggered PKa activity and cHK generation argues against a generalized cutoff value for these parameters in C1INH-HAE management and motivates development of personalized approaches. These assays are useful to monitor the biological activity of the oral PKa inhibitor ATN-249 in plasma.
To cite this abstract in AMA style:Clark C, Hofman ZLM, Hack CE, de Maat S, Maas C. Detecting Oral Kallikrein-Targeting Therapy through Triggered Contact Activation: A Phase I Study [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/detecting-oral-kallikrein-targeting-therapy-through-triggered-contact-activation-a-phase-i-study/. Accessed May 6, 2021.
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