Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans

Abstract

Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

Phase I study of single-agent CC-292, a highly selective Brutons tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia

“…8 On-treatment levels of free BTK in lymph node tissue were determined in 11 patients who participated in optional biopsies taken 4 h post-dose, of which 10 were evaluable (Online Supplementary Figure S2). In 9 patients, no free BTK was detectable in lymph node lysates (<12.5 pg/mL detection limit), although BTK was present by immunoblot.…”

“…8 We report here the results of a phase I study of CC-292 in patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL), Bcell non-Hodgkin lymphoma (B-NHL), and Waldenström macroglobulinemia (WM). A total of 113 patients received continuous dosing with CC-292 in 28-day cycles at doses ranging from 125 mg to 1000 mg once daily, and 375 mg and 500 mg twice daily, continuing into doseexpansion cohorts of 750 mg once daily and a preliminary recommended phase II dose (RP2D)-expansion cohort of 500 mg twice daily.…”

“…Jennifer R. Brown, 1 Wael A. Harb, 2 Brian T. Hill, 3 Janice Gabrilove, 4 Jeff P. Sharman, 5 Marshall T. Schreeder, 6 Paul M. Barr, 7 James M. Foran, 8 …”

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

“…Therefore, a covalent biotinylated probe was developed to assess target occupancy by measuring unoccupied EGFR WT protein after compound exposure. Such an approach has been successfully used in our BTK clinical development program as a translational tool using a specific BTK covalent biotinylated probe (29). A431 cells were treated with compound 3 in a dose-dependent manner and lysates were then assessed for EGFR WT occupancy (Fig.…”

Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib

“…In vitro, CC-292 inhibits autophosphorylation in primary B cells, achieves dose-dependent reduction in CD69 expression, and reduces CLL cell migration and response to chemokines CXCL12 and CXCL13 [Evans et al 2011a;Pierce et al 2013]. In vivo, CC-292 reduces signs of arthritic disease in a manner proportional to percentage BTK occupancy [Evans et al 2013]. In a phase Ia trial, CC-292 was well tolerated over the 0.5-7.0 mg/kg dosage range and there were no reported AEs or SAEs [Evans et al 2013].…”