The effect of AZD0530, a highly selective, orally available Src/Abl kinase inhibitor, on biomarkers of bone resorption in healthy males

Abstract

3041 Background: AZD0530 is a highly selective, dual-specific, orally available small molecule inhibitor of Src kinase and Bcr-Abl. Src kinase activity modulates cell proliferation, adhesion, motility and invasion and in animals its inhibition limits invasion of bone metastases and destructive bone resorption. Src kinase activity is elevated in many human tumors Methods: 2 trials in healthy, male volunteers (18–55 y) assessed the effect of AZD0530 on bone resorption, with a primary objective to establish safety and tolerability. Both were randomized, double-blind and placebo-controlled; one single ascending dose (SAD) study and one multiple ascending dose (MAD) study. The SAD study comprised 27 volunteers (cohorts of 9) who received a single 2.5–1000 mg AZD0530 dose (n=6) or placebo (n=3). In the MAD study 5 cohorts of volunteers received a single 60–250 mg dose (n=9) or placebo (n=3) then, 7–10 days later, multiple doses (10–14 d). After overnight fast, serum and second morning void urine were collected before and 24 and 48 h after the single dose (both studies) and before and 24 and 48 h after the final dose (MAD study). Markers of bone resorption measured were serum cross-linked C telopeptide of type I collagen [sCTX] and urinary cross-linked N telopeptide [NTX], expressed as a ratio to urinary creatinine. Results: In the SAD study mean levels of sCTX and uNTX/Cr significantly decreased from baseline with the 1000 mg dose. Provisional PK-PD modeling suggests the relationship between AZD0530 plasma concentrations and CTX suppression is well described by an inhibitory sigmoid E-max model. Conclusions: These findings are highly suggestive of inhibition of osteoclast-mediated bone resorption via suppression of Src kinase activity. AZD0530 may have therapeutic benefit in treating osteoclast-driven metastatic bone disease and osteoporosis as well as its potential role as an anti-invasive treatment in other cancer types. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca