Effect of L-000845704, an αVβ3 Integrin Antagonist, on Markers of Bone Turnover and Bone Mineral Density in Postmenopausal Osteoporotic Women

Abstract

The alphaVbeta3 integrin (vitronectin receptor) plays a pivotal role in bone resorption. We hypothesized that L-000845704, an alphaVbeta3 integrin antagonist, would potently inhibit bone resorption, thereby increasing bone mass as assessed by bone mineral density (BMD) in women with postmenopausal osteoporosis. In a multicenter, randomized, double-blind, placebo-controlled, 12-month study, 227 women (average 63 yr) with low lumbar spine or femoral neck BMD were randomly assigned to receive 100 or 400 mg L-000845704 once daily (qd), 200 mg L-000845704 twice daily (bid), or placebo. L-000845704 increased lumbar spine BMD (2.1, 3.1, and 3.5% for the 100-mg-qd, 400-mg-qd, and 200-mg-bid treatment groups, respectively, vs. -0.1% for placebo; P < 0.01 all treatments vs. placebo). Only 200 mg L-000845704 bid significantly increased BMD at the hip (1.7 vs. 0.3% for placebo; P < 0.03) and femoral neck (2.4 vs. 0.7% for placebo; P < 0.05). No L-000845704 group increased total body BMD. All doses of L-000845704 resulted in a similar approximately 42% decrease from baseline of N-telopeptide cross-links (P < 0.001 vs. placebo). L-000845704 was generally well tolerated; adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the antiresorptive effect of the alphaVbeta3 integrin antagonist L-000845704 translated into significant increases in lumbar spine BMD. Furthermore, 200 mg L-000845704 bid provided efficacy at the hip sites. These data suggest that the alphaVbeta3 integrin antagonist L-000845704 could be developed as an effective therapeutic agent for osteoporosis.

A novel role for SED1 (MFG-E8) in maintaining the integrity of the epididymal epithelium

“…L-954 is similar to other previously characterized inhibitors (Kumar et al, 2001;Murphy et al, 2005) in being specific for both αVβ3 and αVβ5 heterodimers. The addition of 0.1-1000 nM L-954 resulted in a dose-dependent reduction in cell adhesion to rSED1 but had no effect on cell adhesion to laminin (Fig.…”

Talin1 and Rap1 Are Critical for Osteoclast Function

“…The pragmatic aspect of our study relates to the fact that ␣v␤3 is the only integrin that has served as a clinically tested therapeutic target in the context of osteoporosis (38). The bone-sparing effects of a small-molecule ␣v␤3 inhibitor are relatively modest and thus have not been further pursued.…”

Studies with an Orally Bioavailable αV Integrin Antagonist in Animal Models of Ocular Vasculopathy: Retinal Neovascularization in Mice and Retinal Vascular Permeability in Diabetic Rats

“…Concern has existed regarding the safety of long-term systemic administration of ␣ V antagonists, including potential side effects such as inhibition of wound healing. Recent evidence has lessened this concern, because an orally active ␣ V antagonist L-845704 showed no serious adverse effects after 1 year of treatment in postmenopausal osteoporotic women (Murphy et al, 2005). Furthermore, infusions of monoclonal antibodies to ␣ V ␤ 3 , ␣ V ␤ 5 , or both, resulting in sustained systemic exposure, did not hinder wound healing in monkeys and humans (Martin et al, 2005;Zhang et al, 2007).…”