Clinical development of anti-RANKL therapy

Edward M Schwarz,Christopher T Ritchlin

doi:10.1186/ar2171

Abstract

The receptor activator of nuclear factor-κB ligand (RANKL), its cognate receptor RANK, and its natural decoy receptor osteoprotegerin have been identified as the final effector molecules of osteoclastic bone resorption. This has provided an ideal target for therapeutic interventions in metabolic bone disease. As described in previous reviews in this supplement, RANKL signaling is required for osteoclast differentiation, activation, and survival. Furthermore, in vivo inhibition of RANKL leads to immediate osteoclast apoptosis, and there are no in vivo models of bone resorption that are refractory to RANKL inhibition. Thus, the only step remaining in the development of a clinical intervention is the generation of a safe, effective, and specific drug that can inhibit RANKL in humans. Here we review the clinical development of denosumab (formerly known as AMG 162), which is a fully human mAb directed against RANKL. This discussion includes the breadth of 21 human studies that have led to the current phase 3 clinical trials seeking approval for use of this agent to treat postmenopausal women with low bone mineral density (osteoporosis) and patients with metastatic lytic bone lesions (multiple myeloma, and prostate and breast cancer).

Highlights

As discussed in previous reviews in this supplement, a specific inhibitor of receptor activator of nuclear factor-κB ligand (RANKL) could be of great therapeutic value in the treatment of patients with a variety of metabolic and inflammatory bone disorders
The results from these trials are consistent with our preclinical studies, which showed that TNF protects osteoclasts from alendronate-induced apoptosis by stimulating Bcl-xL expression through Ets-2 [35], while RANKL inhibition in the same setting of inflammation leads to rapid osteoclast apoptosis [36,37]
If the lack of osteogenesis is due to osteoblast toxicity, such as that observed in preclinical models [39], which does not occur with RANKL inhibition [36,40], denosumab would be expected to work in combination with anabolic agents

Summary

Introduction

As discussed in previous reviews in this supplement, a specific inhibitor of receptor activator of nuclear factor-κB ligand (RANKL) could be of great therapeutic value in the treatment of patients with a variety of metabolic and inflammatory bone disorders. Page 4 of 6 (page number not for citation purposes) was able to demonstrate that etidronate therapy had a favorable effect on general bone metabolism (osteopenia), but it did not inhibit serum NTX levels or worsening of erosion scores in patients with RA [34] The results from these trials are consistent with our preclinical studies, which showed that TNF protects osteoclasts from alendronate-induced apoptosis by stimulating Bcl-xL expression through Ets-2 [35], while RANKL inhibition in the same setting of inflammation leads to rapid osteoclast apoptosis [36,37]. If the lack of osteogenesis is due to osteoblast toxicity, such as that observed in preclinical models [39], which does not occur with RANKL inhibition [36,40], denosumab would be expected to work in combination with anabolic agents

Conclusion

10. Green LL: Antibody engineering via genetic engineering of the mouse

12. Kostenuik PJ

Findings

20. Whyte MP