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Clinical development of anti-RANKL therapy
Edward M Schwarz1, Christopher T Ritchlin
1The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642, USA. edward_schwarz@urmc.rochester.edu
Abstract:
The receptor activator of nuclear factor-kappaB 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).
Insights
Denosumab, a fully human monoclonal antibody, targets receptor activator of nuclear factor-kappaB ligand (RANKL) to inhibit osteoclast activity. Clinical trials show its potential for treating osteoporosis and bone metastases.
Area of Science:
- Biochemistry
- Immunology
- Oncology
- Endocrinology
Background:
- Receptor activator of nuclear factor-kappaB ligand (RANKL) and its receptor RANK are key regulators of osteoclast function.
- RANKL signaling is essential for osteoclast differentiation, activation, and survival, making it a therapeutic target for bone diseases.
- Inhibition of RANKL in vivo results in rapid osteoclast apoptosis, with no observed refractory models.
Purpose of the Study:
- To review the clinical development of denosumab, a fully human monoclonal antibody targeting RANKL.
- To discuss the efficacy and safety of denosumab in treating conditions involving excessive bone resorption.
Main Methods:
- Review of 21 human studies on denosumab (AMG 162), a monoclonal antibody against RANKL.
- Analysis of ongoing Phase 3 clinical trials for denosumab.
Main Results:
- Denosumab demonstrates effective inhibition of RANKL.
- Clinical development has progressed through extensive human studies to Phase 3 trials.
Conclusions:
- Denosumab represents a promising therapeutic agent for metabolic bone diseases like osteoporosis.
- It is also being investigated for treating bone metastases in cancers such as multiple myeloma, prostate, and breast cancer.
- The development of denosumab addresses the need for a safe and effective RANKL inhibitor for human use.
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