A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

Abstract

Purpose: Receptor activator of nuclear factor-nB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. Experimental Design: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. Results: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. Conclusions: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.The propensity of breast cancer cells to metastasize and proliferate in bone is currently explained by a ''seed and soil'' concept (1, 2). Once breast cancer cells colonize the bone marrow, they are attracted to bone surfaces by products of resorbing bone and destroy bone via osteoclast stimulation. The importance of direct osteolytic effects of metastatic cancer cells, including the effects of collagenases, remains uncertain. Breast cancer cells (the ''seed'') seem to secrete factors, such as parathyroid hormone-related protein, that potentiate the development of metastases in the skeleton, which constitutes a fertile ''soil'' rich in cytokines and growth factors that stimulate growth of breast cancer cells. Osteoclasts arise from precursor cells in the monocyte-macrophage lineage. Several osteoclastogenic factors have been implicated in the increased recruitment and activity of osteoclasts in myeloma (3). Active osteoclasts are found in proximity to tumor cells (4) and play a key role in bone lysis in patients with multiple myeloma or cancer-related bone metastases. Normal homeostatic mechanisms are unable to control osteoclastic bone resorption in this setting and the bone destruction often leads to dramatic complications, such as pathologic vertebral and long-bone fractures, pain requiring radiotherapy, spinal cord compression, and hypercalcemia (5).Desp...

Prevention of glucocorticoid‐induced bone loss in mice by inhibition of RANKL

“…Denosumab has a rapid onset of action and a long plasma half-life after a single subcutaneous injection, resulting in a sustained clinical effect on bone that lasts for months. In clinical trials, denosumab has been evaluated in postmenopausal women with low bone mass (17,35), women with skeletal metastases due to breast cancer (19,36), and patients with myeloma bone disease (36). In these studies, denosumab increased BMD at the lumbar spine and the proximal femur (17,35) and suppressed biochemical markers of bone turnover (17,19,35,36), findings that are consistent with our study.…”

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…Denosumab (AMG162) is a fully human Xenomouse®-derived IgG 2 antibody directed against human RANKL (85) and is currently undergoing clinical evaluation in cancer and osteoporosis (86)(87)(88). Pharmacokinetic properties of denosumab are highly influenced by target (RANKL) expression and density (28,86,87).…”

“…Denosumab (AMG162) is a fully human Xenomouse®-derived IgG 2 antibody directed against human RANKL (85) and is currently undergoing clinical evaluation in cancer and osteoporosis (86)(87)(88). Pharmacokinetic properties of denosumab are highly influenced by target (RANKL) expression and density (28,86,87). A strong correlation has been observed between the target saturation and other mechanistic bone resorption markers such as N-and C-telopeptides and NTX and CTX (i.e., POP biomarkers) in NHPs and human patients (28,86,87,89).…”

“…Pharmacokinetic properties of denosumab are highly influenced by target (RANKL) expression and density (28,86,87). A strong correlation has been observed between the target saturation and other mechanistic bone resorption markers such as N-and C-telopeptides and NTX and CTX (i.e., POP biomarkers) in NHPs and human patients (28,86,87,89). These POP biomarkers additionally have shown a strong correlation with other POC markers such as bone mineral density, a critical endpoint for evaluation of denosumab therapeutic efficacy (89)(90)(91)(92).…”

Analysis on Survival and Prognostic Factors for Cancer Patients with Malignancy-associated Hypercalcemia

“…Denosumab (AMG162), a fully human monoclonal IgG2 antibody, targets the RANK-RANKL pathway and has been demonstrated to inhibit bone resorption in osteoporosis and bone metastases with a very good profile of tolerability (Body et al, 2006;Stopeck et al, 2009;. A recombinant version of osteoprotegerin (OPG) showed the ability to suppress the activity of RANKL in vitro and both to prevent MAH and normalize bone turnover in mice (Croucher et al, 2001;Morony et al, 2005).…”