| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | RANK ligand |
| Clinical data | |
| Trade names | Prolia, Xgeva |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a610023 |
| Licence data | US FDA:link |
| Pregnancy cat. | C(US) |
| Legal status | ℞-only (US) |
| Routes | subcutaneous injection, every six months |
| Pharmacokinetic data | |
| Bioavailability | N/A |
| Metabolism | proteolysis |
| Identifiers | |
| CAS number | 615258-40-7 |
| ATC code | M05BX04 |
| UNII | 4EQZ6YO2HI |
| KEGG | D03684 |
| ChEMBL | CHEMBL1237023 |
| Synonyms | AMG 162 |
| Chemical data | |
| Formula | C6404H9912N1724O2004S50 |
| Mol. mass | 144.7 kDa |
| (what is this?) (verify) |
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Denosumab[1] is a fully human monoclonal antibody for the treatment of osteoporosis, treatment induced bone loss, bone metastases, rheumatoid arthritis, multiple myeloma and giant cell tumor of bone.[2][3] It was developed by the company Amgen.[4]
Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction.
It was approved by U.S. Food and Drug Administration (FDA) for use in postmenopausal women with risk of osteoporosis in June 2010, under the trade name Prolia,[5] and for the prevention of skeletal-related events in patients with bone metastases from solid tumors in November 2010, as Xgeva,[6] making it the first RANKL inhibitor to be approved by the FDA.[7] In the summer of 2011 clinical trials were investigating giant cell tumors, multiple myeloma with bone metastases, dosing, safety, and hypercalcemia of malignancy.[8]
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Bone remodeling is the process by which the body continuously builds new bone and removes old bone material. It is driven by various types of cells, most notably osteoblasts, which secrete new bone, and osteoclasts, which break it down. The role of osteocytes is not well understood.
Precursors to osteoclasts, called pre-osteoclasts, express a receptor on their surfaces called RANK, short for receptor activator of nuclear factor-kappa B. RANK is a member of the tumor necrosis factor receptor superfamily. RANK is activated by RANKL (the RANK-Ligand), which is produced by osteoblasts. Activation of RANK promotes the maturation of pre-osteoclasts into osteoclasts.
Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. This protects bone from degradation and helps counter the progression of osteoporosis.[2] The drug therefore mimics the endogenous effects of osteoprotegerin, another receptor produced by osteoblasts which can bind RANKL, thus reducing its effect on RANK and helping to modulate bone production.
Amgen has reported on two clinical trials designed and funded by the company:[9]
Both studies showed a decrease of fractures comparable to zoledronic acid and teriparatide, and slightly more than under oral nitrogenous bisphosphonates.
Other studies have been discussed by Baqir and Copeland (Clinical Pharmacist 2010; 2:400). These are DEFEND, DECIDE and STAND. Bone et al. investigated the effects of denosumab on bone mineral density (BMD), in women with BMD T scores between -1 and -2.5, using a randomised trial comparing the treatment with placebo. The primary endpoint, BMD change from baseline in the lumbar spine after two years, was +6.5% for denosumab and -0.6% for placebo (ARR =7%; p<0.0001). Brown et al. compared denosumab with alendronate using BMD in total hip as the primary outcome measure. There was an increase in total hip BMD of 3.5% and 2.6% in the denosumab and alendronate groups respectively (ARR =1%; p<0.0001; NNT = 100). Although this study was not powered to compare fractures, fractures were reported in 4% of the denosumab and 3.2% of the alendronate group. Kendler et al. investigated denosumab therapy following on from alendronate. Women on alendronate 70mg weekly for a run in period of 1 month were switched to denosumab or alendroanate (with matching placebo). The primary hypothesis was that denosumab was non-inferior to alendronate and the primary endpoint was percentage change in total hip BMD at 12 months. BMD was +1.9% vs +1.05% in patients given denosumab vs those continuing on alendronate (ARR = 0.85%; p<0.0001; NNT = 118). Again this study was not powered to compare fracture rates but fractures were reported as adverse events in 8 patients (3.2%) in the denosumab group and 4 patients (1.6%) in the alendronate group.
The most common side effects include infections of the urinary and respiratory tract, cataract, constipation, rashes and joint pain.[13] A small study found a slightly increased risk of cancer and severe infections, but these results did not reach statistical significance.[2] Another trial showed significantly increased rates of eczema and hospitalisation due to infections of the skin.[11] It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system.[14] It is expressed by T helper cells and thought to be involved in dendritic cell maturation.[15]
The drug is contraindicated in patients with hypocalcaemia. Sufficient calcium and vitamin D levels must be reached before starting a denosumab therapy.[16]
Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.[16]
On 13 August 2009, an Amgen press release regarding the meeting that day with the Advisory Committee for Reproductive Health Drugs (ACRHD) of the (FDA), to review the potential uses of Prolia, said:
After reviewing safety and efficacy data from 30 clinical studies involving more than 12,000 patients, the Committee recommended approval of Prolia for the treatment of postmenopausal osteoporosis, and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer.[17]
October 2009: The U.S. Food and Drug Administration (FDA) delayed approval of denosumab because they needed more information.[18]
June 2010: Denosumab was approved for postmenopausal osteoporosis by the US FDA on June 2, 2010.[7]
Common side effects include osteonecrosis of the jaw, back pain, pain in the extremities, musculoskeletal pain, high cholesterol levels, and urinary bladder infections.[6]
November 2010: FDA approved denosumab (to be marketed as Xgeva) for the prevention of skeletal-related events in patients with bone metastases from solid tumors.[6] (Dosing is a 60 mg subcutaneous injection every six months for postmenopausal osteoporosis and 120 mg every 4 weeks for patients with solid tumors).
The Committee for Medicinal Products for Human Use (CHMP) issued a Positive Opinion for denosumab on 17 December 2009, for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with hormone ablation for prostate cancer.[13][19] Denosumab was approved for marketing by the European Commission on May 28, 2010.
Internationally, because of Amgen's relatively weak GP sales force, Amgen is partnering with GlaxoSmithKline (GSK) in Europe, Australia, New Zealand and Mexico to distribute Prolia.[20]
In September 2009, the firm Sanford Bernstein projected that annual worldwide sales of the drug would reach $5 billion in the year 2015.[21] It projected 2010 sales of over $650 million, mostly from use as a twice-yearly injectable for osteoporosis treatment in post-menopausal women over 50.[22]
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