Denosumab

Denosumab 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. It was developed by the company Amgen.

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, and for the prevention of skeletal-related events in patients with bone metastases from solid tumors in November 2010, as Xgeva, making it the first RANKL inhibitor to be approved by the FDA. In the summer of 2011 clinical trials were investigating giant cell tumors, multiple myeloma with bone metastases, dosing, safety, and hypercalcemia of malignancy.

Mechanism of action
Bone remodeling is the process which continuously removes old material from the bone and adds new bone. It is driven by various types of cells, most notably osteoblasts, which secrete new bone, and osteoclasts, which break bone down. The role of osteocytes is not well understood.

Osteoblasts express a protein called receptor activator of nuclear factor-kappa B ligand (RANKL). RANKL binds to its receptor RANK, a member of the tumor necrosis factor receptor superfamily. RANK is expressed by pre-osteoclasts, and induces their conversion into mature osteoclasts. Denosumab inhibits the maturation of osteoclasts by binding to RANKL, protecting the bone from degradation and thus from osteoporosis. The drug therefore mimics the endogenous effects of osteoprotegerin, another protein produced by osteoblasts which acts as an alternate receptor for RANKL, modulating the RANK/RANKL induced osteoclast activity.

Effectiveness
Amgen has reported on two clinical trials designed and funded by the company:


 * In a phase 3 clinical trial ('FREEDOM') involving 7,808 women, aged 60 to 90, there were significant improvements in the subset of women with more severe disease at the beginning of the study (two or more prevalent vertebral fractures and/or one or more prevalent vertebral fractures with moderate or severe deformity). Researchers reported a 35% risk reduction with denosumab compared with placebo (17% vs. 49%), with new vertebral fractures in this subset of only 31% for those taking denosumab, versus 71% receiving the placebo.


 * The second phase 3 clinical trial involved 1,468 prostate cancer patients receiving hormone-deprivation therapy, who were randomised to receive either denosumab or a placebo every 6 months over a 36 month period. All patients also received supplemental calcium and vitamin D. Of those taking the placebo, 3.9% experienced bone fractures during the 36 months, compared with 1.5% of those who received denosumab.

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 densoumab 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.

Adverse effects
The most common side effects include infections of the urinary and respiratory tract, cataract, constipation, rashes and joint pain. A small study found a slightly increased risk of cancer and severe infections, but these results did not reach statistical significance. Another trial showed significantly increased rates of eczema and hospitalisation due to infections of the skin. It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system. It is expressed by T helper cells and thought to be involved in dendritic cell maturation.

Contraindications and interactions
The drug is contraindicated in patients with hypocalcaemia. Sufficient calcium and vitamin D levels must be reached before starting a denosumab therapy.

Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.

United States
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."

October 2009: The U.S. Food and Drug Administration (FDA) delayed approval of denosumab because they needed more information.

June 2010: Denosumab was approved for postmenopausal osteoporosis by the US FDA on June 2, 2010.

Common side effects include osteonecrosis of the jaw, back pain, pain in the extremities, musculoskeletal pain, high cholesterol levels, and urinary bladder infections.

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. (Dosing is a 60 mg subcutaneous injection every six months for postmenopausal osteoporosis and 120 mg every 4 weeks for patients with solid tumors).

Europe
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. Denosumab was approved for marketing by the European Commission on May 28, 2010.

Sales and pricing
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.

In September 2009, the firm Sanford Bernstein projected that annual worldwide sales of the drug would reach $5 billion in the year 2015. 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.