Denosumab
Encyclopedia
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 trial
s were investigating giant cell tumors, multiple myeloma with bone metastases, dosing, safety, and hypercalcemia of malignancy.
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 osteoblast
s, which secrete new bone, and osteoclast
s, which break bone down. The role of osteocyte
s 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.
Both studies showed a decrease of fractures comparable to zoledronic acid and teriparatide
, and slightly more than under oral nitrogenous bisphosphonate
s.
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.
, cataract
, constipation
, rash
es 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.
. 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.
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).
(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.
(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.
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, treatment induced bone loss, bone metastases, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
and giant cell tumor of bone
Giant cell tumor of bone
Giant-cell tumor of the bone is a relatively uncommon tumor of the bone. It is characterized by the presence of multinucleated giant cells . Malignancy in giant cell tumor is not common. However, if malignant degeneration does occur it is likely to metastasize to the lungs. Giant cell tumors are...
. It was developed by the company Amgen
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
.
Denosumab is designed to target RANKL
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...
(RANK
RANK
Receptor Activator of Nuclear Factor κ B , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding...
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
Bone Metastases
Bone metastases, or metastatic bone disease, is a class of cancer metastases that results from primary tumor invasion to bone. Bone-originating cancers like osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare...
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 trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s were investigating giant cell tumors, multiple myeloma with bone metastases, dosing, safety, and hypercalcemia of malignancy.
Mechanism of action
Bone remodelingBone remodeling
Bone remodeling is a lifelong process where mature bone tissue is removed from the skeleton and new bone tissue is formed...
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 osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s, which secrete new bone, and osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
s, which break bone down. The role of osteocyte
Osteocyte
An osteocyte, a star-shaped cell, is the most abundant cell found in compact bone. Cells contain a nucleus and a thin ring of cytoplasm. When osteoblasts become trapped in the matrix they secrete, they become osteocytes...
s 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
Tumor necrosis factor receptor
A tumor necrosis factor receptor , or death receptor, is a trimeric cytokine receptor that binds tumor necrosis factors . The receptor cooperates with an adaptor protein , which is important in determining the outcome of the response A tumor necrosis factor receptor (TNFR), or death receptor, is a...
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
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
effects of osteoprotegerin
Osteoprotegerin
Osteoprotegerin , also known as osteoclastogenesis inhibitory factor , or tumor necrosis factor receptor superfamily member 11B , is a protein that in humans is encoded by the TNFRSF11B gene...
, 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 cancerProstate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
patients receiving hormone-deprivation therapy, who were randomised to receive either denosumab or a placeboPlaceboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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
Teriparatide
Teriparatide is a recombinant form of parathyroid hormone, used in the treatment of some forms of osteoporosis. It is manufactured and marketed by Eli Lilly and Company.-Administration:...
, and slightly more than under oral nitrogenous bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s.
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.
Adverse effects
The most common side effects include infections of the urinary and respiratory tractRespiratory tract
In humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...
, cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
es and joint pain. A small study found a slightly increased risk of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and severe infections, but these results did not reach statistical significance
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
. Another trial showed significantly increased rates of eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. It is expressed by T helper cells and thought to be involved in dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
maturation.
Contraindications and interactions
The drug is contraindicated in patients with hypocalcaemiaHypocalcaemia
In medicine, hypocalcaemia is the presence of low serum calcium levels in the blood, usually taken as less than 2.1 mmol/L or 9 mg/dl or an ionized calcium level of less than 1.1 mmol/L or 4.5 mg/dL. It is a type of electrolyte disturbance...
. Sufficient calcium and vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
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 UseCommittee for Medicinal Products for Human Use
The Committee for Medicinal Products for Human Use , formerly known as Committee for Proprietary Medicinal Products , is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding medicinal products for human use.E.g.: In June 2007 the CHMP...
(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 GlaxoSmithKlineGlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
(GSK) in Europe, Australia, New Zealand and Mexico to distribute Prolia.
In September 2009, the firm Sanford Bernstein
Sanford Bernstein
Sanford C. Bernstein & Co., also known as Bernstein, is the sell-side research unit of AllianceBernstein L.P.Sanford C. Bernstein was founded in 1967 as an investment-management firm for private clients. In October 2000, Alliance Capital acquired Sanford C...
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
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
treatment in post-menopausal women over 50.