Status: BLA approved in June 2010; MAA approved in May 2010

Organizations involved:

Amgen Inc. – Manuf.; R&D; Tech.; USA mark.; Europe mark.; Parent

GlaxoSmithKline (GSK) – Intl. mark.

Daiichi Sankyo Co., Ltd. – Japan mark.

Abgenix, Inc. – R&D; Tech.

Immunex Corp. – R&D; Tech.; Former

Description: Xgeva (for cancer indications)/Prolia (for osteoporosis indications) refers to aqueous formulation of denosumab, a fully human dimeric (double-stranded) recombinant monoclonal antibody expressed by Chinese hamster ovary (CHO) cells that targets human RANKL (receptor activator of nuclear factor kappa-B ligand). The dimer has a molecular weight of ~144.7 kDa, with a calculated molecular formula of C6404H9912N1724O2004S50

Prolia is apackaged in single-use prefilled syringes containing 60 mg in a 1 mL solution and single-use vials containing 60 mg in a 1 mL solution. Each 1 mL single-use prefilled syringe of Prolia contains 60 mg denosumab (60mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20 (Tween 20), Water for Injection (USP), and sodium hydroxide to a pH of 5.2. Each 1 mL single-use vial of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2. Prolia is strored in a refrigerator at 2°C to 8°C (36°F to 46°F) in its original carton.

Xgeva is packaged in 120 mg/1.7 mL (70 mg/mL) single-use vials. Each vial of Xgeva contains 120 mg denosumab, 4.6% sorbitol, 18 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2. Neither product contains preservatives.

Prolia has been cited as the first biopharmaceutical likely to be prescribed by patients’ primary physicians rather than specialists, and "the first biotech product introduced into a general practice environment." These statements, apparently originating from Amgen, are wrong, or require\ additional qualification, e.g., many vaccines would need to be eliminated from consideration,

Note, much more XGEVA is used for its bone cancer metastasis-related indication (to prevent fractures in cancer patients whose tumors have spread to the bone) than Prolia for its osteoporosis indication. Osteoporosis involves a 60 mg injection every 6 months, while cancer-related use involved 120 mg (twice as much) administered each months (6x as much), with a 12-times as much Prolia used for cancer-related indications: annually compared to osteoporosis. Thus, the primary potential market for Prolia, in terms of revenue, is for its prostate and potentially other cancer-related indications.

to prevent fractures in cancer patients whose tumors have spread to the bone Nomenclature: RANKL Mab, rDNA [BIO]; Prolia [TR for osteoporosis indications]; XGEVA [TR for cancer indications]; denosumab [USAN; INN]; immunoglobulin G2, anti-(human osteoclast differentiation factor) (human monoclonal AMG162 heavy chain), disulfide with human monoclonal AMG162 light chain, dimer [CAS]; immunoglobulin G2, anti-(human RANK ligand) (human monoclonal AMG162 heavy chain), disulfide with human monoclonal AMG162 light chain, dimer [CAS]; 15258-40-7 [CAS RN]; AMG 162 [SY]; receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal antibody [SY]; NDC 55513-710-01 and NDC 55513-720-01 [NDC]

Biological.: Receptor activator of NF-kappaB (NF-kB) ligand (RANKL), its cellular receptor RANK, and osteoprotegerin (OPG), the physiological inhibitor/ligand of RANKL, were discovered by Immunex using a genomics-based approach. Signals mediated by the RANK/RANKL interaction are involved in stimulating the differentiation and function of osteoclasts, the cells responsible for bone resorption/loss. Denosumab is designed to target and bind RANKL, preventing its binding to RANK, preventing or slowing bone resorption.

RANK (Receptor Activator of NF-kB) and its ligand (RANKL) are a receptor/ligand pair that play an important role in immune responses and bone metabolism. NF-kB is a ubiquitous transcription factor that is extensively utilized in cells of the immune system. RANK is a member of the tumor necrosis factor (TNF) superfamily of cytokines. RANKL also has been referred to as “osteoprotegerin binding protein,” “osteoclastogenesis differentiation factor,” and “TRANCE.” The RANK protein instigates intracellular events by interacting with various TNF Receptor Associated Factors (TRAFs). RANK and RANKL, both murine and human, have been cloned and characterized (e.g., U. S. 6,017,729, WO 98/25958, EP 0873 998, EP 0911 342, U. S. 5,843,678, WO 98/46751 and WO 98/54201). RANK is expressed primarily on the surface of epithelial cells, some B and T cell lines, fibroblasts, dendritic cells and osteoclasts and their precursors. RANKL, which also exists in a soluble form, is expressed primarily in hematopoietic tissues, such as bone marrow, thymus and spleen, and also T cells and osteoblast lineage cells. RANKL binds not only to RANK, but also to a naturally occurring RANK decoy protein called osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family (e.g., U. S. 6,015,938 and WO98/46751). OPG is a naturally occurring protein which inhibits RANK Ligand and its ability to activate bone-resorbing osteoclasts.

RANKL, RANK, and OPG form an essential cytokine system that is capable of regulating all aspects of osteoclast (bone-resorbing) functions, including proliferation, differentiation, fusion, activation, and apoptosis. Signals mediated by the RANK/RANKL interaction are involved in stimulating the differentiation and function of osteoclasts, the cells responsible for bone resorption. The activation of RANK, such as by its interaction with RANKL, activates TRAF-mediated intracellular events that result in the upregulation of the transcription factor NF-kB, a ubiquitous transcription factor that is extensively utilized in cells of the immune system.

Osteoclasts are cells responsible for bone removal, and inhibiting the formation or functioning of these cells reduces bone resorption (loss of bone cells). Bone is constantly being formed and removed through a natural process of remodeling. Abnormal bone resorption due to local or systemic stimulation of osteoclast differentiation and activation is a hallmark of various benign and malignant bone diseases. Bone resorption/loss is dependent on RANKL, the primary mediator of osteoclast formation, function, and survival. The study of the RANK/RANKL/OPG axis in animal models has firmly established the importance of this pathway in bone mass regulation and provides the rationale for the design of a mechanism-based targeted approach to inhibit RANKL in pathologic bone loss settings.

The balance of bone resorption naturally depends on the local RANKL-to-OPG ratio, which is enhanced in bone metastases and humoral hypercalcemia of malignancy. Exogenous administration of OPG (or other agents that bind RANKL, e.g., denosumab) to tumor-bearing animals corrects the increased RANKL-to-OPG ratio, inhibits the activity of RANKL and reverses the skeletal complications of malignancies.

Denosumab is a fully human monoclonal antibody that can bind and inhibit human RANKL in a way that mimics the natural bone-protecting actions of OPG. RANKL-binding inhibitors (RANKL antagonists), e.g., denosumab, that bind to RANKL and do not activate RANK may be useful for treatment of osteoporosis, rheumatoid arthritis, prosthetic loosening, and malignant bone diseases, including tumor metastasis, humoral hypercalcemia of malignancy, and multiple myeloma.

Preclinical models have shown that inhibiting RANKL, e.g., by binding it with an antibody (e.g., denosumab), significantly improves cortical and trabecular bone density, volume and strength. Cortical bone is the protective outer shell around every bone in the body. Trabecular bone is known as spongy bone and is surrounded by the harder cortical layer.

As shown in trials (see Trials section below), a single subcutaneous injection of denosumab causes rapid and sustained suppression of bone turnover/resorption markers.

Denosumab, i.e, the recombinant molecule, was created/discovered using Abgenix’s XenoMouse antibody generation and screening technology. See the Biological section of the Panitumumab (Vectibix) entry for further information.

Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Companies.: Prolia is manufactured by Amgen Inc., CBER/FDA est. no. 1080. Amgen holds full worldwide rights to denosumab.

Denosumab was originally developed by Abgenix, Inc. in collaboration with Immunex Corp., which was acquired by Amgen in 2002. In Dec. 2006, Amgen also acquired Abgenix for ~$2.2 billion, and subsequently lead development of denosumab. This acquisition eliminated the tiered royalty that Amgen would have paid to Abgenix on future sales of denosumab.

In July 2007, Daiichi Sankyo acquired exclusive marketing rights in Japan. The company paid $20 million upfront; will pay unspecified royalties on sales in Japan; assumed all development costs for denosumab in Japan. Daiichi Sankyo and will pay ~$150 million of projected worldwide development costs for denosumab through 2009.

In July 2009, Amgen and GlaxoSmithKline (GSK) concluded a collaboration agreement to jointly commercialize Prolia for postmenopausal osteoporosis in Europe, Australia, New Zealand and Mexico once the product is approved in these countries. Amgen handles Prolia's postmenopausal osteoporosis and oncology indications: in the U.S. and Canada, and all oncology indications: in Europe and in other specified markets. GSK registers and commercialize denosumab for all indications: in countries where Amgen does not currently have a commercial presence, including China, Brazil, India and South Korea but excluding Japan. Amgen has the option of its expanded role in commercialization in both Europe and certain emerging markets in the future.

In April 2014, Amgen and GSK modified their marketing agreements. Amgen assumed full marketing duties in areas including the EU, Switzerland, Norway, Russia and Mexico. GSK retained rights in Australia for the bone indications and in countries such as China, Brazil, India and South Korea to sell it for other uses. FDA class: Biologic BLA

Approvals: Date = 20100601, BLA 125320

Date = 20101118; BLA supplement; Indication = for the prevention of skeletal-related events in patients with bone metastases from solid tumors

the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors Date = 2010601; BLA supplement; Indication = broad approval for osteoporosis in postmenopausal women Indications: [Full text of the Xgeva "Indications and USAGE" section of product insert/labeling, 6/2012]:

Xgeva is a RANK ligand (RANKL) inhibitor indicated for:
Prevention of skeletal-related events in patients with bone metastases from solid tumors
Important limitation of use: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Status: In Dec. 2006, Amgen filed a BLA for FDA approval of denosumab for the treatment of metastatic colorectal cancer patients who have failed standard chemotherapy (second-line treatment).

In Dec. 2008 Amgen filed and on Feb. 18, 2009 FDA accepted a BLA for filing for treatment and prevention of postmenopausal osteoporosis (PMO) in women and treatment and prevention of bone loss in patients undergoing hormone ablation therapy for either prostate or breast cancer. The Prescription Drug User Fee Act (PDUFA) action date was Oct. 19, 2009.

As of Feb. 2009, Amgen had also submitted marketing applications for use of denosumab for these indications: in the European Union, Canada, Switzerland, and Australia.

On Aug. 14, 2009, the Advisory Committee for Reproductive Health Drugs (ACRHD), FDA, reviewed the Prolia for the prevention and treatment of postmenopausal osteoporosis and the prevention and treatment of bone loss in patients undergoing hormone ablation for either prostate cancer or breast cancer. ACRHD recommended approval for the treatment of postmenopausal osteoporosis and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer. The Committee recommended against approval of Prolia to treat or prevent bone loss in women with breast cancer undergoing hormone ablation until additional data are available. The Committee also recommended against approval of Prolia to prevent bone loss in low-risk patients in all three populations. ACRHD also recommended that Prolia have a Risk Evaluation and Mitigation Strategy (REMS), which could include a medication guide and a healthcare provider communications plan.

In Oct. 2009, Amgen received a complete response letter from the FDA's Division of Reproductive and Urologic Products that sought more information on several items including its postmarket surveillance plan. The letter did not require additional pre-marketing trials to complete the review of the osteoporosis treatment indication. The FDA also requested all updated safety data related to Prolia. Amgen submitted the requested information for the treatment indication in late Jan. 2010, and the PDUFA date was reset to July 25, 2010.

On May 28, 2010, Prolia received European Union (EU) approval "for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures" [an indication not approved by FDA in its initial approval]. The MAA for Prolia included data from six Phase III trials, including two pivotal Phase III studies with fracture endpoints in the osteoporosis and prostate cancer settings. All six studies showed Prolia's ability to increase bone mineral density (a measure of bone strength) at all skeletal sites measured. With this approval, Prolia became is the first and only product approved in Europe for the treatment of bone loss associated with hormone ablation in men with prostate cancer.

On June 1, 2010, FDA granted approval to Prolia. This was about two months ahead of the PDUFA date. Prolia was approved with a risk evaluation and mitigation strategy (REMS) that included a Medication Guide for patients and communications to health care providers to explains its risks and benefits. Note, approval was granted about two months earlier than the PDUFA deadline (somewhat unusual for FDA). The REMS involves comprehensive post-marketing surveillance, with Amgen continuing to gather data from extension studies in more than 4,500 women with postmenopausal osteoporosis who will have exposure to Prolia for up to 10 years. Amgen will also implement an international Prolia long-term safety observational study to assess pre-specified adverse events of special interest based on seven existing data systems from five countries, which will include healthcare administrative databases, electronic medical records, and national health registries. These women with postmenopausal osteoporosis who received Prolia will be followed long term. Amgen also will launch the Prolia Post marketing Active Safety Surveillance Program to monitor the long-term safety of Prolia and improve the quality of data collected in the post-marketing setting. This program is intended to enhance the adverse event reporting system by soliciting reports of pre-specified adverse events of special interest.

On May 20, 2011, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended a positive opinion for the marketing authorization of XGEVA for the prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumors. The CHMP also recommended to grant XGEVA an additional year of data and market exclusivity in the EU since the indication was considered significantly new for XGEVA, and based on the significant clinical benefit of the product in comparison with existing therapies.

Upon original FDA approval, Amgen filed a sBLA seeking approval for prevention of metastasis to bone in prostate cancer patients, with clinical trial results expected later in 2010. Also upon its original approvals, regulatory filings were pending in Switzerland, Canada, Australia, and Japan.

In Feb. 2012, and FDA review committee voted against a new use for Xgeva [denosumab] in prostate cancer, citing Xgeva's ability to slow the spread of the disease as not translating into meaningful benefits for patients, specifically as a preventive measure for men with recurring prostate cancer that is at high risk of spreading to the bones amd who have also attempted and failed treatment with hormone therapy. The panel voted 12 to 1 that the benefits of the drug did not outweigh its risks, which included bone disease in about 6% of patients. A 1,432-patient study conducted by Amgen showed Xgeva slowed the spread of cancer to the bone by about 4.2 months when compared to patients who received placebo. Although "that delay was statistically significant, the FDA's reviewers questioned whether it is 'an adequate measure of clinical benefit' for patients with prostate cancer."

On April 26, 2012, FDA issued Amgen a Complete Response Letter (CRL) for its supplemental BLA (sBLA) for XGEVA to treat men with castration-resistant prostate cancer (CRPC) at high risk of developing bone metastases. FDA determined that the effect on bone metastases-free survival (BMFS) was of insufficient magnitude to outweigh the risks (including osteonecrosis of the jaw) of XGEVA in the intended population, and requested data from an adequate and well-controlled trial(s) demonstrating a favorable risk-benefit profile for XGEVA that is generalizable to the U.S. population.

In late May 2010, EMA/EU granted broad approval for osteoporosis in postmenopausal women, with FDA granting approval about a week later (with this granted almost two months earlier than expected).

In June 2011, Amgen submitted a sBLA to tcastrate-resistant prostate cancer to reduce the risk of developing bone metastases. The sBLA submission was based on a pivotal Phase III study ('147), which evaluated Xgeva versus placebo in 1,432 men with castrate-resistant prostate cancer. The results demonstrated that Xgeva significantly prolonged bone metastasis-free survival by more than 4 months compared with placebo (29.5 vs 25.2 months, respectively) in men with castrate-resistant prostate cancer that had not yet spread to the bone. A PDUFA) target action date of April 26, 2012 was assigned.

Tech. transfer: The U.S. Xgeva product insert cites 6,740,522, "Antibodies against ligand for receptor activator of NF-kB," assigned to Immunex, expiring Dec. 22, 2017; 7,411,050, "Monoclonal blocking antibody to human RANKL," assigned to Immunex, expiring Dec. 22, 2017; 7,097,834. "Osteoprotegerin binding proteins." assigned to Amgen, expiring Apr 16, 2017; and 7,364,736, "Antibodies to OPGL," assigned to Amgen, expiring Jun 25, 2022. U.S. 7,097,834 and 7,411,050, "Monoclonal blocking antibody to human RANKL," assigned to Immunex, now Amgen, appears to specifically cover denosumab, with the claims citing the antibody sequence and monoclonal antibody. U.S. 7,364,736, " Antibodies to OPGL," claims various antibodies and antibody structures that inhibit binding of a human osteoprotegerin ligand (OPGL) to an osteoclast differentiation and activation receptor (ODAR).

The U.S. Prolia product insert cites " 6,740,522; 7,097,834; 7,364,736; and 7,411,050, ["Monoclonal blocking antibody to human RANKL," assigned to Immunex, expiring Dec 22, 2017] as well as other patents or patents pending."

Other denosumab-related patents/applications, originally assigned to Immunex, now Amgen, include 6,740,522 (and related 6,419,929; 6,242,213 and application US2002086826), “Antibodies against ligand for receptor activator of NF-kB,” including claims for denosumab; 2003017151 A1, “Therapeutic Use of RANK Antagonists”; and 6,017,729, “Receptor activator of NF-.kappa.B.”

EP 0975754, "OSTEOPROTEGERIN BINDING PROTEINS AND RECEPTORS," assigned to Amgen, expires in 2018. EP 0946725, "RECEPTOR ACTIVATOR OF NF-KAPPA B, RECEPTOR IS MEMBER OF TNF RECEPTOR SUPERFAMILY, assigned to Immunex, expires in 2017

Trials: Pivotal Phase III trials for colorectal cancer appear not to have been reported yet (as of July 2007).

Phase III clinical studies with denosumab for osteoporosis were initiated in 2004; and for metastatic bone disease in cancer patients in 2006. In the oncology setting, denosumab is being investigated for its potential to delay bone metastases as well as inhibit and treat bone destruction across many stages of cancer. It is also being studied in a range of bone loss conditions including treatment-induced bone loss, multiple myeloma, osteoporosis, and bone erosions in rheumatoid arthritis.

In the Feb. 23, 2006 issue of the New England Journal of Medicine, 12-month results were reported from a Phase II dose-ranging study for osteoporosis using subcutaneously administered denosumab in 412 postmenopausal women with low bone mineral density. Subjects randomly received denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7% (compared with an increase of 4.6% with alendronate and a loss of 0.8% with placebo), at the total hip of 1.9 to 3.6% (compared with an increase of 2.1% with alendronate and a loss of 0.6% with placebo), and at the distal third of the radius of 0.4 to 1.3% (as compared with decreases of 0.5% with alendronate and 2.0% with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline, a biomarker of bone resorption, were evident three days after administration of denosumab, showing that denosumab had a rapid onset of action. The duration of the suppression of bone turnover appeared to be dose-dependent. No neutralizing antibodies to denosumab were observed throughout the two years. Adverse events was similar among the denosumab, placebo and Fosamax groups and showed no new pattern of events in the second year of treatment.

In June 2006, interim data from two Phase II studies showed denosumab treatment in 255 IV bisphosphonate-naïve breast cancer patients with established bone metastases resulted in a rapid suppression of bone turnover among advanced cancer patients with bone metastases. These results were also sustained at all time points measured in the study. Bone metastases are one of the most frequent causes of pain in people with cancer, and may lead to skeletal-related events (SREs) such as fractures, the need for bone surgery or radiation, and other complications. When tumor cells invade bone, they secrete growth factors that stimulate RANK Ligand production, promoting increased bone resorption (bone loss). In an interim analysis of a separate Phase II study of 49 prostate, breast, and multiple myeloma patients on established IV bisphosphonate therapy, twice as many patients achieved normalization of bone turnover when they were switched from IV bisphosphonate therapy to denosumab. At week 13, 76% of denosumab patients and 38% of patients who remained on the IV bisphosphonate achieved normal levels of bone turnover.

In Sept. 2006, results from a post-hoc exploratory analysis of an ongoing, multicenter, Phase II study (12-month results reported in NEJM in Feb.) showed that subjects treated with denosumab subcutaneously, 60 mg twice yearly for up to 24 months, experience an improvement not only in bone mineral density (BMD) but also in parameters of hip structural analysis (HSA), a technique that estimates geometric properties of bone strength. These results support the potential of targeting RANK Ligand using denosumab to improve bone structural strength.

In June 2007, results from a Phase II study indicated that denosumab may be useful for treatment of rheumatoid arthritis (RA). Denosumab reduced bone erosion, but did not significantly improve patients’ ACR scores (which would be expected, since Denosumab does not affect inflammation within joints). Denosumab may be useful and tested in combination with accepted RA treatments.

In Jan. 2008, results were reported from a head-to-head, one year, double-blind study comparing the effects of twice-yearly subcutaneous injections of denosumab versus weekly oral doses of alendronate (Fosamax) on bone mineral density (BMD) in 1,189 postmenopausal women with low bone mineral density. The study met primary and all secondary endpoints. Denosumab achieved significantly greater BMD gains at the total hip, hip trochanter and distal radius compared with alendronate . For the primary endpoint, the relative magnitude of BMD improvement at the total hip was ~40% greater in the denosumab versus the alendronate group. The changes in BMD in the alendronate group were consistent with previously reported studies.

In April 2008, results were published in the Journal of Clinical Endocrinology and Metabolism from a 24-month, 332-patient Phase III pivotal study in women with early and late stage postmenopausal osteoporosis. Twice-yearly subcutaneous injections of denosumab increased bone mineral density (BMD) at all sites measured, including in highly cortical areas of the skeleton. Cortical bone comprises 75% of skeletal mass and is a primary determinant of overall strength in vertebral and non-vertebral sites throughout the skeleton. Denosumab significantly increased lumbar spine BMD compared with placebo at 24 months (6.5% vs. -0.6% ; P<0.0001). Denosumab also = significantly increased in BMD at the total hip (3.4% vs. -1.1%; P<0.0001), 1/3 distal radius (wrist) (1.4% vs. -2.1%; P<0.0001), and total body (2.4% vs. -1.4%; P<0.0001). Time since menopause did not influence the BMD response to denosumab. The overall incidence of adverse events was similar between the denosumab and placebo groups. The most common adverse events in both treatment groups were arthralgia, nasopharyngitis, and back pain. No opportunistic infections were reported. No infections were considered by the site investigators to be related to denosumab treatment.

In July 2008, results were disclosed from the pivotal fracture Phase III trial evaluating denosumab for postmenopausal osteoporosis. In this pivotal, three-year, international, Phase 3 study of ~7,800 women with osteoporosis, patients were randomized to receive either denosumab, given by subcutaneous injection once every six months, or placebo injections. For the primary endpoint, treatment with denosumab resulted in a statistically significant reduction in the incidence of new vertebral fractures compared with placebo treatment. In addition, women receiving denosumab experienced a statistically significant reduction in the incidence of new non-vertebral and hip fractures (each secondary endpoints) compared with those receiving placebo. The incidence and types of both adverse and serious adverse events observed in this study, including serious infections and neoplasms, were similar between the denosumab and placebo groups. The most common adverse events across both treatment arms were arthralgia, back pain, hypertension and nasopharyngitis. It was concluded that denosumab treatment both increases bone mass and reduces the risk of skeletal fractures in women with postmenopausal osteoporosis.

In Sept. 2008, results from the STAND (Study of Transitioning from AleNdronate to Denosumab) trial showed that subcutaneous injections of denosumab every six months achieved significantly greater increases in bone mineral density (BMD) versus those achieved with alendronate at all sites measured. This was a non-pivotal Phase III head-to-head, double-blind trial comparing BMD gains in postmenopausal women with low bone mass who transitioned from weekly oral alendronate (Fosamax from Merck) to denosumab versus those who continued alendronate. This type of result had not been reported in any previous study transitioning patients from one bisphosphonate to another. For the primary endpoint, denosumab resulted in significant increases in BMD at the total hip compared with alendronate (1.9% vs. 1.05%, p <0.0001). Denosumab also resulted in significant increases in BMD compared with continued alendronate treatment at all secondary endpoints including the lumbar spine, femoral neck, hip trochanter and 1/3 radius. The incidence and types of adverse events, including neoplasm and infection, were well-balanced between denosumab and alendronate treatment groups.

Also in Sept. 2008, the DECIDE head-to-head trial showed that more than 75% of patients preferred the twice-yearly subcutaneous injection (denosumab) Compared to a weekly oral tablet. More than 75% of patients in both study arms preferred subcutaneous injection over oral pills (p <0.0001)

In support of the original EU approval (for prostate cancer-related treatment), results from the pivotal HALT (Hormone Ablation Bone Loss Trial) study, which evaluated change from baseline in lumbar spine BMD in 1,468 men undergoing androgen deprivation therapy (ADT) for non-metastatic prostate cancer, showed that patients treated with Prolia experienced a 62% reduction in the relative risk of a new vertebral fracture with Prolia compared to placebo at 36 months, with significant reduction observed as early as month 12.(ii)

The BLA submission contained data from six Phase III trials involving more than 11,000 patients. Two Phase III pivotal studies with fracture endpoints, in the postmenopausal osteoporosis (PMO) and prostate cancer settings, demonstrated denosumab's ability to reduce fracture, and all six studies showed denosumab's ability to increase bone mineral density at all skeletal sites measured.

In support of original approals, the pivotal three-year Phase III Fracture REduction Evaluation of Denosumab in Osteoporosis every six Months (FREEDOM) study in 7,808 women with postmenopausal osteoporosis demonstrated that Prolia, administered as a 60mg subcutaneous injection every six months, compared with placebo at three years resulted in a 68% reduction in vertebral fractures (4.8% absolute risk reduction). The incidence of new spine fractures was 2.3% with Prolia vs. 7.2% with placebo. There was a 40% reduction in hip fractures (0.3% absolute risk reduction). The incidence of hip fractures was 0.7% with Prolia vs. 1.2% with placebo. There was a 20% reduction in non-vertebral fractures (1.5% absolute risk reduction). The incidence of non-spine fractures was 6.5% with Prolia vs. 8% with placebo. Significant bone density increases were seen at all key sites measured (8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck).

In the pivotal Phase III FREEDOM {Fracture REduction Evaluation of Denosumab in Osteoporosis every six Months] study in7,808 women with postmenopausal osteoporosis, Prolia, administered as a 60mg subcutaneous injection every six months was compared with placebo at three years. Results included a 68% reduction in vertebral fractures (4.8% absolute risk reduction). The incidence of new spine fractures was 2.3% with Prolia vs. 7.2% with placebo, and there was a 40% reduction in hip fractures (0.3 percent absolute risk reduction). The incidence of hip fractures was 0.7% with Prolia vs. 1.2% with placebo, and a 20% reduction in non-vertebral fractures (1.5% absolute risk reduction). The incidence of non-spine fractures was 6.5% with Prolia vs. 8% with placebo. Significant bone density increases were observed at all key sites measured (8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck). However, serious infections leading to hospitalizations were reported more frequently in the Prolia-treated patient group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear, were more frequent in patients treated with Prolia. Endocarditis was reported more frequently in the Prolia-treated patient group. Epidermal and dermal adverse events such as dermatitis, rashes, and eczema have been reported.

Upon FDA approval, ongoing trials included six late-stage trials supporting prevention of metastasis in prostate cancer.

Medical: Denosumab can be administered to stimulate bone formation in patients having lost bone density but who are not actively losing bone. Patients who will benefit include those whose condition is not characterized by loss of bone density, but who nonetheless require new bone formation, such as for example, accident victims who have lost bone due to traumatic injury.

The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen.

The recommended dose of Prollia is 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen

Xgeva/Prolia causes significant suppression of bone turnover and this suppression may contribute to the occurrence of osteonecrosis of the jaw, a severe bone disease that affects the jaw, atypical fractures, and delayed fracture healing.

Market: Denosumab could become a major alternative for treatment of osteoporosis. Its annual dosage is much less frequent than for some other major osteoporosis therapeutics. It would only require a physician visit once-a-year. It could also become a major trreatment for prevention of metastasis to bone in prostate and other cancer treatment. However, particularly for its osteoporosis indication, where there is considerable competition, market uptake is expected to not be rapid.

Xgeva/Prolia is claimed to the first biopharmaceutical to be prescribed by patients’ primary physicians rather than specialists.

Total 2013 sales were $744 million; 2012 sales of Xgeva/Prolia by Amgen were ~$750 million. Total sales by GSK in its territories in 2013 was $84.6 million.

Upon FDA approval (for osteoporosis), Amgen reported Prolia cost $825 per 60-milligram dose, which is injected just under the skin twice a year, bringing the total close to $1,650 a year. This is generally competitive with other branded osteoporosis therapies.

Prolia costs for cancer-related treatment (once monthly at double the dose) will be higher than for osteoporosis, with patients receiving double the dose monthly, not twice annually. At the U.S. market launch price, the annual cost for the cancer indications: would be $19,800.

Upon approval analysts surveyed by Bloomberg projected Prolia may have sales of $942 million in 2010, rising to $2.9 billion annually by 2013. Similarly, Oppenheimer & Co. projected global sales for osteoporosis reaching more than $2 billion a year. Cowen & Co. projected sales of $1.4 billion/year, based on osteoporosis use with Prolia eventually capturing 28% of this market; and increasing to $6 billion/year, if widely accepted for prostate cancer treatment. Sanford Bernstein estimated that the post-menopausal osteoporosis market will be $4.8-$4.9 billion by 2015, with denosumab having a 20% market share and sales of $1.7 billion for the year.

Amgen was expected to experience delays and problems in launching Prolia, particularly since it lacks a detailing staff directed to general practitioners, with all of its other products marketed to specialists. With just about every other larger pharmaceutical company already having a broad-based detail staff, Amgen was one of the few major companies lacking such capabilities and no U.S. company had initiated comparable efforts to develop such as broad detailing staff in recent years. Amgen has been reported to be hiring "mobile representatives" across the U.S. The positions are part of a "rotational program" for 18 to 24 months in which a rep must cover required territories, with "significant travel," and then be willing to relocate to any territory within the state upon completion.

In June 2010, the National Institute for Health and Clinical Excellence (NICE), U.K., published draft guidance recommending that the National Health Service (NHS) use Prolia for the primary and secondary prevention of osteoporosis when treatment with currently available oral bisphosphonates is unsuitable.

In Aug. 2010, the National Institute for Health and Clinical Excellence (NICE), U.K. terminated its review of Prolia for the National Health Service for the treatment of therapy-induced bone loss in patients with non-metastatic prostate cancer due to a lack of evidence of efficacy and safety. Amgen, inexplicably, informed the Institute it would not be submitting any evidence for Prolia for this indication.

In Oct. 2010, NICE published final guidance recommending the use of Prolia on the National Health Service for women patients unable to take the oral bisphosphonates alendronate and either Procter & Gamble’s Actonel (risedronate) or etidronat, providing another treatment pathway for those at risk from osteoporotic fractures in whom standard therapy is not an option. NICE approval was based on data from the FREEDOM study, which clearly showed its fracture-reducing properties after the 36-month incidence of new radiographically-diagnosed vertebral fractures was found to be just 2.3% in women taking Prolia compared to 7.2% in those given a placebo. Prolia was deemed to have a relatively reasonable price – costing the NHS around £366 per patient per year.

In April 2012, NICE issued draft guidance recommending Xgeva use for certain groups of cancer patients whose disease has spread to their bones. Based on current prices and with the discount available under the patient access scheme (PAS) agreed for Xgeva between Amgen and the Department of Health, NICE's independent appraisal committee considered Xgeva to be a cost-effective option in people who would be treated with Novartis' Zometa (zoledronic acid) - or other bisphosphonates in the case of metastatic breast cancer. However, the panel added that, in comparison with best supportive care, and even with the PAS in place, Xgeva was associated with high incremental cost-effectiveness ratios (ICERs), the lowest of which remained above £70,000 per quality-adjusted life year (QALY) gained, so it could not be considered cost-effective when compared with best supportive care. Amgen estimated that there are over 150,000 patients in the UK with solid tumors and bone metastases, of which breast and prostate cancer account for more than 80%.

In Aug. 2012, the National Institute for Health and Clinical Excellence (NICE), U.K. in final draft guidance, recommended Xgeva as a treatment for cancer patients with bone metastases, to prevent skeletal events--e.g., fractures--in breast cancer patients and others whose cancer has spread from solid tumors (excluding prostate cancer). NICE had previously ruled Xgeva was too costly for its benefitsm with its retail price for 13 courses or a year's treatment just over £4,000 ($6,277). But Amgen offered the NHS a discount (not disclosed), which altered its final decision. The draft guidance is expected to be finalized completely later in 2012, making Xgeva available for National Health Service eligible patients.

In 2012, Xgeva looks as though it could experience significant market expansion in coming years, particularly if approved for prevention of prostate and breast cancer spread to the bone. Amgen started a trial in June 2012 to test Xvega's ability to prevent breast cancer metastasis to bone; designed to enroll 4,500 women, with results in 2016. These approvals could add up to $2 billion/year in sales, with the prostate cancer indication accounting for $.5-$1 billion.

Competition: Upon original approval, the worldwide osteoporosis treatment market was reported to be $8 billion or more. The osteoporisis market is now rather crowded, with a variety of treatments available. Bisphosphonates, particularly Merck & Co.'s Fosamax, are the leading product in this class and are increasingly available as cheap generics.