Compound Name:DenosumabMolecular Target:RANKL (receptor activator of nuclear factor kappa-B ligand)Molecular Structure:Human IgG2 monoclonal antibodyLicensed Indication:Xgeva: Prevention of skeletal-related events in patients with bone metastases from solid tumors; Prolia: treatment of postmenopausal osteoporosis; treatment of men receiving androgen deprivation therapy for non-metastatic prostate cancer; treatment of womManufacturer and/or Distributor:AmgenInitial FDA Approval2010SummaryDenosumab is a humanized recombinant IgG2 monoclonal antibody which is sold under two brand names, Prolia® or Xgeva®. Prolia® is approved for treating patients at high risk for fracture receiving androgen deprivation therapy (ADT) for non-metastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer to increase bone mass; and Xgeva®, for use in bone metastatic solid cancer to prevent further skeletal-related events. Mechanistically, Denosumab binds receptor activator of nuclear factor kappa-B ligand (RANKL) with high affinity and specificity which in turn interfering with its ability to bind to its receptor, receptor activator of nuclear factor kappa-B (RANK). RANK (or CD265), a type I membrane protein and a member of the tumor necrosis factor receptor superfamily, is found on pre-osteoclasts. RANKL (or CD254), tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is expressed on the surface of some T cells and on stromal cells. As bone homeostasis is a constant and continuous cellular balance between old bone break down or removal by osteoclasts, the resorbing cells and new bone synthesis by osteoblasts. In fact, denosumab works by blocking the ability of RANKL to bind to RANK, thereby interfering with activation of this pre-osteoclast and osteoclast cell surface receptor (Figure 1). The absence of RANKL-RANK signaling suppresses maturation of RANK-bearing pre-osteoclasts into osteoclasts and thus preventing from activating osteoclasts in bone resorption/destruction (Castellano, D., et al., 2011). Therefore, the net effect of denosumab interference with osteoclast activation is suppression of bone breakdown, with a shift in the balance toward net bone build-up. In this way denosumab mimics the natural factor, osteoprotegerin, which binds to and therefore counterbalances RANKL effect. Thus, Denosumab inhibits the formation, function, and survival of activated osteoclasts, bone destruction, and localized tumor growth. Currently, Denosumab has shown to be more effective in delaying or preventing skeletal morbidity in patients with bone metastases from several types of cancers (Gravalos, C., et al., 2016). Denosumab is contraindicated for patients with hypocalcaemia. Both calcium and vitamin D repletion therapy should be completed before denosumab therapy is initiated. There are no data concerning interactions with other drugs. Given its mechanism of action it seems unlikely that denosumab will have clinically relevant interactions with small molecules, either immunomodulatory or otherwise. Since RANKL and RANK are expressed on T cells and dendritic cells, respectively, it is possible that denosumab may have immunomodulatory effects. Denosumab has been developed in two distinct dosing regimens with separate approvals and brand names: 1.) As PROLIA® (60 mg given subcutaneously every 6 months), denosumab was approved in 2010 for treatment to increase bone mass in (1) men or postmenopausal women with osteoporosis at high risk for fracture, in which PROLIA® reduces the incidence of vertebral, nonvertebral, and hip fractures; (2) men at risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, in which PROLIA® significantly reduces the incidence of vertebral fractures at 36 months; and (3) women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. Recent studies have shown that PROLIA® not only successfully treat bony metastases and prevent treatment-induced bone loss, it also reduces recurrence and improves survival of postmenopausal breast cancer patients (Gnant, M., Pfeiler, G. & Dubsky, P.C, et al., 2015). Adverse reactions to denosumab in the PROLIA® formulation include: hypocalcemia (especially in patients with severe renal impairment or receiving dialysis), arthralgia, back pain, pain in extremity, osteonecrosis of the jaw, atypical femoral fractures, severe skin rashes and infections, musculoskeletal pain, and hypercholesterolemia. The most common adverse reactions leading to discontinuation of PROLIA® are back pain and constipation. Hypocalcemia, pregnancy, and known hypersensitivity are contraindications. PROLIA® is pregnancy category X-Not for use in pregnancy. 2.) As XGEVA® (120 mg given subcutaneously every 4 weeks) denosumab was approved in 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors and giant cell tumors of the bone. Adverse reactions to denosumab in the XGEVA® formulation include: hypocalcemia, hypophosphatemia, osteonecrosis of the jaw, atypical femoral fractures, embryo-fetal toxicity and hypersensitivity. XGEVA® is pregnancy category D. References

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