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XGEVA (denosumab)

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Mechanism of action

XGEVA® (denosumab) binds to RANKL to inhibit bone resorption [SmPC, p. 9]

Denosumab, the active substance in XGEVA®, is a human monoclonal antibody, which targets and binds with high specificity and affinity to a protein known as RANK ligand (RANKL).[SmPC, p. 9; CHMP AR, p. 6]

RANKL is, together with its receptor RANK and osteoprotegerin (OPG), the key mediator in the pathway involved in regulating bone resorption.[CHMP AR, p. 14]

RANKL exists as a transmembrane or soluble protein, and is essential in the formation, function and survival of osteoclasts, the cells responsible for bone resorption and destruction of bone.[SmPC, p. 9]

XGEVA® blocks the formation, activation, and survival of osteoclasts and reduces bone resorption. In effect, this reduces the loss of bone, reducing the risk of skeletal-related events (SREs).[CHMP AR, p. 6]

XGEVA® (denosumab) mechanism of action

Bone destruction in metastatic bone disease occurs mainly as a result of increased osteoclast activity, stimulated by RANKL. Bone loss in giant cell tumours of bone is also mediated by the RANK/RANKL interaction. OPG is a physiologically occurring receptor that binds to and blocks the RANKL, leading to an increase in bone mass. Similarly, inhibition of the RANK/RANKL by XGEVA® affects the bone remodelling cycle and reduces bone resorption as well as cancer-induced bone destruction.[CHMP AR, pp. 6, 14; SmPC, p. 9]


XGEVA® (denosumab) molecular properties

XGEVA® is a fully human monoclonal IgG2 antibody produced by recombinant DNA technology.[SmPC, p. 2]

XGEVA® (denosumab) pharmacodynamics

Phase II clinical studies in patients with advanced malignancies involving bone showed that XGEVA® lowered levels of several bone resorption markers (uNTx/Cr, serum CTx). Median reductions of approximately 80% for uNTx/Cr occurred within 1 week, regardless of baseline uNTx/Cr levels or previous therapy with bisphosphonates.[SmPC, p. 9]

In the phase III clinical studies, median reductions of approximately 80% were maintained in uNTx/Cr after 3 months of treatment in patients naïve to IV-bisphosphonate treatments.[SmPC, p. 9]

XGEVA® (denosumab) pharmacokinetics

Following administration, XGEVA® bioavailability is 62%. Since XGEVA® consists of only amino acids and carbohydrates as native immunoglobulin, it is unlikely to be eliminated via hepatic metabolism. Metabolism and elimination of XGEVA® are expected to follow immunoglobulin clearance pathways, with small peptides and amino acids as final products of metabolism. After 6 months of treatment with multiple doses of 120 mg every four weeks an approximately 2-fold accumulation in serum XGEVA® concentration was observed. In patients who discontinued this dosing, the mean half-life was 28 days (range 14–55 days). No clinically significant changes in systemic exposure of XGEVA® at steady state have been observed related to differences in age, ethnicity, gender or solid tumour type. Body weight has been shown to be inversely related to systemic exposure, but differences were not clinically relevant. XGEVA® has displayed non-linear pharmacokinetics over a wide dose range.[SmPC, p. 13]

Renal impairment

XGEVA® has been assessed in patients with varying degrees of renal function, including patients on dialysis, and the degree of renal impairment has no effect on the pharmacokinetics of XGEVA®. No dose adjustment or renal monitoring is required in patients with renal impairment receiving XGEVA® therapy.[SmPC, p. 13]

Hepatic impairment

No specific studies have been conducted in patients with impaired hepatic function, but since monoclonal antibodies are generally not eliminated by hepatic metabolism mechanisms, hepatic impairment is not expected to affect XGEVA® pharmacokinetics.[SmPC, p. 13]

Paediatric population

XGEVA® pharmacokinetics have not been assessed in paediatric patients.[SmPC, p. 14]

XGEVA® (denosumab) immunogenicity

Neutralising antibodies have not been observed for XGEVA® in clinical studies. A minority (<1%) of patients treated with XGEVA® for up to 3 years tested positive for non-neutralising antibodies, but there was no evidence of alteration to pharmacokinetics, toxicity or clinical response in these cases.[SmPC, p. 9]