Exjiva, 120 mg (70 mg/ml) 1.7 ml

Pharmacotherapeutic Group

Drugs for the treatment of bone diseases – other drugs affecting bone structure and mineralization. Monoclonal antibodies.

ATX code: M05BX04

Pharmacological Properties

Pharmacodynamics

Mechanism of action
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The RANK ligand is a protein present as a membrane-bound or soluble form. RANKL is essential for the formation, function and survival of osteoclasts, the only cell type responsible for bone resorption. Increased osteoclast activity induced by RANKL is a major cause of bone destruction in metastatic bone disease and multiple myeloma.
Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing interaction between RANKL and RANK, resulting in a reduction in the number of osteoclasts and inhibition of their function, reducing the resulting bone resorption and bone destruction induced by malignancy.

Gigantocellular bone tumors are characterized by the presence of neoplastic stromal cells expressing RANK ligand and giant osteoclast-like cells expressing RANK. In patients with gigantocellular bone tumors, denosumab binds to RANK ligand and significantly reduces the number of giant osteoclast-like cells or eliminates them completely. As a result, osteolysis is reduced and the proliferative tumor stroma is replaced by nonproliferative, differentiated and dense new bone tissue.

Pharmacodynamic effects

In phase II clinical trials in patients with advanced malignant tumors with bone metastases, subcutaneous administration of Exjiva® every 4 weeks or every 12 weeks resulted in a rapid decrease in concentrations of bone resorption markers (urinary creatinine-adjusted N telopeptide (uNTx/Cr) serum 1C telopeptide (STx)), with a median reduction in uNTx/Cr concentrations of approximately 80% achieved within 1 week, regardless of prior bisphosphonate therapy or baseline uNTx/Cr levels. In phase III clinical trials involving patients with advanced malignant tumors with bone metastases, the median reduction in uNTx/Cr was approximately 80% and was maintained during 49 weeks of treatment with Exjiva® (120 mg every 4 weeks).

Immunogenicity

No neutralizing antibodies to denosumab have been identified in clinical studies in patients with advanced malignant neoplasms or giant cell bone tumor. Less than 1% of patients receiving denosumab for up to 3 years had binding but not neutralizing antibodies determined by sensitive immunologic testing with no evidence of changes in pharmacokinetics, toxic profile, or clinical response.

Clinical efficacy

Exjiva® reduces or prevents the risk of bone complications (BC) and multiple BCs (first and subsequent) in patients with bone metastases in solid tumors and in patients with multiple myeloma. Exjiva® increases the rate of objective tumor response, reduces the risk of progression and eliminates the need for surgery in adult patients and adolescents with an established skeleton who have a gigantocellular bone tumor.

Children

The European Medicines Agency has rescinded its obligation to provide final results of the Exjiva® study in all subgroups of the pediatric population where the drug was used to prevent bone complications in patients with bone metastases and subgroups of children under 12 years of age who received therapy for gigantocellular bone tumor (see See “Administration and Dosages” for information on use in children).

In Study 6, Exjiva® was studied in a subgroup involving 28 adolescents (ages 13 to 17 years) with a gigantocellular bone tumor and a mature skeleton, as determined by the identification of at least one fully formed long tubular bone (e.g., closed epiphyseal growth zones of the humerus) and a body weight ≥45 kg. One adolescent with unresectable disease had recurrence (N = 14) at the time of initial treatment. Thirteen of 14 patients with conditionally unresectable disease, in whom planned surgery was associated with worsening disease severity, had not undergone surgery by 6 months.

The treatment of hypercalcemia in malignant tumors

The safety and efficacy of Exjiva® was studied in an open noncomparative phase II study involving 33 adult patients with hypercalcemia in malignant tumors (with or without bone metastases) resistant to treatment with intravenous bisphosphonates. Patients received 120 mg of Exjiva® subcutaneously every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of treatment.

Refractory hypercalcemia in malignancies was defined as an albumin-adjusted calcium concentration > 12.5 mg/dL (3.1 mmol/L) despite treatment with intravenous bisphosphonates in the last 7-30 days. The primary endpoint was the number of patients achieving a response, defined as a serum albumin-corrected calcium concentration (CSC) ≤ 11.5 mg/dL (2.9 mmol/L), within 10 days of administration of Exjiva®. Exjiva® caused a rapid and sustained reduction in serum albumin-corrected calcium concentrations in most patients, including patients with or without bone metastases.

Pharmacokinetics

absorption

After subcutaneous administration, bioavailability was 62%.

Biotransformation

Denosumab is composed of amino acids and carbohydrates, like natural immunoglobulin, so its excretion through hepatic metabolic pathways is unlikely. The metabolism and excretion of denosumab presumably follow the same mechanisms as for immunoglobulins, with degradation to small peptides and individual amino acids.

Elevation

In patients with advanced malignancy who received multiple doses of 120 mg every 4 weeks, approximately a twofold increase in serum concentrations of denosumab was observed with reaching equilibrium status by approximately 6 months of treatment according to time-independent pharmacokinetics. In patients with multiple myeloma who received 120 mg every 4 weeks, median residual levels varied by less than 8% between 6 m and 12 m months. In patients with gigantocellular bone tumor who received 120 mg every 4 weeks with loading doses on days 8 and 15, equilibrium was reached during the first month of treatment. Between weeks 9 and 49, the median minimum concentration changed by no more than 9%. In patients who discontinued 120 mg every 4 weeks, the median half-life was approximately 28 days (range: 14 to 55 days).

Population pharmacokinetic analysis showed no clinically significant changes in systemic exposure to denosumab at steady state associated with age (18 to 87 years), race/ethnicity (studies were conducted with black, Hispanic, Asian and Caucasian patients), sex, solid tumor types or in patients with multiple myeloma. Higher body weight was associated with lower systemic exposure and vice versa. These changes were not found to be clinically significant because the pharmacodynamic effects of the drug, expressed as an effect on markers of bone remodeling, were similar in patients with different body weights.

Linearity/nonlinearity

When administered subcutaneously, denosumab is characterized by nonlinear pharmacokinetics over a wide dose range, with approximately dose-dependent increases in exposure for doses of 60 mg (or 1 mg/kg) and higher. The nonlinearity of pharmacokinetics is likely due to the saturation of target-mediated elimination pathways important at low concentrations of the drug.

Particular populations

Elderly patients (age 65 years or older)

In general, no differences were found regarding the safety or efficacy of the drug between elderly patients and younger patients. Controlled clinical trials of Exjiva® involving patients over 65 years of age with advanced malignancies and bone metastases showed similar efficacy and safety in elderly and younger patients. No dose adjustment is required in elderly patients.

Children and adolescents (under 18 years of age)

In adolescents with an established skeleton (age 12-17 years) with gigantocellular bone tumor (GCOC) who received 120 mg once every 4 weeks with loading dose on days 8 and 15, the pharmacokinetics of denosumab were similar to those of adult patients with GCOC.

Patients with impaired renal function

In studies of denosumab (60 mg, n = 55 and 120 mg, n = 32) in patients without advanced malignancies but with varying degrees of renal impairment, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab, thus no dosing adjustment for impaired renal function is necessary. There is no need to monitor renal function during treatment with Exjiva®.

Chronic hepatic impairment

No special studies have been performed in patients with hepatic impairment. In general, monoclonal antibodies are not excreted through hepatic metabolic pathways. The pharmacokinetics of denosumab are not expected to be affected by hepatic insufficiency.