Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases – other drugs affecting bone structure and mineralization, ATC code: M05BX04.

Mechanism of action

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a key mediator 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 the RANKL/RANK interaction from occurring and resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction.

Giant cell tumors of bone are characterized by neoplastic stromal cells expressing RANK ligand and osteoclast-like giant cells expressing RANK. In patients with giant cell tumor of bone, denosumab binds to RANK ligand, significantly reducing or eliminating osteoclast-like giant cells. Consequently, osteolysis is reduced and proliferative tumor stroma is replaced with non-proliferative, differentiated, densely woven new bone.

Pharmacodynamic effects

In phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC) dosing of XGEVA administered either every 4 weeks (Q4W) or every 12 weeks resulted in a rapid reduction in markers of bone resorption (uNTx/Cr, serum CTx), with median reductions of approximately 80% for uNTx/Cr occurring within 1 week regardless of prior bisphosphonate therapy or baseline uNTx/Cr level. In phase III clinical trials of patients with advanced malignancies involving bone, median uNTx/Cr reductions of approximately 80% were maintained through 49 weeks of XGEVA treatment (120 mg every Q4W).

Immunogenicity

In clinical studies, neutralizing antibodies have not been observed for denosumab in advanced cancer patients or giant cell tumor of bone patients. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 3 years tested positive for non-neutralizing binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Clinical efficacy and safety in patients with bone metastases from solid tumors 
Efficacy and safety of 120 mg XGEVA SC every 4 weeks or 4 mg zoledronic acid (dose-adjusted for reduced renal function) IV every 4 weeks were compared in three randomized, double-blind, active-controlled studies, in IV-bisphosphonate naïve patients with advanced malignancies involving bone: adults with breast cancer (study 1), other solid tumors or multiple myeloma (study 2), and castrate-resistant prostate cancer (study 3). Within these active-controlled clinical trials, safety was evaluated in 5,931 patients. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure, were not eligible for inclusion in these studies. The primary and secondary endpoints evaluated the occurrence of one or more skeletal related events (SREs). In studies demonstrating superiority of XGEVA to zoledronic acid, patients were offered open-label XGEVA in a pre-specified 2-year extension treatment phase. An SRE was defined as any of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.

XGEVA reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumors (see table 2).

Table 2. Efficacy results in patients with advanced malignancies involving bone 
Study 1                   Study 2                     Study 3                Combined breast cancer          other solid tumors**           prostate cancer        advanced cancer or multiple myeloma
XGEVA        zoledronic   XGEVA            zoledronic   XGEVA      zoledronic   XGEVA     zoledronic acid                          acid                    acid                   acid N                           1,026         1,020        886               890        950          951       2,862       2,861 First SRE
Median time (months)         NR               26.4     20.6             16.3        20.7            17.1    27.6         19.4 Difference in median                 NA                         4.2                          3.5                   8.2 time (months)
HR (95% CI)/RRR (%)         0.82 (0.71, 0.95)/18      0.84 (0.71, 0.98)/16         0.82 (0.71, 0.95)/18    0.83 (0.76, 0.90)/17 
Non-                      < 0.0001†/0.0101†             0.0007†/0.0619†             0.0002†/0.0085†        < 0.0001/< 0.0001 inferiority/Superiority p-values
Proportion of patients    30.7         36.5            31.4             36.3        35.9            40.6    32.6         37.8 (%)
First and subsequent SRE*
Mean number/patient       0.46         0.60            0.44             0.49        0.52            0.61    0.48         0.57 
Rate ratio (95%             0.77 (0.66, 0.89)/23      0.90 (0.77, 1.04)/10         0.82 (0.71, 0.94)/18    0.82 (0.75, 0.89)/18 CI)/RRR (%)
Superiority p-value                 0.0012†                   0.1447†                      0.0085†              < 0.0001 SMR per Year                 0.45             0.58     0.86             1.04        0.79            0.83    0.69         0.81 First SRE or HCM
Median time (months)         NR            25.2        19.0          14.4           20.3         17.1       26.6         19.4 HR (95% CI)/RRR (%)         0.82 (0.70, 0.95)/18      0.83 (0.71, 0.97)/17         0.83 (0.72, 0.96)/17    0.83 (0.76, 0.90)/17 
Superiority p-value                 0.0074                    0.0215                       0.0134               < 0.0001 First radiation to bone
Median time (months)         NR            NR          NR             NR            NR           28.6       NR           33.2 HR (95% CI)/RRR (%)         0.74 (0.59, 0.94)/26      0.78 (0.63, 0.97)/22         0.78 (0.66, 0.94)/22    0.77 (0.69, 0.87)/23 Superiority p-value                 0.0121                    0.0256                       0.0071               < 0.0001 NR = not reached; NA = not available; HCM = hypercalcemia of malignancy; SMR = skeletal morbidity rate; HR = hazard ratio; RRR = relative risk reduction;
†
Adjusted p-values are presented for studies 1, 2 and 3 (first SRE and first and subsequent SRE endpoints); * Accounts for all skeletal events over time; only events occurring ≥ 21 days after the previous event are counted; ** Including NSCLC, renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, GI/genitourinary cancer and others, excluding breast and prostate cancer.



Figure 1. Kaplan-Meier plots of time to first on-study SRE



Disease progression and overall survival with bone metastases from solid tumors 
Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three studies combined.

In studies 1, 2 and 3, overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and 95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91, 1.17]), and patients with other solid tumors or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). A post-hoc analysis in study 2 (patients with other solid tumors or multiple myeloma) examined overall survival for the 3 tumor types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between XGEVA and zoledronic acid in other tumor types (hazard ratio [95% CI] of 1.08 [0.90, 1.30]; n = 894). This study did not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]).

Effect on pain

The time to pain improvement (i.e. ≥ 2-point decrease from baseline in BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and the integrated analyzes. In a post-hoc analysis of the combined dataset, the median time to worsening pain (> 4-point worst pain score) in patients with mild or no pain at baseline was delayed for XGEVA compared to zoledronic acid (198 versus 143 days) (p = 0.0002).

Clinical efficacy in patients with multiple myeloma

XGEVA was evaluated in an international, randomized (1:1), double-blind, active-controlled study comparing XGEVA with zoledronic acid in patients with newly diagnosed multiple myeloma, study 4.

In this study, 1,718 multiple myeloma patients with at least one bone lesion were randomized to receive 120 mg XGEVA subcutaneously every 4 weeks (Q4W) or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose-adjusted for renal function). The primary outcome measure was demonstration of non-inferiority of time to first on-study skeletal related event (SRE) as compared to zoledronic acid. Secondary outcome measures included superiority of time to first SRE, superiority of time to first and subsequent SRE, and overall survival. An SRE was defined as any of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.


Across both study arms, 54.5% of patients intended to undergo autologous PBSC transplantation, 95.8% patients utilized/planned to utilize a novel anti-myeloma agent (novel therapies include bortezomib, lenalidomide, or thalidomide) in first-line therapy, and 60.7% of patients had a previous SRE. The number of patients across both study arms with ISS stage I, stage II, and stage III at diagnosis were 32.4%, 38.2%, and 29.3%, respectively.

The median number of doses administered was 16 for XGEVA and 15 for zoledronic acid.

Efficacy results from study 4 are presented in figure 2 and table 3.
Figure 2. Kaplan-Meier plot for time to first on-study SRE in patients with newly diagnosed multiple myeloma 


Table 3. Efficacy results for XGEVA compared to zoledronic acid in patients with newly diagnosed multiple myeloma

XGEVA                             Zoledronic Acid
(N = 859)                             (N = 859)
First SRE
Number of patients who had SREs (%)                     376 (43.8)                          383 (44.6) Median time to SRE (months)                           22.8 (14.7, NE)                   23.98 (16.56, 33.31) Hazard ratio (95% CI)                                                   0.98 (0.85, 1.14) 
First and subsequent SRE
Mean number of events/patient                               0.66                                 0.66 Rate ratio (95% CI)                                                     1.01 (0.89, 1.15) Skeletal morbidity rate per year                            0.61                                 0.62 
First SRE or HCM
Median time (months)                                22.14 (14.26, NE)                    21.32 (13.86, 29.7) Hazard ratio (95% CI)                                                   0.98 (0.85, 1.12) 
First radiation to bone
Hazard ratio (95% CI)                                                   0.78 (0.53, 1.14) 
Overall survival
Hazard ratio (95% CI)                                                   0.90 (0.70, 1.16) NE = not estimable
HCM = hypercalcemia of malignancy

Clinical efficacy and safety in adults and skeletally mature adolescents with giant cell tumor of bone 
The safety and efficacy of XGEVA was studied in two phase II open-label, single-arm trials (studies 5 and 6) that enrolled 554 patients with giant cell tumor of bone that was either unresectable or for which surgery would be associated with severe morbidity and a prospective, multicenter, open-label, phase IV study (study 7) that provided long-term safety follow-up for patients who completed study 6. Patients received 120 mg XGEVA subcutaneously every 4 weeks with a loading dose of 120 mg on days 8 and 15. Patients who discontinued XGEVA then entered the safety follow-up phase for a minimum of 60 months. Retreatment with XGEVA while in safety follow-up was allowed for patients who initially demonstrated a response to XGEVA (e.g., in the case of recurrent disease).

Study 5 enrolled 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumor of bone.
The main outcome measure of the trial was response rate, defined as either at least 90% elimination of giant cells relative to baseline (or complete elimination of giant cells in cases where giant cells represent < 5% of tumor cells), or a lack of progression of the target lesion by radiographic measurements in cases where histopathology was not available. Of the 35 patients included in the efficacy analysis, 85.7% (95% CI: 69.7, 95.2) had a treatment response to XGEVA. All 20 patients (100%) with histology assessments met response criteria. Of the remaining 15 patients, 10 (67%) radiographic measurements showed no progression of the target lesion.

Study 6 enrolled 535 adult or skeletally mature adolescents with giant cell tumor of bone. Of these patients, 28 were aged 12-17 years. Patients were assigned to one of three cohorts: cohort 1 included patients with surgically unsalvageable disease (e.g., sacral, spinal, or multiple lesions, including pulmonary metastases); cohort 2 included patients with surgically salvageable disease whose planned surgery was associated with severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy); cohort 3 included patients previously participating in study 5 and rolled over into this study. The primary objective was to evaluate the safety profile of denosumab in patients with giant cell tumor of bone. The secondary outcome measures of the study included time to disease progression (based on investigator assessment) for cohort 1 and proportion of patients without any surgery at month 6 for cohort 2.

In cohort 1 at the final analysis, 28 of the 260 treated patients (10.8%) had disease progression. In cohort 2, 219 of the 238 (92.0%; 95% CI: 87.8%, 95.1%) evaluable patients treated with XGEVA had not undergone surgery by month 6.
Of the 239 patients in cohort 2 with baseline target lesion location or on-study location not in lungs or soft tissue, a total of 82 subjects (34.3%) were able to avoid on-study surgery. Overall, efficacy results in skeletally mature adolescents were similar to those observed in adults.

Study 7 enrolled 85 adult patients who were previously enrolled and completed study 6. Patients were allowed to receive denosumab treatment for GCTB, and all patients were followed for 5 years. The primary objective was to evaluate the long-term safety profile of denosumab in patients with giant cell tumor of the bone.

Effect on pain

In the final analysis cohorts 1 and 2 combined, a clinically meaningful reduction in worst pain (i.e. ≥ 2-point decrease from baseline) was reported for 30.8% of patients at risk (i.e. those who had a worst pain score of ≥ 2 at baseline) within 1 week of treatment, and ≥ 50% at week 5. These pain improvements were maintained at all subsequent evaluations.

Pediatric population

In study 6, XGEVA has been evaluated in a subset of 28 adolescent patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal maturity defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and body weight ≥ 45 kg. One adolescent patients with surgically unsalvageable disease (N = 14) had disease recurrence during initial treatment. Thirteen of the 14 patients with surgically salvageable disease whose planned surgery was associated with severe morbidity had not undergone surgery by month 6.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
Following subcutaneous administration, bioavailability was 62%.
Biotransformation

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Elimination

In patients with advanced cancer, who received multiple doses of 120 mg every 4 weeks an approximate 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months, consistent with time-independent pharmacokinetics. In patients with multiple myeloma who received 120 mg every 4 weeks, median trough levels varied by less than 8% between months 6 and 12. In patients with giant cell tumor of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first month of treatment. Between weeks 9 and 49, median trough levels varied by less than 9%. In patients who discontinued 120 mg every 4 weeks, the mean half-life was 28 days (range: 14 to 55 days).

A population pharmacokinetic analysis did not indicate clinically significant changes in the systemic exposure of denosumab at steady-state with respect to age (18 to 87 years), race/ethnicity (Blacks, Hispanics, Asians and Caucasians explored), gender or solid tumor types or patients with multiple myeloma. Increasing body weight was associated with decreases in systemic exposure, and vice versa. The alterations were not considered clinically-relevant, since pharmacodynamic effects based on bone turnover markers were consistent across a wide range of body weight.

Linearity/non-linearity

Denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, but approximately dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher. The non-linearity is likely due to a saturable target-mediated elimination pathway of importance at low concentrations.

Renal impairment

In studies of denosumab (60 mg, n = 55 and 120 mg, n = 32) in patients without advanced cancer but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus dose adjustment for renal impairment is not required. There is no need for renal monitoring with XGEVA dosing.

Hepatic impairment

No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.

Elderly

No overall differences in safety or efficacy were observed between geriatric patients and younger patients. Controlled clinical studies of XGEVA in patients with advanced malignancies involving bone over age 65 revealed similar efficacy and safety in older and younger patients. No dose adjustment is required in elderly patients.

Pediatric population

In skeletally-mature adolescents (12-17 years of age) with giant cell tumor of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, the pharmacokinetics of denosumab were similar to those observed in adult patients with GCTB.