Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Denosumab · 33 trials · 56 indications
Lumbar spine BMD was assessed by DXA and analyzed by analysis of covariance (ANCOVA) including treatment (denosumab vs placebo), baseline age, and baseline BMD z-score. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement.
Lumbar spine bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
A skeletal-related event (SRE) is defined as one 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. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
A skeletal-related event (SRE) is defined as one 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.
A skeletal-related event (SRE) is defined as one 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.
Bone mineral density at the lumbar spine was measured by dual-energy x-ray absorptiometry (DXA).
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. The event does not necessarily have a causal relationship with study treatment. Each AE was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE. Treatment-related adverse events (TRAEs) includes events for which the investigator indicated there was a reasonable possibility they may have been caused by investigational product.
A serious adverse event is defined as an adverse event that meets at least one of the following serious criteria: • fatal, • life threatening, • requires in-patient hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, • congenital anomaly/birth defect, and/or • other significant medical hazard. The adverse event severity grading scale used was the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, according to the following: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE. The investigator assessed whether each adverse event was possibly related to the investigational product (IP).
The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline.
Percent change from the 20050179 Baseline in cortical thickness at the distal radius as determined by high-resolution peripheral quantitative computed tomography (HR-pQCT) at an average of 32 months since the last subcutaneous dose of denosumab or placebo in study 20050179.
A serious adverse event (SAE) is defined as an adverse event that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.
Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.
An electrochemiluminescent bridging immunoassay was used to test blood samples for binding antibodies to denosumab.
The time to first on-study clinical fracture was defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture is any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier.
Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method.
Time to first on-study skeletal-related event (SRE) using a non-inferiority analysis. The median time to first skeletal-related event could not be estimated in one treatment arm, so the subject incidence is presented.
The time to the first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause. Participants who did not experience bone metastasis or on-study death were censored at the last on-study contact date or the primary analysis data cutoff date, whichever came first. Median bone metastasis-free survival time was estimated using the Kaplan-Meier method.
A new vertebral fracture, assessed by lateral spine X-ray using Genant semiquantitative scoring method, was identified as an ≥ 1 grade increase from the Baseline grade of 0 in any vertebra from T4 to L4. New vertebral fractures included morphometric vertebral fractures (assessed at scheduled visits and not associated with signs or symptoms \[or both\] indicative of a fracture) and clinical vertebral fractures (assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms indicative of a fracture, excluding any fracture associated with high trauma severity or a pathologic fracture).
Risk Categories: Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present Risk Factors: 1. BM plasma cell % ≥50 2. M-protein ≥ 3g/dL 3. Involved/ un-involved free light chains ≥ 8
Breast density will be measured via non-contrast MRI before and after 6 months on denosumab
Overall survival was calculated as the time from the date of randomization to the date of death from any cause. Participants last known to be alive were censored at the last contact date.
Response is defined as corrected serum calcium (CSC) ≤ 11.5 mg/dL, within 10 days after the first dose of denosumab. For all CSC values, if albumin was \< 4 g/dL, the following formula was used to calculate CSC: CSC = Total serum calcium \[mg/dL\] + (0.8 x (4 - serum albumin \[g/dL\]))
AE defined as any untoward medical occurrence in a clinical trial participant. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results are presented for treatment-emergent events (TEAEs) and included all AEs occurring from first dose in initial treatment phase to end of initial treatment phase (or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase).
Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively.
A treatment response was defined for participants with tissue samples obtained and measured by histopathology as: • 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. A response was defined for participants who have only radiographs (histopathology not available) as lack of progression of the target lesion at week 25 by radiographic measurements compared with Baseline. For participants with both a core biopsy and resected tissue obtained, the sample closest to week 25 was used in the analysis.
Complete response or partial response based on serum M-Protein assessments. Complete response is defined as absence of original M-protein in serum by immunofixation, and partial response is defined as ≥ 50% reduction from baseline in serum M-protein, both maintained for a minimum of 6 weeks.
Percent change from Baseline to Week 13 in Urinary N-telopeptide corrected by creatinine (uNTx/Cr) calculated using ((Week 13 value - Baseline value) / Baseline value ) x 100.
Fifteen sites in each wrist and 10 sites in each hand were assessed by a blinded and independent reader. Each site was scored from 0 to 10 (in accordance with the European League Against Rheumatism \[EULAR\]-Outcome Measures in Rheumatology Clinical Trials convention), with each unit increment representing 10% incremental loss of the peripheral 1 cm of articular bone. The Erosion Score is a sum of erosion scores from 50 joint sites in both hands/wrists and ranges from 0 (normal, no erosion) to 500 (worst possible erosion).
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from Baseline to Month 12 calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.
Ki-67 is a marker for cell proliferation. Participants underwent percutaneous core needle breast biopsies on Day 1 (Baseline, prior to treatment) and Day 28. Levels of Ki67 were measured using immunohistochemical staining and digital imaging. The proliferation index was calculated as the percentage of Ki-67 positive terminal ductal lobular unit (TDLU) and duct epithelial cells. The higher the percentage, the higher the rate of epithelial cell proliferation.
The area under the denosumab seminal fluid concentration-time curve from time zero to last quantifiable concentration (AUClast), estimated using the linear trapezoidal method.
Clinically significant hypocalcemia is defined as albumin-adjusted calcium \< 7.0 mg/dL or symptomatic hypocalcemia. Symptomatic hypocalcemiais is defined as both a clinical adverse event of hypocalcemia and a concomitant symptom of hypocalcemia (e.g., hypoesthesia, paresthesia, muscle cramps, seizure, prolonged QT interval) that occurred along with the hypocalcemia event or decreased serum calcium levels.
The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability
Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability
The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
| Arm | Type | Description |
|---|---|---|
| Placebo | OTHER | SC Q6M placebo |
| Denosumab | EXPERIMENTAL | 1 mg/kg BW (up to a maximum of 60 mg) SC Q6M |
| Denosumab CP2 | ACTIVE_COMPARATOR | Participants received 60 mg denosumab manufactured using the current CP2 process subcutaneously once every 6 months for 1 year. |
| Denosumab CP4 | EXPERIMENTAL | Participants received 60 mg denosumab manufactured using the new CP4 process subcutaneously once every 6 months for 1 year. |
| Zoledronic acid | ACTIVE_COMPARATOR | Zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaniously (SC) once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) |
| Risendronate | EXPERIMENTAL | Participants received 5 mg risedronate orally once a day for 24 months and placebo to densumab by subcutaneous injection on day 1 and at months 6, 12, and 18. |
| 2 | PLACEBO_COMPARATOR | Subjects will receive placebo for denosumab (SC injection every 6 months) for 1 year (double-blind phase) followed by 60 mg denosumab (SC injection every 6 months) for 1 year (open-label phase) |
| 1 | EXPERIMENTAL | 60 mg denosumab (SC injection every 6 months) for 1 year (double-blind phase) followed by 60 mg denosumab(SC injection every 6 months) for 1 year (open-label phase). These subjects will be on denosumab for a total of 2 years. |
| Arm 1 | OTHER | Participants who were randomized to either denosumab or placebo in Study 20050179 and at least 12 months had elapsed from their 20050179 end-of-study visit had dual energy X-ray absorptiometry (DXA) of the forearm and HR-pQCT of the tibia and radius on Day 1 of this study. No study drug was administered. |
| Denosumab - Vial | EXPERIMENTAL | Participants received denosumab 60 mg subcutaneous injection using a standard vial on Day 1 and at Month 6. |
| Denosumab - Prefilled syringe | EXPERIMENTAL | Participants received denosumab 60 mg subcutaneous injection using a pre-filled syringe on Day 1 and at Month 6. |
| SubStudy: Zoledronic Acid | EXPERIMENTAL | Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive a single 5 mg intravenous dose of zoledronic acid 8 months after the last open-label dose of denosumab. |
| Substudy: Standard of Care | OTHER | Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive standard of care 8 months after the last open-label dose of denosumab. |
| Denosumb | EXPERIMENTAL | Participants received 120 mg denosumab administered by subcutaneous injection every 4 weeks during the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injection every 4 weeks during the open-label extension phase. |
| Denosumab 60 mg Q6M | EXPERIMENTAL | Denosumab 60 mg administered subcutaneously once every 6 months (Q6M) for 3 years. |
| nab-Paclitaxel weekly | EXPERIMENTAL | nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel. |
| nab-paclitaxel 2 of 3 weeks | EXPERIMENTAL | nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel. |
| EC every two weeks or every three weeks | EXPERIMENTAL | Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. |
| Denosumab 60 mg every 12 weeks | EXPERIMENTAL | Denosumab 60 mg by subcutaneous injection once every 12 weeks (Q12W) for 25 weeks. |
| Denosumab 120 mg every 4 weeks | EXPERIMENTAL | Denosumab 120 mg by subcutaneous injection once every 4 weeks (Q4W) for 25 weeks. |
| Denosumab 180 mg every 4 weeks | EXPERIMENTAL | Denosumab 180 mg by subcutaneous injection once every 4 weeks (Q4W) for 25 weeks. |
| IV bisphosphonates every 4 weeks | ACTIVE_COMPARATOR | Open label bisphosphonate every 4 weeks (Q4W) by intravenous infusion for 25 weeks. |
| Denosumab 180 mg every 12 weeks | EXPERIMENTAL | Denosumab 180 mg by subcutaneous injection once every 12 weeks (Q12W) for 25 weeks. |
| Denosumab 30 mg every 4 weeks | EXPERIMENTAL | Denosumab 30 mg by subcutaneous injection once every 4 weeks (Q4W) for 25 weeks. |
| Denosumab 180 mg | EXPERIMENTAL | Participants received 180 mg denosumab by subcutaneous injection on Day 1 and at Month 6. |
| Denosumab 60 mg | EXPERIMENTAL | Participants received 60 mg denosumab by subcutaneous injection on Day 1 and at Month 6. |
| Denosumab 6 mg every 3 months | EXPERIMENTAL | Participants received denosumab 6 mg SC every 3 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42. |
| Denosumab 14 mg every 3 months | EXPERIMENTAL | Participants received denosumab 14 mg SC every 3 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42. |
| Denosumab 30 mg every 3 months | EXPERIMENTAL | Participants received denosumab 30 mg SC every 3 months until Month 21 then placebo SC every 6 months at Month 24 and Month 30 and then denosumab 60 mg SC every 6 months at Month 36 and Month 42. |
| Denosumab 14 mg every 6 months | EXPERIMENTAL | Participants received denosumab 14 mg SC every 6 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42. |
| Denosumab 60 mg every 6 months | EXPERIMENTAL | Participants received denosumab 60 mg SC every 6 months until Month 42. |
| Denosumab 100 mg every 6 months | EXPERIMENTAL | Participants received denosumab 100 mg SC every 6 months until Month 21 and then denosumab 60 mg every 6 months from Month 24 through Month 42. |
| Denosumab 210 mg every 6 months | EXPERIMENTAL | Participants received denosumab 210 mg SC every 6 months until Month 21 and then placebo every 6 months from Month 24 through Month 42. |
| Alendronate 70 mg | ACTIVE_COMPARATOR | Participants received open-label alendronate 70 mg tablets orally once a week through Month 24. From Month 24 to Month 48 participants received no treatment. |
| No treatment | OTHER | Participants received no treatment and underwent percutaneous core needle breast biopsies on Day 1 and Day 28. |
| Denosumab 120 mg | EXPERIMENTAL | Participants received 120 mg denosumab by subcutaneous injection on Day 1 and underwent percutaneous core needle breast biopsies on Day 1 (prior to study treatment) and Day 28. |
| Midazolam | OTHER | All 27 subjects will receive midazolam. |
| Name | Type | Description |
|---|---|---|
| Denosumab | DRUG | 1mg/kg BW (up to a maximum of 60 mg) SC Q6M |
| Placebo | OTHER | SC Q6M placebo |
| Denosumab (CP2) | DRUG | Denosumab produced by a process referred to as CP2, administered subcutaneously from a prefilled syringe. |
| Denosumab (CP4) | DRUG | Denosumab produced by a process referred to as CP4, administered subcutaneously from a prefilled syringe. |
| Zoledronic acid | DRUG | Administered by intravenous infusion over 15 minutes once every 4 weeks |
| Placebo to Denosumab | DRUG | Administered by subcutaneous injection once every 4 weeks. |
| Placebo to zoledronic acid | DRUG | Administered by intravenous infusion over 15 minutes once every 4 weeks |
| Denosumab (for the open-label treatment phase) | DRUG | Administered by subcutaneous injection once every 4 weeks. |
| Placebo for risendronate | DRUG | Administered orally once a day |
| Risendronate | DRUG | Administered orally once a day |
| Placebo for denosumab | DRUG | Administered by subcutaneous injection once every 6 months |
| 60 mg denosumab | DRUG | 60 mg denosumab (SC injection every 6 months) |
| high-resolution peripheral quantitative computed tomography (HR-pQCT) | PROCEDURE | Bone densitometry and microarchitecture assessments of the distal radius and the distal tibia by HR-pQCT on Day 1. |
| Dual energy X-ray absorptiometry (DXA) | PROCEDURE | Bone densitometry assessments of the forearm by DXA on day 1. |
| Non-steroidal aromatase inhibitor therapy | DRUG | An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting |
| Standard of Care | OTHER | Standard of care (SoC) as recommended by the treating physician, depending on individual factors such as bone density, lifestyle recommendations by the Investigator such as diet, physical activities and sun exposure, as well as local treatment standards. |
| nab-Paclitaxel | DRUG | nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks) |
| Epirubicin | DRUG | Epirubicin 90 mg/m² every 2 or 3 weeks for 4 times |
| Cyclophosphamide | DRUG | Cyclophosphamide 600 mg/m² every 2 or 3 weeks for 4 times |
| Carboplatin | DRUG | Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel |
| Trastuzumab | DRUG | Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles |
| Pertuzumab | DRUG | Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles |
| Standard Chemotherapy | DRUG | Standard of care chemotherapy consisting of pemetrexed or gemcitabine in combination with cisplatin or carboplatin administered according to local practice. |
| Calcium/Vitamin D | DIETARY_SUPPLEMENT | - |
| IV Bisphosphonates | DRUG | Commercially available intravenous (IV) bisphosphonates administered per package insert, included pamidronate, ibandronic acid, and zoledronic acid |
| Alendronate | DRUG | Alendronate 70 mg tablets |
| Percutaneous core needle breast biopsy | PROCEDURE | - |
| Midazolam | DRUG | All subjects will receive two oral dose administrations of midazolam. |
Inclusion Criteria: * Male or female subjects, age 5 to 17 years, inclusive, at the time of informed consent. * Clinical diagnosis of GiOP as defined by the following (and consistent with the International Society for Clinical Densitometry definition of osteoporosis in children and adolescents \[Bi...
Denosumab is used for bone metastases in men with hormone-refractory prostate cancer, osteopenia, osteoporosis, bone metastases, giant cell tumor (GCT), and renal impairment. It is also studied in conditions like glucocorticoid-induced osteoporosis and smoldering multiple myeloma. Denosumab is developed by Amgen Inc. (AMGN) and is currently in Phase 2 clinical development.
Denosumab targets RANKL, a protein involved in bone resorption. By inhibiting RANKL, denosumab reduces osteoclast activity, which helps prevent bone loss and treat conditions like osteoporosis and bone metastases. This mechanism is relevant across its studied indications, including prostate cancer bone metastases and giant cell tumor.
Denosumab is developed by Amgen Inc., a biopharmaceutical company traded on NASDAQ under the ticker AMGN. Amgen is conducting clinical trials to evaluate denosumab for various bone-related conditions, including osteoporosis, bone metastases, and osteopenia.
Denosumab is in Phase 2 clinical development, based on the most advanced ongoing trial. However, it has completed four trials, including Phase 3 studies for osteoporosis and prostate cancer bone metastases. Denosumab is investigational and not yet approved for the indications studied in these trials.
Denosumab has completed four clinical trials: NCT00523341 (long-term safety and efficacy in osteoporosis, Phase 3), NCT01824342 (bone metastasis-free survival in hormone-refractory prostate cancer, Phase 3), NCT03164928 (pediatric glucocorticoid-induced osteoporosis, Phase 3), and NCT03839459 (smoldering multiple myeloma, Phase 2). All trials are completed.
Denosumab is also known as Denosumab 60 MG/ML Prefilled Syringe [Prolia] and Denosumab/ML Prefilled Syringe. Prolia is a brand name for denosumab, specifically the 60 mg/mL formulation used for osteoporosis and osteopenia. The drug is being studied under the name denosumab across various indications.