Study Investigating PK, PD, Efficacy, Safety, and Immunogenicity of Biosimilar Denosumab (GP2411) in Patients With Postmenopausal Osteoporosis

Phase 3

Completed

Conditions: Postmenopausal Women With Osteoporosis

Interventions: Biological: EU-Prolia (EU-authorized Prolia®)
Biological: GP2411

Registration Number: NCT03974100

Lead Sponsor: Sandoz

Brief Summary: This study was conducted to assess if there were any clinically meaningful differences in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety, or immunogenicity between GP2411 (proposed biosimilar denosumab) and EU-authorized Prolia® (denosumab).

Detailed Description: This was an international, multicenter, randomized, double-blind, parallel-group study with a total duration of up to 83 weeks.

The study comprised a screening period of up to 5 weeks to assess a subject's eligibility and two treatment periods: Treatment Period 1 (TP1) from Day 1 to Week 52 and Treatment Period 2 (TP2) from Week 52 to Week 78.

Women with postmenopausal osteoporosis (PMO) were randomized on Day 1 in a 1:1 ratio to receive either two 60 mg subcutaneous (s.c.) doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) or EU-Prolia (EU-authorized Prolia®) during TP1. At Week 52, participants in the EU-Prolia group were re-randomized 1:1 to either continue with a third dose of EU-Prolia or switch to GP2411 for TP2. Participants in the GP2411 group continued the treatment with a third dose of GP2411 in TP2. The End of Study was achieved at Week 78.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 527

Inclusion Criteria

Postmenopausal women, diagnosed with osteoporosis
Aged ≥ 55 and ≤ 80 years at screening
Body weight ≥ 50 kg and ≤ 90 kg at screening
Absolute bone mineral density consistent with T-score ≤ -2.5 and ≥ -4.0 at the lumbar spine as measured by DXA
At least two vertebrae in the L1-L4 region and at least one hip joint are evaluable by DXA

Exclusion Criteria

Previous exposure to denosumab (Prolia, Xgeva, or biosimilar denosumab)
History and/or presence of one severe or more than two moderate vertebral fractures or hip fracture
History and/or presence of bone metastases, bone disease or metabolic disease
Ongoing use of any osteoporosis treatment or use of prohibited treatment
Other bone active drugs
History and/or current hypoparathyroidism or hyperparathyroidism, hypocalcemia or hypercalcemia

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EU authorized Prolia	EU-Prolia (EU-authorized Prolia®)	60 mg /mL subcutaneous injection every 6 months
GP2411	GP2411	60 mg /mL subcutaneous injection every 6 months

Primary Outcome Measures

Name	Time	Method
Area Under the Effect-time Curve (AUEC) of Percentage Change From Baseline in Serum CTX Concentrations After First Dose - Pharmacodynamic Analysis Set	Baseline (pre-dose Day 1), up to Week 26	Carboxy-terminal crosslinked telopeptides of type I collagen (CTX) is a bone resorption biomarker. Serum CTX concentration-time data were analyzed by non-compartmental methods. The AUEC of baseline corrected serum CTX concentrations (% change from baseline) was calculated using the linear trapezoidal method. Values below the lower limit of quantification (LLOQ) were imputed with the actual value for the LLOQ.
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - Per-Protocol Set	Baseline (screening), up to Week 52	Bone density measurements were performed by dual energy X-ray absorptiometry (DXA). Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in LS-BMD for all post-baseline time points up to Week 52. Values at Week 52 were estimated from the model and are presented in the table.
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - TP1 Full Analysis Set	Baseline (screening), up to Week 52	Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis. A MMRM was fitted to the changes from baseline in LS-BMD for all post-baseline time points up to Week 52. Missing values were assumed to be missing at random (MAR) using the MMRM model. Values at Week 52 were estimated from the model and are presented in the table.
Maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose	Baseline (pre-dose Day 1), up to Week 26	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Missing denosumab serum concentrations or concentrations below the LLOQ were not imputed and handled as missing values, except for the pre-dose sample which were treated as zero.
Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Denosumab After First Dose	Baseline (pre-dose Day 1), up to Week 26	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Missing denosumab serum concentrations or concentrations below the LLOQ were not imputed and handled as missing values, except for the pre-dose sample which were treated as zero. The linear-up log-down trapezoidal method was used for the AUCinf calculation.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)	Baseline (screening), Week 78	Bone density measurement were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (Per-Protocol Set)	Baseline (screening), Week 26	Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1	Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52	CTX is a bone resorption biomarker. Serum samples were analyzed for CTX concentrations. CTX serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set)	Baseline (screening), Week 26 and Week 52	Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1	Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52	Procollagen I N-terminal propeptide (PINP) is a bone formation biomarker. Serum samples were analyzed for PINP concentrations. PINP serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2	Week 56, Week 65 and Week 78	PINP is a bone formation biomarker. Serum samples were analyzed for PINP concentrations. PINP serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (TP1 Full Analysis Set)	Baseline (screening), Week 26 and Week 52	Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set)	Baseline (screening), Week 26 and Week 52	Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (TP1 Full Analysis Set)	Baseline (screening), Week 26 and Week 52	Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)	Baseline (screening), Week 78	Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1	From first dose of study treatment on Day 1 up to pre-dose at Week 52	Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during Treatment Period 1. The number of participants in each category is reported in the table.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2	From dosing of study treatment at Week 52 up to Week 78	Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during Treatment Period 2. The number of participants in each category is reported in the table.
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (TP1 Full Analysis Set)	Baseline (screening), Week 26	Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2	Week 52 and Week 78	Vertebral fractures were assessed by independent radiologists at the central imaging vendor. The radiologists assessed lateral thoracic (vertebrae T4 to T12) and lumbar (vertebrae L1 to L4) spine radiographs for vertebral fractures. New and worsening vertebral fractures are defined as occurrence of new fracture (i.e. change in Genant score from 0 at Week 52 to 1 or higher at a later time point) or worsening fracture (i.e. increase in Genant score from Week 52 at a later time point) in any assessed vertebra. The Genant classification of vertebral fractures is based on the vertebral shape, with respect to vertebral height loss involving the anterior, posterior, and/or middle vertebral body and ranges between 0 (normal) and 3 (severe fracture, \>40% loss of height). The number of participants in each category is reported in the table.
Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)	Baseline (screening), Week 78	Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2	From dosing of study treatment at Week 52 up to Week 78	Information about any nonvertebral fractures while on study were recorded as adverse events. The diagnosis of nonvertebral fractures did not require central X-ray reading and was based on local radiology reports. The number of participants in each category is reported in the table.
Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2	From dosing of study treatment at Week 52 up to Week 78	The injection site reaction (ISR) assessment was done by the investigator/designee. It consisted of grading the severity of each injection reaction based on criteria the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The ISR grading was defined as follows: * Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching) * Grade 2: Pain; lipodystrophy; edema; phlebitis * Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated * Grade 4: Life-threatening consequences; urgent intervention indicated The number of participants in each category is reported in the table.
CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2	Week 56, Week 65 and Week 78	CTX is a bone resorption biomarker. Serum samples were analyzed for CTX concentrations. CTX serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1	Baseline (screening) and Week 52	Vertebral fractures were assessed by independent radiologists at the central imaging vendor. The radiologists assessed lateral thoracic (vertebrae T4 to T12) and lumbar (vertebrae L1 to L4) spine radiographs for vertebral fractures. New and worsening vertebral fractures are defined as occurrence of new fracture (i.e. change in Genant score from 0 at baseline to 1 or higher at a later time point) or worsening fracture (i.e. increase in Genant score from baseline at a later time point) in any assessed vertebra. The Genant classification of vertebral fractures is based on the vertebral shape, with respect to vertebral height loss involving the anterior, posterior, and/or middle vertebral body and ranges between 0 (normal) and 3 (severe fracture, \>40% loss of height). The number of participants in each category is reported in the table.
Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1	From first dose of study treatment on Day 1 up to pre-dose at Week 52	The injection site reaction (ISR) assessment was done by the investigator/designee. It consisted of grading the severity of each injection reaction based on criteria the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The ISR grading was defined as follows: * Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching) * Grade 2: Pain; lipodystrophy; edema; phlebitis * Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated * Grade 4: Life-threatening consequences; urgent intervention indicated The number of participants in each category is reported in the table.
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1	Baseline (pre-dose Day 1), Day 4, Week 1, Week 2, Week 8, Week 14, Week 18, Week 22, Week 26, Week 39 and Week 52	Serum samples were analyzed for concentrations of free denosumab by using a validated ligand binding assay. Briefly, the concentration of free denosumab was determined by binding to coated ligand molecules. Denosumab concentrations below the LLOQ were set to zero in order to calculate arithmetic means.
Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2	Week 56, Week 65 and Week 78	Serum samples were analyzed for concentrations of free denosumab by using a validated ligand binding assay. Briefly, the concentration of free denosumab was determined by binding to coated ligand molecules. Denosumab concentrations below the LLOQ were set to zero in order to calculate arithmetic means.
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1	From first dose of study treatment on Day 1 up to pre-dose at Week 52	Information about any nonvertebral fractures while on study were recorded as adverse events. The diagnosis of nonvertebral fractures did not require central X-ray reading and was based on local radiology reports. The number of participants in each category is reported in the table.
Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2	From Week 56 up to Week 78	Immunogenicity was evaluated in serum. Samples were screened for potential anti-drug antibodies (ADA) and positive screen results were confirmed using a confirmatory assay. For confirmed ADA positive samples, titers were determined. Confirmed ADAs were also analyzed for their neutralization potential. Patient ADA status was defined as follows: * ADA Positive: ADA-positive sample at any time point during TP1 * ADA Positive, Persistent: 'Persistent' indicates a subject experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results * ADA Positive, Transient: 'Transient' indicates a subject experiencing positive ADA result but not qualifying as 'Persistent' * ADA titer positive: ADA-positive sample with a titer result ≥ 20 ng/mL * NAb Positive: ADA-positive sample with presence of neutralizing antibodies (NAb) The number of participants in each category is reported in the table.
Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1	From Week 2 up to Week 52	Immunogenicity was evaluated in serum. Samples were screened for potential anti-drug antibodies (ADA) and positive screen results were confirmed using a confirmatory assay. For confirmed ADA positive samples, titers were determined. Confirmed ADAs were also analyzed for their neutralization potential. Patient ADA status was defined as follows: * ADA Positive: ADA-positive sample at any time point during TP1 * ADA Positive, Persistent: 'Persistent' indicates a subject experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results * ADA Positive, Transient: 'Transient' indicates a subject experiencing positive ADA result but not qualifying as 'Persistent' * ADA titer positive: ADA-positive sample with a titer result ≥ 20 ng/mL * NAb Positive: ADA-positive sample with presence of neutralizing antibodies (NAb) The number of participants in each category is reported in the table.