A Study to Compare Efficacy, PK, PD, Safety and IMM of MB09 to Prolia® [EU-sourced] in Postmenopausal Osteoporosis.

To demonstrate equivalent efficacy of MB09 to EU Prolia in postmenopausal women with osteoporosis in terms of lumbar spine BMD at Week 52 (Month 12). The main analysis method was on the mFAS using a mixed model for repeated measures (MMRM) fitted to the composite %CfB lumbar spine BMD at Month 6 and Month 12, without any imputation of missing data. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA) and assessments of the lumbar spine (L1 to L4) were performed at a central imaging vendor.

Time frame: Baseline (Screening), up to Week 52

Population: Modified Full Analysis Set (mFAS) is a subset of subjects in the FAS who met all eligibility criteria. The mFAS term defined a set at the data point level which included a data record at each timepoint for all eligible subjects in the FAS but excluded data observed after the first occurrence of those intercurrent events (ICEs) where a hypothetical strategy was taken (eg, missing a dose, errors or deviations in dosing, or receipt of any prohibited therapies or other osteoporosis medication).

To assess the efficacy of MB09 to EU-Prolia in postmenopausal women with osteoporosis in terms of Lumbar Spine at Month 6 and Total Hip and Femur Neck BMD at Month 6 and Month12. The difference in means in %CfB in lumbar spine BMD between MB09 and Prolia at Month 6 and Total Hip and Femur Neck at Month 6 and Month 12 from an MMRM presented for the mFAS. Bone density measurements were performed by DXA. All DXA scans were submitted to a central imaging vendor for analysis.

Time frame: Baseline (screening), Month 6 and Month 12.

Population: Modified Full Analysis Set (mFAS) is a subset of subjects in the FAS who met all eligibility criteria. The mFAS term defined a set at the data point level which included a data record at each timepoint for all eligible subjects in the FAS but excluded data observed after the first occurrence of those intercurrent events (ICEs) where a hypothetical strategy was taken (eg, missing a dose, errors or deviations in dosing, or receipt of any prohibited therapies or other osteoporosis medication).

To assess the efficacy of MB09 to EU-Prolia in postmenopausal women with osteoporosis in terms of the difference in means (MB09-Prolia) in the %CfB in Lumbar Spine BMD at Month 6 and Total Hip and Femur Neck BMD at Month 6 and 12 in postmenopausal women with osteoporosis treated with SC denosumab injections every 6 months. This included all subjects and data records irrespective of failed eligibility criteria, receipt of prohibited medications, discontinued treatment for any reason, had errors or deviations in dosing, or receipt of both doses. Bone density measurement were performed by DXA. All DXA scans were submitted to a central imaging vendor for analysis.

Time frame: Baseline (screening), Month 6, Month 12.

Population: The Full Analysis Set (FAS) consisted of all consenting randomised subjects who received at least one dose of study treatment.

Difference in means (MB09-Prolia) in the %CfB in lumbar spine BMD after 12 months in postmenopausal women with osteoporosis treated with SC denosumab injections every 6 months. This included all subjects and data records irrespective of failed eligibility criteria, receipt of prohibited medications, discontinued treatment for any reason, had errors or deviations in dosing, or receipt of both doses. Estimation was via Multiple Imputation (MI) and ANCOVA on the FAS. Since the retrieved dropout rate was low, a treatment-failure (TF) penalty was applied to the imputed values at Month 12 for those subjects who received only one dose of the study treatment to centre the distribution of each subject's %CfB values around their baseline level. Bone density measurements were performed by DXA. All DXA scans were submitted to a central imaging vendor for analysis.

Time frame: Baseline (screening), up to Week 52

Population: The Full Analysis Set (FAS) consisted of all consenting randomised subjects who received at least one dose of study treatment.

Number of subjects experiencing treatment-induced immunogenicity: Binding and neutralising serum denosumab antibodies from baseline up to and including Month 18. Analysis of immunogenicity data will be based on ADA evaluable subjects defined as all SAF or SAF-TP subjects with baseline and at least one post-baseline immunogenicity assessment within the Main Treatment Period or the Transition Period. The formation of ADAs against MB09 or EU-Prolia was assessed in blood samples.

Time frame: From baseline (pre-dose) up to and including Month 18.

Population: Safety Analysis Set (SAF) and Safety Analysis Set for Transition Period (SAF-TP)

AUIC0-6 months = Area under the inhibition curve for % change from baseline sCTX concentrations from time zero to 6 months

Time frame: Baseline (pre-dose Day 1), up to Month 6.

Population: Modified Full Analysis Set (mFAS)

Geometric meant (geometric CV%) sCTX Area under the effect curve from zero to 6 months (AUEC0-6 months) after first dose in postmenopausal women with osteoporosis treated with SC denosumab injections every 6 months assuming all women received their first denosumab dose without any errors in dosing and without receipt of any prohibited therapies or other osteoporosis medications up to 6 months after first dose.

Time frame: Baseline (pre-dose Day 1), up to Month 6.

Population: Modified Full Analysis Set (mFAS)

To assess the PK profile of MB09 compared with EU-Prolia following the first dose, maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose study treatment (Pharmacokinetic Parameter Analysis Set).

Time frame: Baseline (pre-dose Day 1), up to Month 6

Population: Pharmacokinetic Parameter Analysis Set (PKPS) comprises all subjects who have at least three measurable concentrations in PKCS which must include Day 11 to allow for reliable estimation of both Cmax and AUC0-6 months.

Area under the concentration-time curve from time zero to 6 months analysed on the log scale by ANCOVA. The model will include treatment and stratification variables (baseline BMD T-score at the lumbar spine (≤ -3.0 and \> -3.0 SD), body mass index (\< 25 and ≥ 25 kg/m2), age at study entry (≥ 55 to \< 68 years versus ≥ 68 to ≤ 80 years) and prior bisphosphonate medication use at study entry (prior use of bisphosphonates versus no prior bisphosphonate use as fixed effects. The estimated mean difference with 95% CI will be back-transformed to give the ratio of geometric means (MB09/EU-Prolia) with 95% CI following the first dose in the Main Treatment Period.

Time frame: Baseline (pre-dose Day 1), up to Month 6.

Population: Pharmacokinetic Parameter Analysis Set (PKPS) comprises all subjects who have at least three measurable concentrations in PKCS wich must include Day 11 to allow for reliable estimation of both Cmax and AUC0-6 months.

For the Main Treatment Period, TEAE was an event observed after first dose on Day 1 until Month 12 and no more than 6 months after the last dose in case of early treatment discontinuation unless the TEAE was considered as related to the study treatment by investigator. For Transition Period, TEAE was an event observed after the third dose of study treatment at Month 12 until Month 18. Throughout the study, TEAE was an event observed after first dose on Day 1 until Month 18.

Time frame: All participants in the Main Treatment Period and Transition Period (From Day 1 untill Month 18)

Population: Safety Analysis Set (SAF) and Safety Analysis Set for Transition Period (SAF-TP)

For Main Treatment Period, treatment-emergent adverse event (TEAE) was an event observed after first dose on Day 1 until Month 12 and no more than 6 months after the last dose in case of early treatment discontinuation unless the TEAE was considered as related to the study treatment by investigator. For Transition Period, TEAE was an event observed after the third dose of study treatment at Month 12 until Month 18. Throughout the study, TEAE was an event observed after first dose on Day 1 until Month 18.

Time frame: From first administration of study treatment on Day 1 until Month 18

Population: The Safety Analysis Set (SAF) and Safety Analysis Set for Transition Period (SAF-TP)