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

Phase 3

Completed

Conditions: Postmenopausal Women With Osteoporosis

Interventions: Drug: MB09 (denosumab biosimilar)
Dietary Supplement: Elemental Calcium
Drug: EU-Prolia
Dietary Supplement: Vitamin D

Registration Number: NCT05338086

Lead Sponsor: mAbxience Research S.L.

Brief Summary: This was a randomized, double-blind, parallel, multicenter, multinational study to compare the efficacy, pharmacokinetics, pharmacodynamics, safety and immunogenicity of MB09 versus Prolia® in postmenopausal women with osteoporosis

Detailed Description: The study was planning to randomise approximately 528 postmenopausal women with osteoporosis aged ≥55 and ≤80 years old with a Bone Mineral Density (BMD) consistent with T-score of ≤ -2.5 and ≥ -4 at the lumbar spine or total hip as measured by DXA during the Screening Period. Screening evaluations were to be completed within 28 days prior to randomisation.

On Day 1, 528 eligible postmenopausal women with osteoporosis were to be randomised in a 2:1:1 ratio to receive MB09-MB09 (Arm 1), Prolia-MB09 (Arm 2), or Prolia-Prolia (Arm 3) using an Interactive Response Sys-tem (IRT).

During the Main Treatment Period, subjects received one subcutaneous injection (60 mg/mL) of study drug on Day 1 and at Month 6. At Month 12, after all efficacy and safety assessments have been performed, the subject were to be enter the Transition/Safety Follow Up Period and were to receive the third dose of study drug. Subjects assigned to the MB09 MB09 arm (Arm 1) received MB09 on Day 1, at Month 6 and at Month 12. Subjects assigned to the Prolia MB09 arm (Arm 2) received EU-Prolia on Day 1 and at Month 6, and MB09 at Month 12. Subjects assigned to the Prolia-Prolia arm (Arm 3) received EU-Prolia on Day 1, at Month 6, and at Month 12. All subjects were to be followed up to Transition Period Month 6.

All subjects received daily supplementation of calcium and vitamin D.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 558

Inclusion Criteria

Postmenopausal women, diagnosed with osteoporosis.
Aged ≥ 55 and ≤ 80 years at screening.
Body weight ≥ 50 kg and ≤ 99.9 kg, and a body mass index of ≤30 kg/m2 at screening.
Absolute bone mineral density consistent with T-score ≤ -2.5 and ≥ -4.0 at the lumbar spine or total hip as measured by Dual-energy X-ray Absorptiometry (DXA).
At least two intact, nonfractured vertebrae in the L1-L4 region and at least one hip joint evaluable by DXA.
Adequate organ function.

Exclusion Criteria

Previous exposure to denosumab (Prolia®, Xgeva®, or denosumab biosimilar) or other monoclonal antibody.
History and/or presence of one severe or more than two moderate vertebral fractures or hip fracture.
Recent long bone fracture (within 6 months).
History and/or presence of bone metastases, bone disease or other metabolic disease.
Intravenous bisphosphonate administered within 5 years of screening.
Oral bisphosphonates ≥12 months cumulative use prior to screening. If used <12 months cumulatively and the last dose was ≥12 months before screening, the subject could be enrolled.
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.
Other Inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MB09-MB09	MB09 (denosumab biosimilar)	Subjects randomised into MB09-MB09 group were administered MB09 (60 mg in 1 mL) SC injection every 6 months.
MB09-MB09	Elemental Calcium	Subjects randomised into MB09-MB09 group were administered MB09 (60 mg in 1 mL) SC injection every 6 months.
Prolia-Prolia	Elemental Calcium	Subjects randomised into Prolia-Prolia group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
MB09-MB09	Vitamin D	Subjects randomised into MB09-MB09 group were administered MB09 (60 mg in 1 mL) SC injection every 6 months.
Prolia-MB09	Vitamin D	Subjects randomised into Prolia- MB09 group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
Prolia-MB09	MB09 (denosumab biosimilar)	Subjects randomised into Prolia- MB09 group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
Prolia-MB09	EU-Prolia	Subjects randomised into Prolia- MB09 group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
Prolia-MB09	Elemental Calcium	Subjects randomised into Prolia- MB09 group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
Prolia-Prolia	EU-Prolia	Subjects randomised into Prolia-Prolia group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.
Prolia-Prolia	Vitamin D	Subjects randomised into Prolia-Prolia group were administered Prolia® (60 mg in 1 mL) SC injection every 6 months.

Primary Outcome Measures

Name	Time	Method
Efficacy: Percentage Change From Baseline (%CfB) in Lumbar Spine Bone Mineral Density (LS-BMD) at 52 Weeks - Modified Full Analysis Set (mFAS)	Baseline (Screening), up to Week 52	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.

Secondary Outcome Measures

Name	Time	Method
Efficacy: Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - Full Analysis Set (FAS)	Baseline (screening), up to Week 52	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.
Efficacy: Percentage Change From Baseline (%CfB) in Lumbar Spine at Month 6 and Total Hip and Femur Neck BMD at Month 6 and Month12 - MMRM on mFAS	Baseline (screening), Month 6 and Month 12.	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.
Efficacy: Percentage Change From Baseline (%CfB) in Lumbar Spine BMD at Month 6 and Total Hip and Femur Neck BMD at Month 6 and 12 - ANCOVA on FAS	Baseline (screening), Month 6, Month 12.	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.
Pharmacodynamics: Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen (sCTX) Area Under the Effect Curve From Zero to 6 Months (AUEC0-6 Months) After First Dose - Modified Full Analysis Set (mFAS)	Baseline (pre-dose Day 1), up to Month 6.	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.
Pharmacodynamics: %CfB Area Under the Percent Inhibition Curve From Time Zero to 6 Months (AUIC0-6 Months) in sCTX - on mFAS	Baseline (pre-dose Day 1), up to Month 6.	AUIC0-6 months = Area under the inhibition curve for % change from baseline sCTX concentrations from time zero to 6 months
Pharmacokinetics: Maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose Study Treatment (Pharmacokinetic Parameter Analysis Set)	Baseline (pre-dose Day 1), up to Month 6	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).
Pharmacokinetics: To Assess the PK Profile of MB09 Compared With EU Prolia (AUC0-6 Months) Following the First Dose	Baseline (pre-dose Day 1), up to Month 6.	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.
Safety: Overall Summary of Adverse Events - Main Treatment Period - Safety Analysis Set (SAF) and Safety Analysis Set for Transition Period (SAF-TP)	From first administration of study treatment on Day 1 until Month 18	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.
Safety: New Clinical Bone Fractures - TEAEs (Throughout the Study - From Day 1 Untill Month 18)	All participants in the Main Treatment Period and Transition Period (From Day 1 untill Month 18)	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.
Overall Incidence of Antidrug Antibodies (ADA) - Safety Analysis Set (SAF) and Safety Analysis Set for Transition Period (SAF-TP)	From baseline (pre-dose) up to and including Month 18.	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.

Trial Locations

Locations (64): Medical Center Hera EOOD
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Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment - Prof. Dr. Stoyan Kirkovich AD
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Stara Zagora, Bulgaria
New Medical Center EOOD
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Vratsa, Bulgaria
Medical Center Medconsult Pleven OOD
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Pleven, Bulgaria
Medical Center Artmed OOD
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Plovdiv, Bulgaria
Multiprofile Hospital for Active Treatment Plovdiv
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Plovdiv, Bulgaria
Outpatient Clinic for Specialized Medical Help - Medical Center Kuchuk Paris "OOD"
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Plovdiv, Bulgaria
KLV Arstikabinet
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Pärnu, Pärnu Maakon, Estonia
National Institute of Endocrinology
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Tbilisi, Georgia
Tbilisi Heart and Vascular Clinic Ltd
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Tbilisi, Georgia
Csongrad Megyei Dr. Bugyi Istvan Korhaz
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Szentes, Csongrád, Hungary
Bekes Megyei Kozponti Korhaz
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Békéscsaba, Békés, Hungary
AES - DRS - Synexus Gyula - Magyarország Egészségügyi Szolgáltató Kft
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Gyula, Békés, Hungary
Pest Megyei Flór Ferenc Kórház
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Kistarcsa, Pest, Hungary
Centro Integral Medico SJR S.C
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Querétaro, Mexico
Centrum Medyczne Katowice - PRATIA - PPDS
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Katowice, Poland
Sigulda Hospital, Outpatient Clinic
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Sigulda, Siguldas Pilsēta, Latvia
AES - DRS - Synexus Budapest - Magyarország Egészségügyi Szolgáltató Kft
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Budapest, Hungary
Vital Medical Center
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Veszprém, Hungary
Outpatient Clinic Veselibas Centrs 4
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Riga, Riga Rajon, Latvia
RSU Ambulance
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Riga, Latvia
Centro de Estudios de Investigacion Basica Y Clinica SC
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Guadalajara, Jalisco, Mexico
Hospital Central Dr Ignacio Morones Prieto
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San Luis Potosí, Mexico
MCM Krakow - PRATIA - PPDS
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Kraków, Poland
Centrum Medyczne AMED
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Warsaw, Poland
Centrum Medyczne Reuma Park NZOZ
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Warsaw, Poland
Institute of Rheumatology Belgrade - PPDS
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Belgrad, Serbia
Globe Badania Kliniczne Spólka z o.o.
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Kłodzko, Dolnoslaskie, Poland
Lubelskie Centrum Diagnostyczne (Lotników Polskich)
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Świdnik, Lubelskie, Poland
Krakowskie Centrum Medyczne
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Krakow, Poland
Lubelskie Centrum Diagnostyczne
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Świdnik, Lubelskie, Poland
NZOZ Osteo Medic SC Artur Racewicz Jerzy Supronik
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Bialystok, Podlaskie, Poland
AES - DRS - Synexus Polska Sp. z o.o. Oddzial w Warszawie
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Warszawa, Mazowieckie, Poland
Bialystok - ClinicMed Daniluk, Nowak Spólka Jawna
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Bialystok, Podlaskie, Poland
Rheuma Medicus Specjalistyczne Centrum Reumatologii i Osteoporozy
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Warsaw, Poland
Centrum Medyczne Czestochowa - PRATIA - PPDS
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Częstochowa, Slaskie, Poland
AES - DRS - Synexus Polska Sp. z o.o. Oddzial w Poznaniu
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Poznań, Wielkopolskie, Poland
Centrum Medyczne Linden
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Kraków, Poland
Military Medical Academy
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Belgrad, Serbia
Tbilisi Heart Center Ltd.
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Tbilisi, Georgia
Medical Center Excelsior OOD - PPDS
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Sofia, Bulgaria
Specialized outpatient medical facility - Rheumatology Centre St. Irina EOOD
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Sofia, Bulgaria
East Tallinn Central Hospital
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Tallinn, Harjumaa, Estonia
Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
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Bydgoszcz, Poland
Clinical Research Centre Ltd
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Tartu, Tartumaa, Estonia
AES - DRS - Synexus Debrecen Magyarország Egészségügyi Szolgáltató Kft
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Debrecen, Hajdú-Bihar, Hungary
Outpatient Clinic Adoria
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Riga, Rigas Rajons, Latvia
AES - DRS - Synexus Polska Sp. z o.o. Oddzial we Wroclawiu
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Wrocław, Poland
Hospital Universitario Dr. Jose Eleuterio González
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Monterrey, Nuevo León, Mexico
Diagnostic and Consulting Center Aleksandrovska EOOD
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Sofia, Bulgaria
AES - DRS - Medical Center Synexus Sofia EOOD
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Sofia, Sofia-Grad, Bulgaria
Diagnostic- Consultative Center Convex EOOD
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Sofia, Bulgaria
Center For Clinical And Basic Research
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Tallinn, Harjumaa, Estonia
North Estonia Medical Centre Foundation
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Tallinn, Harjumaa, Estonia
Tartu University Hospital
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Tartu, Tartumaa, Estonia
MediTrials OÜ
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Tartu, Tartumaa, Estonia
MÁV Kórház és Rendelointézet Szolnok
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Szolnok, Jász-Nagykun-Szolnok, Hungary
AES - DRS - Synexus Zalaegerszeg Magyarország Egészségügyi Kft
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Zalaegerszeg, Zala, Hungary
QUALICLINIC Kft
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Budapest, Hungary
Óbudai Egészségügyi Centrum Kft
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Budapest, Hungary
Private Practice of Laila Atike
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Liepāja, Liepājas Rajon, Latvia
Clinical Centre of Vojvodina
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Novi Sad, Serbia
Hospital Angeles Lindavista (Consultorio de Reumatologia)
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Ciudad de Mexico, Distrito Federal, Mexico
University Clinical Center of Serbia - PPDS
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Belgrad, Serbia