Healthy Volunteers
Conditions
Brief summary
Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare the PK, PD, safety and immunogenicity profile of MB09 with EU/US-Xgeva® in healthy male subjects. During the course of the study, the similarity in pharmacokinetics will be assessed by sampling the levels of drug in the blood, and by comparing these levels among the different administration arms. Pharmacodynamics, safety, tolerability, and immunologic response to the administered drugs will also be evaluated throughout.
Detailed description
The primary PK parameter endpoints are AUC0-last and Cmax for denosumab. The secondary PK endpoints will include all other PK parameters for denosumab, including AUC0-∞, Tmax, CL and t1/2. For the primary PK Analysis, an analysis of variance (ANOVA) model with treatment and stratification factors as fixed effects will be performed on the natural log transformed values of Cmax, AUC0 last, and AUC0-∞. Estimates of geometric mean ratios together with the corresponding 90% confidence intervals (CI) will be derived for the comparisons of the PK parameters as follows: * MB09 versus EU-Xgeva® * MB09 versus US-Xgeva® * EU-Xgeva® versus US-Xgeva® Bioequivalence will be concluded if the 90% CIs for the test to reference ratios of the geometric least square means for AUC0-last and Cmax are entirely contained within the \[80%, 125%\] interval. For the PD Analysis, an analysis of covariance (ANCOVA) model with treatment and stratification factors as fixed effects and logged pre-dose sCTX concentrations fitted as a covariate will be performed on the natural log-transformed values of AUEC0 253 and AUIC0 253. Adverse events will be coded using MedDRA Version 24. All AE data will be presented in a data listing. Treatment-emergent AEs will be summarised by treatment and overall, as well as by severity and relationship to study drug. Serious AEs and AEs leading to discontinuation of study drug will also be presented in the data listings and summarised by treatment and overall. The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADAs will be reported. All immunogenicity data will be presented in the data listings.
Interventions
DRUGMB09
Single dose of 35mg SC administered
DRUGUS-sourced Xgeva
Single dose of 35mg SC administered
DRUGEU-sourced Xgeva
Single dose of 35mg SC administered
Sponsors
mAbxience Research S.L.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
28 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. The subject is a male of any race, between 28 and 55 years of age, inclusive, at screening. 2. The subject has a BMI between 18.5 and 29.9 kg/m2, inclusive, (total body weight between 60 and 95 kg, inclusive) at screening and check-in. 3. The subject is considered by the investigator to be in good general health as determined by medical history, clinical laboratory test results (congenital nonhaemolytic hyperbilirubinemia \[eg, Gilbert's syndrome\] is acceptable), vital sign measurements (systolic BP ≥90 mm Hg and ≤140 mm Hg, diastolic BP ≥50 mm Hg and ≤90 mm Hg), 12 lead ECG results, and physical examination findings at screening and check in. 4. The subject must use an adequate method of contraception (eg, condom) or be willing to practice sexual abstinence during the study starting from the day of dosing and for 140 days after dosing. The subject must agree to not donating sperm during the study and for at least 140 days after dosing. Participating subject's female partner of childbearing potential should use an additional form of contraception such as an intra uterine device, barrier method with spermicide, oral contraceptive, injectable progesterone, or sub-dermal implant starting from the male partner's day of dosing until at least 140 days after dosing. The female partner of the participating subject should be familiar with the use of the respective contraceptive methods. Intra-uterine devices and hormonal methods for contraception should be used for at least 1 menstruation cycle prior to the administration of study drug. 5. The subject must be able to comprehend and willing to sign an ICF and to abide by the study restrictions. Subjects must have signed an ICF before any study-related procedure or evaluation is performed.
Exclusion criteria
1. The subject has had previous exposure to denosumab. 2. The subject has a significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the investigator. 3. The subject has a history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator. 4. The subject has any current or recent history of infections, including localised infections (within 2 months prior to screening for any serious infection that requires hospitalisation or IV anti-infective or within 14 days prior to screening for any active infection which requires oral treatment). 5. The subject has a dental or jaw disease requiring oral surgery or dental surgery within 6 months prior to study product administration or plans to have dental surgery within 6 months after dosing. 6. The subject has a history of osteomyelitis or osteonecrosis of the jaw requiring suturing within 30 days before dosing, or within 30 days after the last study visit. 7. The subject has a medically significant dental disease or dental neglect, with signs and/or symptoms of local or systemic infection that would likely require a dental procedure during the course of the study. Standard dentistry treatments (eg, dental filling or prophylaxis/cleaning) are allowed. 8. The subject has clinically relevant history of alcoholism, addiction or drug/chemical abuse prior to check in, and/or positive urinary test for alcohol or drugs of abuse at screening or check in. 9. The subject has positive hepatitis panel (HBV and HCV) or positive HIV test. Subjects whose results are compatible with prior immunisation and not infection may be included at the discretion of the investigator. 10. The subject has participated in a clinical study involving administration of an investigational drug (new chemical entity), with dosing in the past 90 days prior to Day 1, or within 5 half-lives of the investigational drug used in the study, whichever is longer. 11. The subject has used or intends to use slow-release medications/products considered to still be active within 30 days prior to check in, unless deemed acceptable by the investigator. 12. The subject has used or intends to use any nonprescription medications/products (except paracetamol \[up to 2 g/day\] and ibuprofen \[800 mg/day\]), including vitamins, minerals, supplements (eg, Biotin), and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check in, unless deemed acceptable by the investigator. Vitamin C, vitamin D, and calcium in daily recommended doses (≤1000 mg elemental calcium and 1000 IU vitamin D based on screening levels of vitamin D) are allowed. 13. The subject has received the COVID-19 vaccine within 14 days before Day 1 or plans to receive a COVID-19 vaccine within 12 weeks after study drug dosing or has positive test for COVID 19 during screening or presence of COVID 19 symptoms within 4 weeks prior to Day -1. 14. The subject has received a live or attenuated vaccine within 3 months prior to screening or has the intention to receive a vaccine during the study. The subject intends to travel to a region where a vaccination will be required due to endemic disease during the study. 15. The subject has used tobacco- or nicotine-containing products within 1 year prior to check-in or anytime during the study, or has a positive cotinine test upon screening or check-in. 16. The subject has donated blood within 60 days prior to dosing, plasma from 14 days prior to screening, or platelets from 42 days prior to dosing. 17. The subject has poor peripheral venous access. 18. Subjects who, in the opinion of the investigator, should not participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-last | Day 1 to Day 253 | Area under the plasma concentration versus time curve from time zero to the last quantifiable concentration |
| Cmax | Day 1 to Day 253 | Maximum observed plasma concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CL | Day 1 to Day 253 | Clearance |
| t1/2 | Day 1 to Day 253 | Terminal half-life |
| Pharmacodynamics (sCTX) AUEC0-253 | Day 1 to Day 253 | Observed concentration of serum C-terminal telopeptide of Type 1 collagen (sCTX) parameter will be calculated as PD endpoint. AUC0-253: area under the plasma concentration versus time curve from time 0 to day 253 |
| AUC0-∞ | Day 1 to Day 253 | Area under the plasma concentration versus time curve from time zero extrapolated to infinity |
| Incidence of Anti-denosumab Antibodies (ADA) | Day 1 to Day 253 | The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADA. The immunogenicity endpoint included denosumab anti-drug antibodies (ADA). |
| Incidence of Neutralizing Antibodies (NAb) | Day 1 to Day 253 | The incidence the neutralizing potential and titre of positive ADA. |
| Incidence of Treatment Emergent Adverse Events (TEAEs) | Day 1 to Day 253 | A treatment-emergent adverse event is defined as any event not present before exposure to study drug or any event already present that worsens in intensity or frequency after exposure. |
| Tmax | Day 1 to Day 253 | Time to reach Cmax |
Countries
Poland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MB09 (Denosumab Biosimilar) Sterile vial 120mg/1.7mL, Single dose, 35mg SC
MB09: Single dose of 35mg SC administered | 85 |
| US-sourced Xgeva Sterile vial 120mg/1.7mL, Single dose, 35mg SC
US-sourced Xgeva: Single dose of 35mg SC administered | 85 |
| EU-sourced Xgeva Sterile vial 120mg/1.7mL, Single dose, 35mg SC
EU-sourced Xgeva: Single dose of 35mg SC administered | 85 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | EU-sourced Xgeva | MB09 (Denosumab Biosimilar) | US-sourced Xgeva |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 255 Participants | 85 Participants | 85 Participants | 85 Participants |
| Age, Continuous | 39.5 years STANDARD_DEVIATION 6.9 | 39.4 years STANDARD_DEVIATION 7.15 | 40.5 years STANDARD_DEVIATION 6.93 | 38.8 years STANDARD_DEVIATION 6.59 |
| Body Mass Index | 25.98 kg/m^2 STANDARD_DEVIATION 2.396 | 26.05 kg/m^2 STANDARD_DEVIATION 2.415 | 26.13 kg/m^2 STANDARD_DEVIATION 2.441 | 25.76 kg/m^2 STANDARD_DEVIATION 2.344 |
| Height | 178.66 cm STANDARD_DEVIATION 6.227 | 177.72 cm STANDARD_DEVIATION 5.857 | 179.07 cm STANDARD_DEVIATION 6.098 | 179.20 cm STANDARD_DEVIATION 6.662 |
| Race/Ethnicity, Customized Race & Ethnicity : Not Hispanic or Latino | 255 participants | 85 participants | 85 participants | 85 participants |
| Race/Ethnicity, Customized Race & Ethnicity : White | 255 participants | 85 participants | 85 participants | 85 participants |
| Region of Enrollment Poland | 255 Participants | 85 Participants | 85 Participants | 85 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 255 Participants | 85 Participants | 85 Participants | 85 Participants |
| Weight | 82.97 Kg STANDARD_DEVIATION 8.492 | 82.48 Kg STANDARD_DEVIATION 8.643 | 83.68 Kg STANDARD_DEVIATION 8.55 | 82.74 Kg STANDARD_DEVIATION 8.334 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 85 | 0 / 85 |
| other Total, other adverse events | 18 / 85 | 17 / 85 | 28 / 85 |
| serious Total, serious adverse events | 2 / 85 | 0 / 85 | 0 / 85 |
Outcome results
Primary
AUC0-last
Area under the plasma concentration versus time curve from time zero to the last quantifiable concentration
Time frame: Day 1 to Day 253
Population: Pharmacokinetic population includes subjects who received the study treatment, who did not have major protocol deviations, and had sufficient data to calculate primary PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | AUC0-last | 146000 day*ng/mL | Geometric Coefficient of Variation 26.8 |
| US-sourced Xgeva | AUC0-last | 134000 day*ng/mL | Geometric Coefficient of Variation 27.4 |
| EU-sourced Xgeva | AUC0-last | 138000 day*ng/mL | Geometric Coefficient of Variation 24.1 |
Primary
Cmax
Maximum observed plasma concentration
Time frame: Day 1 to Day 253
Population: Pharmacokinetic population includes subjects who received the study treatment, who did not have major protocol deviations, and had sufficient data to calculate primary PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | Cmax | 3240 ng/mL | Geometric Coefficient of Variation 22 |
| US-sourced Xgeva | Cmax | 3100 ng/mL | Geometric Coefficient of Variation 27 |
| EU-sourced Xgeva | Cmax | 3090 ng/mL | Geometric Coefficient of Variation 25.4 |
Secondary
AUC0-∞
Area under the plasma concentration versus time curve from time zero extrapolated to infinity
Time frame: Day 1 to Day 253
Population: Pharmacokinetic population includes subjects who received the study treatment, who did not have major protocol deviations, and had sufficient data to calculate primary PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | AUC0-∞ | 147000 day*ng/mL | Geometric Coefficient of Variation 26.9 |
| US-sourced Xgeva | AUC0-∞ | 136000 day*ng/mL | Geometric Coefficient of Variation 27.4 |
| EU-sourced Xgeva | AUC0-∞ | 139000 day*ng/mL | Geometric Coefficient of Variation 24.3 |
Secondary
CL
Clearance
Time frame: Day 1 to Day 253
Population: Pharmacokinetic population includes subjects who received the study treatment, who did not have major protocol deviations, and had sufficient data to calculate primary PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | CL | 0.238 L/day | Geometric Coefficient of Variation 26.9 |
| US-sourced Xgeva | CL | 0.258 L/day | Geometric Coefficient of Variation 27.4 |
| EU-sourced Xgeva | CL | 0.251 L/day | Geometric Coefficient of Variation 24.3 |
Secondary
Incidence of Anti-denosumab Antibodies (ADA)
The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADA. The immunogenicity endpoint included denosumab anti-drug antibodies (ADA).
Time frame: Day 1 to Day 253
Population: Treatment-induced ADA positive (TIADA): includes subjects with only post-treatment positive ADA results.~Overall: includes all subjects with any TIADA positive result at any time. Percentages are based on TIADA positive subjects in the Safety population within each treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | Incidence of Anti-denosumab Antibodies (ADA) | overall negative ADA | 83 Participants |
| MB09 (Denosumab Biosimilar) | Incidence of Anti-denosumab Antibodies (ADA) | overall positive ADA | 1 Participants |
| US-sourced Xgeva | Incidence of Anti-denosumab Antibodies (ADA) | overall negative ADA | 83 Participants |
| US-sourced Xgeva | Incidence of Anti-denosumab Antibodies (ADA) | overall positive ADA | 1 Participants |
| EU-sourced Xgeva | Incidence of Anti-denosumab Antibodies (ADA) | overall negative ADA | 82 Participants |
| EU-sourced Xgeva | Incidence of Anti-denosumab Antibodies (ADA) | overall positive ADA | 2 Participants |
Secondary
Incidence of Neutralizing Antibodies (NAb)
The incidence the neutralizing potential and titre of positive ADA.
Time frame: Day 1 to Day 253
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MB09 (Denosumab Biosimilar) | Incidence of Neutralizing Antibodies (NAb) | 0 Participants |
| US-sourced Xgeva | Incidence of Neutralizing Antibodies (NAb) | 0 Participants |
| EU-sourced Xgeva | Incidence of Neutralizing Antibodies (NAb) | 0 Participants |
Secondary
Incidence of Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent adverse event is defined as any event not present before exposure to study drug or any event already present that worsens in intensity or frequency after exposure.
Time frame: Day 1 to Day 253
Population: At each level of subject summarization, a subject is counted once for the most related event. Percentages are based on the number of subjects in the Safety Population within each treatment and overall.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 3 or higher TEAE | 9 Participants |
| MB09 (Denosumab Biosimilar) | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 2 TEAE | 10 Participants |
| MB09 (Denosumab Biosimilar) | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 18 Participants |
| MB09 (Denosumab Biosimilar) | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 1 TEAE | 4 Participants |
| MB09 (Denosumab Biosimilar) | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 2 Participants |
| US-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 2 TEAE | 11 Participants |
| US-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 17 Participants |
| US-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 1 TEAE | 3 Participants |
| US-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 3 or higher TEAE | 4 Participants |
| US-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 Participants |
| EU-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 Participants |
| EU-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 3 or higher TEAE | 13 Participants |
| EU-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 28 Participants |
| EU-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 2 TEAE | 14 Participants |
| EU-sourced Xgeva | Incidence of Treatment Emergent Adverse Events (TEAEs) | Any Grade 1 TEAE | 5 Participants |
Secondary
Pharmacodynamics (sCTX) AUEC0-253
Observed concentration of serum C-terminal telopeptide of Type 1 collagen (sCTX) parameter will be calculated as PD endpoint. AUC0-253: area under the plasma concentration versus time curve from time 0 to day 253
Time frame: Day 1 to Day 253
Population: Absolute sCTX concentrations below the limit of quantification were taken as ½ lower limit of quantification (LLOQ) for parameter estimation (LLOQ: 70.0 pg/mL).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | Pharmacodynamics (sCTX) AUEC0-253 | 30000 day*ng/mL | Geometric Coefficient of Variation 57.2 |
| US-sourced Xgeva | Pharmacodynamics (sCTX) AUEC0-253 | 31800 day*ng/mL | Geometric Coefficient of Variation 61.5 |
| EU-sourced Xgeva | Pharmacodynamics (sCTX) AUEC0-253 | 33400 day*ng/mL | Geometric Coefficient of Variation 45.8 |
Secondary
t1/2
Terminal half-life
Time frame: Day 1 to Day 253
Population: Pharmacokinetic population includes subjects who received the study treatment, who did not have major protocol deviations, and had sufficient data to calculate primary PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MB09 (Denosumab Biosimilar) | t1/2 | 12.5 days | Geometric Coefficient of Variation 38.6 |
| US-sourced Xgeva | t1/2 | 12.1 days | Geometric Coefficient of Variation 37.2 |
| EU-sourced Xgeva | t1/2 | 12.4 days | Geometric Coefficient of Variation 37.6 |
Secondary
Tmax
Time to reach Cmax
Time frame: Day 1 to Day 253
Population: Pharmacokinetic population includes subjects who received the study treatment, who did not have major protocol deviations, and had sufficient data to calculate primary PK endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MB09 (Denosumab Biosimilar) | Tmax | 10.00 day |
| US-sourced Xgeva | Tmax | 9.95 day |
| EU-sourced Xgeva | Tmax | 9.99 day |