Healthy Male Subjects
Conditions
Brief summary
This is a randomized, double-blind, three-arm, parallel-group, single-dose study to demonstrate bioequivalence of ENZ215 and EU- and US-sourced Prolia after a single 60-mg dose administered subcutaneously in healthy adult male volunteers.
Detailed description
Approximately 207 subjects will be enrolled into 3 groups (69 in each group) in parallel. The subjects may be enrolled in multiple groups at the site. All eligible subjects will be assigned to one of the three treatment groups in 1:1:1 ratio i.e. ENZ215 or US-sourced Prolia® or EU-sourced Prolia® to enter into the study period of 39 weeks. The study duration will be approximately 16 months (i.e. 6 months of recruitment period, 4 weeks of screening period and approximately 39 weeks (270 days) of study period). Each subject will be required to visit the site for a total of 20 visits: visit 1 - screening visit, visit 2 - day 0 to day 2, visit 3 - day 3, visit 4 - day 4, visit 5 - day 5, visit 6 - day 6, visit 7 - day 8, visit 8 - day 10, visit 9 - day 12, visit 10 - day 16, visit 11 - day 21, visit 12 - day 28 (week 4), visit 13 - day 42 (week 6), visit 14 - day 63 (week 9), visit 15 - day 90 (week 13), visit 16 - day 119 (week 17), visit 17 - day 147 (week 21), visit 18 - day 180 (week 26), visit 19 day - 224 (week 32), and visit 20 - day 270 (week 39). A window period of ±1 day is allowed for visit 12 (day 28), window period of ±3 days are allowed from day 42 (week 6) to day 180 (week 26), A window period of ±5 days are allowed from day 224 (week 32) to day 270 (week 39). End of Study Assessment will be performed on day 270 (week 39) or at the time of early discontinuation of the subject.
Interventions
BIOLOGICALENZ215
healthy volunteers receive ENZ215 (60mg) once
BIOLOGICALEU Sourced Prolia
healthy volunteers receive Denosumab (60mg) once
BIOLOGICALUS Sourced Prolia
healthy volunteers receive Denosumab (60mg) once
Sponsors
Alkem Laboratories Ltd
Enzene Biosciences Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Arm 1: ENZ215 Arm 2 : EU Sourced Prolia Arm 3: US Sourced Prolia
Eligibility
Sex/Gender
MALE
Age
28 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
The subjects will be included in the study based on the following criteria: 1. Able to understand and give written, voluntary informed consent for the study 2. Healthy adult male volunteers between 28 to 55 years of age (both inclusive) 3. Body Mass Index (BMI) ≥ 18.50 and ≤ 30.00 kg/m2 at the time of screening 4. Medically healthy with no clinically significant medical history, vital signs, physical examination, and laboratory profiles 5. Normal or clinically acceptable 12-lead electrocardiogram, QT interval corrected for heart rate (QTc interval)\* ≤ 450 msec at the time of screening 6. Subjects with negative alcohol test (breath analyzer or any suitable test) at the time of screening and admission (pre-dose) 7. Male subjects with female partners who agree to use effective contraception during study# 8. Male subjects who agree not to donate sperm during study 9. Willing and able to comply with the protocol requirements 10. Willing for multiple sampling and admission at the phase 1 study site day before dosing. * Note: QTc interval will be calculated using the Bazette and Fridericia formula. * Effective contraception: A non-vasectomised Male volunteers with female partners of child bearing potential should use dual method of contraception i.e. condom with spermicide method of contraception. Female partners should use hormonal or non-hormonal method of contraception. (No restrictions are required for a vasectomised male provided his vasectomy has been performed 4 months or more prior to the first dosing. A male who has been vasectomised less than 4 months prior to the first dosing must follow the same restrictions as a non-vasectomised male).
Exclusion criteria
The subjects will be excluded from the study based on the following criteria: 1. Known hypersensitivity to Denosumab or to any of the components of the study drug 2. Participating or has received any investigational drug (or is currently using an investigational device) within 30 days before receiving the study drug, or at least 10 times the respective elimination halflife (whichever period is longer) \* \* For monoclonal antibody refer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Drug Concentration-time Curve From Day 0 to Day 270 (AUC0-t) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 270 days | A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method. |
| Area Under the Drug Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 270 days | A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method. |
| Maximum Observed Drug Concentration (Cmax) of ENZ215 and EU- and US-sourced Prolia® | 270 days | A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Elimination Half-life (t1/2) | 270 days | t1/2 was compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate. |
| Area Under the Effect Curve (AUEC) From Time 0 to Day 270 for Serum CTX-1 Percent Inhibition Percent Inhibition | 270 days | The AUEC was calculated as the area under the effect curve from baseline until CTX-1 values return to baseline for the first time. A total of sixteen (16) blood samples for serum CTX-1 estimation of 3.5 mL each was collected from each subject in the study. For CTX-1, blood samples were collected at the same time and after a minimum of 10 hours of fasting. |
| Apparent Systemic Clearance (CL/F) | 270 days | CL/F was compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate. |
| Partial Area Under the Drug Concentration-time Curve From Time 0 (Pre-dose) to Day 28 | 28 days | AUC0-28 days were compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate. |
| Time to Reach Cmax (Tmax) | 270 days | The non-parametric analysis was used for the comparison of tmax between ENZ215 and Prolia®. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | 270 days | A total of 10 blood Immunogenicity assessment samples of 5.0 mL for NAb and ADA were collected from each subject in the study. The frequency and percentage of positive ADA or NAb result was provided. The proportion of positive ADA or NAb in each treatment group was compared using chi-square or Fisher's exact tests. The p-value, relative risk, and corresponding 95% CI was presented. |
| Incidence of Adverse Events | 270 days | Adverse events and SAEs as and when occurred, were properly recorded, evaluated, managed, and reported from signing informed consent till end of Study Assessment visit. All AEs were summarized using appropriate medical coding dictionary. |
Countries
Bulgaria, Poland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ENZ215 ENZ215 is the proposed biosimilar for Prolia® (denosumab). Subjects in this arm received a single 60 mg dose of ENZ215 as a subcutaneous injection.
ENZ215 (denosumab biosimilar) : Single dose of 60mg SC administered | 68 |
| EU Sourced Prolia EU-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of EU-Prolia® as a subcutaneous injection.
EU-Prolia® : Single dose of 60mg SC administered | 69 |
| US Licensed Prolia US-Prolia® (denosumab) is the proposed active comparator for ENZ215. Subjects in this arm received a single 60 mg dose of US-Prolia® as a subcutaneous injection.
US-Prolia® : Single dose of 60mg SC administered | 70 |
| Total | 207 |
Baseline characteristics
| Characteristic | ENZ215 | EU Sourced Prolia | US Licensed Prolia | Total |
|---|---|---|---|---|
| Age, Continuous | 37.9 Years STANDARD_DEVIATION 8.1 | 38.9 Years STANDARD_DEVIATION 7.7 | 40.1 Years STANDARD_DEVIATION 7.8 | 39.0 Years STANDARD_DEVIATION 7.9 |
| BMI | 26.219 kg/m^2 STANDARD_DEVIATION 2.601 | 26.260 kg/m^2 STANDARD_DEVIATION 2.76 | 25.562 kg/m^2 STANDARD_DEVIATION 2.835 | 26.010 kg/m^2 STANDARD_DEVIATION 2.74 |
| Height | 178.39 cm STANDARD_DEVIATION 6.22 | 178.96 cm STANDARD_DEVIATION 6.44 | 178.41 cm STANDARD_DEVIATION 7.69 | 178.59 cm STANDARD_DEVIATION 6.79 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 67 Participants | 69 Participants | 70 Participants | 206 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 68 Participants | 69 Participants | 70 Participants | 207 Participants |
| Weight | 83.62 kg STANDARD_DEVIATION 10.75 | 84.16 kg STANDARD_DEVIATION 10.34 | 81.56 kg STANDARD_DEVIATION 11.67 | 83.10 kg STANDARD_DEVIATION 10.94 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 69 | 0 / 69 |
| other Total, other adverse events | 28 / 68 | 39 / 69 | 32 / 69 |
| serious Total, serious adverse events | 0 / 68 | 1 / 69 | 0 / 69 |
Outcome results
Primary
Area Under the Drug Concentration-time Curve From Day 0 to Day 270 (AUC0-t) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia®
A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method.
Time frame: 270 days
Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Area Under the Drug Concentration-time Curve From Day 0 to Day 270 (AUC0-t) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 7508134.18 h*ng/mL | Geometric Coefficient of Variation 36.8 |
| EU Sourced Prolia | Area Under the Drug Concentration-time Curve From Day 0 to Day 270 (AUC0-t) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 7674912.81 h*ng/mL | Geometric Coefficient of Variation 24.9 |
| US Licensed Prolia | Area Under the Drug Concentration-time Curve From Day 0 to Day 270 (AUC0-t) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 7842297.13 h*ng/mL | Geometric Coefficient of Variation 28.8 |
Primary
Area Under the Drug Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia®
A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method.
Time frame: 270 days
Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Area Under the Drug Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 7622698.42 h*ng/mL | Geometric Coefficient of Variation 36.4 |
| EU Sourced Prolia | Area Under the Drug Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 7779487.60 h*ng/mL | Geometric Coefficient of Variation 24.7 |
| US Licensed Prolia | Area Under the Drug Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ENZ215, EU- and US-sourced Prolia®. and EU- and US-sourced Prolia® | 7934699.65 h*ng/mL | Geometric Coefficient of Variation 28.9 |
Primary
Maximum Observed Drug Concentration (Cmax) of ENZ215 and EU- and US-sourced Prolia®
A total of twenty four blood PK samples of 2.5 mL each were collected from each subject in the study. Pre-dose sample were collected within 30 minutes prior to IP administration. Post-dose samples up to Day 2 were collected within ± 10 minutes, within ± 2 hours from Day 3 to Day 21, within ± 1 day on Day 28, within ± 3 days from Day 42 to Day 180 and within ±5 days from Day 224 to Day 270. Serum concentrations of denosumab were measured at central laboratory by a validated analytical method.
Time frame: 270 days
Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Maximum Observed Drug Concentration (Cmax) of ENZ215 and EU- and US-sourced Prolia® | 7662.99 ng/ml | Geometric Coefficient of Variation 32.6 |
| EU Sourced Prolia | Maximum Observed Drug Concentration (Cmax) of ENZ215 and EU- and US-sourced Prolia® | 7742.64 ng/ml | Geometric Coefficient of Variation 23.2 |
| US Licensed Prolia | Maximum Observed Drug Concentration (Cmax) of ENZ215 and EU- and US-sourced Prolia® | 8033.14 ng/ml | Geometric Coefficient of Variation 24.9 |
Secondary
Apparent Systemic Clearance (CL/F)
CL/F was compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate.
Time frame: 270 days
Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Apparent Systemic Clearance (CL/F) | 0.008 mL/h | Geometric Coefficient of Variation 36.4 |
| EU Sourced Prolia | Apparent Systemic Clearance (CL/F) | 0.008 mL/h | Geometric Coefficient of Variation 24.7 |
| US Licensed Prolia | Apparent Systemic Clearance (CL/F) | 0.008 mL/h | Geometric Coefficient of Variation 28.9 |
Secondary
Area Under the Effect Curve (AUEC) From Time 0 to Day 270 for Serum CTX-1 Percent Inhibition Percent Inhibition
The AUEC was calculated as the area under the effect curve from baseline until CTX-1 values return to baseline for the first time. A total of sixteen (16) blood samples for serum CTX-1 estimation of 3.5 mL each was collected from each subject in the study. For CTX-1, blood samples were collected at the same time and after a minimum of 10 hours of fasting.
Time frame: 270 days
Population: Pharmacodynamic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PD assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Area Under the Effect Curve (AUEC) From Time 0 to Day 270 for Serum CTX-1 Percent Inhibition Percent Inhibition | 432174.780 h*% | Geometric Coefficient of Variation 20.1 |
| EU Sourced Prolia | Area Under the Effect Curve (AUEC) From Time 0 to Day 270 for Serum CTX-1 Percent Inhibition Percent Inhibition | 442806.204 h*% | Geometric Coefficient of Variation 13.6 |
| US Licensed Prolia | Area Under the Effect Curve (AUEC) From Time 0 to Day 270 for Serum CTX-1 Percent Inhibition Percent Inhibition | 436622.000 h*% | Geometric Coefficient of Variation 18.6 |
Secondary
Partial Area Under the Drug Concentration-time Curve From Time 0 (Pre-dose) to Day 28
AUC0-28 days were compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate.
Time frame: 28 days
Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Partial Area Under the Drug Concentration-time Curve From Time 0 (Pre-dose) to Day 28 | 3608894.44 h*ng/mL | Geometric Coefficient of Variation 28.9 |
| EU Sourced Prolia | Partial Area Under the Drug Concentration-time Curve From Time 0 (Pre-dose) to Day 28 | 3721138.61 h*ng/mL | Geometric Coefficient of Variation 20.6 |
| US Licensed Prolia | Partial Area Under the Drug Concentration-time Curve From Time 0 (Pre-dose) to Day 28 | 3796048.41 h*ng/mL | Geometric Coefficient of Variation 22.5 |
Secondary
Terminal Elimination Half-life (t1/2)
t1/2 was compared between ENZ215 and Prolia® using tests after log-transformation wherever appropriate.
Time frame: 270 days
Population: Pharmacokinetic population includes subjects who complied sufficiently with the protocol, who received a single-dose of the study drug and had 1 pre-dose and at least 1 post-dose measurement of any of the PK assessment not impacted by any protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ENZ215 | Terminal Elimination Half-life (t1/2) | 450.745 hours | Geometric Coefficient of Variation 28.3 |
| EU Sourced Prolia | Terminal Elimination Half-life (t1/2) | 450.207 hours | Geometric Coefficient of Variation 23.2 |
| US Licensed Prolia | Terminal Elimination Half-life (t1/2) | 441.262 hours | Geometric Coefficient of Variation 27.1 |
Secondary
Time to Reach Cmax (Tmax)
The non-parametric analysis was used for the comparison of tmax between ENZ215 and Prolia®.
Time frame: 270 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENZ215 | Time to Reach Cmax (Tmax) | 120.62 hours |
| EU Sourced Prolia | Time to Reach Cmax (Tmax) | 120.08 hours |
| US Licensed Prolia | Time to Reach Cmax (Tmax) | 120.28 hours |
Other Pre-specified
Incidence of Adverse Events
Adverse events and SAEs as and when occurred, were properly recorded, evaluated, managed, and reported from signing informed consent till end of Study Assessment visit. All AEs were summarized using appropriate medical coding dictionary.
Time frame: 270 days
Population: Total 207 subjects randomized i.e. in 68 subjects in ENZ215, 70 subjects in US-Prolia® \& 69 subjects in EU-Prolia® randomized. However, in US-Prolia® 69 subjects dosed as 1 subject withdrawn his consent before dosing, in ENZ215 \& EU-Prolia® all randomized subjects dosed. Hence in US-Prolia® 69 subjects, EU-Prolia® 69 subjects \& ENZ215 68 subjects evaluated in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ENZ215 | Incidence of Adverse Events | 28 Participants |
| EU Sourced Prolia | Incidence of Adverse Events | 39 Participants |
| US Licensed Prolia | Incidence of Adverse Events | 32 Participants |
Other Pre-specified
Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies
A total of 10 blood Immunogenicity assessment samples of 5.0 mL for NAb and ADA were collected from each subject in the study. The frequency and percentage of positive ADA or NAb result was provided. The proportion of positive ADA or NAb in each treatment group was compared using chi-square or Fisher's exact tests. The p-value, relative risk, and corresponding 95% CI was presented.
Time frame: 270 days
Population: Total 207 subjects randomized i.e. in 68 subjects in ENZ215, 70 subjects in US-Prolia® \& 69 subjects in EU-Prolia® randomized. However, in US-Prolia® 69 subjects dosed as 1 subject withdrawn his consent before dosing, in ENZ215 \& EU-Prolia® all randomized subjects dosed. Hence in US-Prolia® 69 subjects, EU-Prolia® 69 subjects \& ENZ215 68 subjects evaluated in the study.~Number subjects showed nAb.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ENZ215 | Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | ADA positive subjects | 68 participants |
| ENZ215 | Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | nAb positive subjects | 3 participants |
| EU Sourced Prolia | Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | ADA positive subjects | 69 participants |
| EU Sourced Prolia | Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | nAb positive subjects | 3 participants |
| US Licensed Prolia | Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | ADA positive subjects | 69 participants |
| US Licensed Prolia | Number of Subjects Who Developed Denosumab Neutralizing Antibodies and Antidrug Antibodies. Antibodies | nAb positive subjects | 2 participants |