Fabry Disease
Conditions
Keywords
Fabry Disease, agalsidase beta, phase 1
Brief summary
Pharmacokinetic/Pharmacodynamic Study of 2 agalsidase beta Formulations in Single Dose Administered to Healthy Volunteers as intravenous infusion, at a concentration of 1 mg/kg
Detailed description
Volunteers will receive either one or the other agalsidase beta formulation. Drug will be administered as an intravenous 5h infusion. Plasma samples will be taken at different time points, from before infusion up to 12h later. Pharmacokinetic (PK) and pharmacodynamic (PD) profile will be determined, and bioequivalence evaluated.
Interventions
BIOLOGICALAgalsidase beta from Biosidus 1 mg/kg
Patients received an infusion of 1 mg/kg of Agalsidase Beta from Biosidus. Final infusion dose is achieved with lyophilized drug at concentration 35 mg and 5 mg
BIOLOGICALFabrazyme (agalsidase beta) 1 mg/kg
Patients received an infusion of 1 mg/kg of Fabrazyme. Final infusion dose is achieved with lyophilized drug at concentration 35 mg and 5 mg
Sponsors
Bio Sidus SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male subjects between the ages of 18 and 40 2. Body mass index (BMI) between 19 and 25 kg/m². 3. Volunteers whose complementary exams (ECG, chest X-ray, blood and urine, PCR for COVID-19), performed prior to their inclusion are within the normal range and/or are not clinically significant according to the investigator's judgement. 4. Subjects with systolic blood pressure higher than 110 mmHg and lower than 139 mmHg, diastolic blood pressure higher than 70 mmHg and lower than 89 mmHg with a heart rate higher than 50 and lower than 90 beats per minute after being seated for 5 minutes and, then, standing up (extreme values are included) 5. Volunteers who are well disposed to the study and have signed the approved informed consent prior to the start of the study
Exclusion criteria
1. History of clinically significant allergies (except for untreated asymptomatic seasonal allergies) 2. A drop of ≥ 20 mmHg of systolic blood pressure or ≥ 10 mmHg of diastolic blood pressure within the first 3 minutes after the postural change 3. Volunteers who are receiving other drugs (prescription or over-the-counter) or who have within the 2 weeks prior to the study 4. Volunteers with history of autoimmune diseases. 5. Chronic disorders of the CNS, psychological and/or psychiatric disorders: bipolar disorder, severe depression, insomnia, changes in personality 6. Active or chronic infections 7. Having received live or inactivated viral or bacterial vaccines, within the fifteen days prior to visits 1 or 2 8. For COVID vaccines, a 15 day window period prior to visits #1 or #2 must be respected. This period was taken from the recommendations published by the National Ministry of Health on May 29th 2021. The volunteer will be able to receive the vaccine 35 days after receiving the investigational product. 9. Known allergies to any of the components of the formulations 10. Active smoker, of more than 10 cigarettes/day 11. Current clinical evidence of severe digestive disorders, surgeries of the gastrointestinal tract (except for appendectomy) 12. Current clinical evidence of kidney disease 13. Current clinical evidence of liver disorders 14. Current clinical evidence of respiratory and cardiac disease 15. Presence of diabetes mellitus, thyroid dysfunction or other endocrine disorders 16. Evidence of active gastroduodenal disease 17. History of peripheral thrombotic phenomena 18. Underlying neurological disease 19. Presence of a current progressive chronic disease 20. History of drug or alcohol abuse or addiction within the last three years 21. Participation in a clinical study within the last three months 22. Use of any drug within the fourteen days prior to the start of the study that, according to the principal investigator's judgement may interfere with the biodistribution of the medicinal product. 23. Subjects who have donated or suffered from blood loss within the twelve weeks prior to the start of the study, or intends to donate blood within the following three months after the completion of the study. 24. Excessive drinker of tea, cocoa, mate, coffee and/or caffeinated drinks (\>5 cups/day) or of wine (\>0.5 L/day) or alcohol (\>50 ml/day) 25. Significant abnormalities in the electrocardiogram 26. Positive PCR test for COVID-19 27. Positive serology for HIV, hepatitis B or hepatitis C 28. Abnormal clinical laboratory test results (that according to the principal investigator's judgement are considered clinically significant) 29. Uncooperative volunteers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Serum Concentration of Agalsidase Beta (Cmax) | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | Compare the maximum serum concentration of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T) |
| Area Under the Curve of Serum Concentration Between Times 0 and 12 Hours of Agalsidase Beta | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | Compare the area under the curve between times 0 and 12 hours of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T) |
| Time at Which Maximum Serum Concentration of Agalsidase Beta is Observed (Tmax) | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | Compare the time at which maximum serum concentration of agalsidase beta is observed of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T) |
| Area Under the Curve of Serum Concentration, Resulting From the Extrapolation From Time 0 to Infinite Time | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | Compare the area under the curve of serum concentration, resulting from the extrapolation from time 0 to infinite time of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events | From infusion to 35 days after | Evaluation of the product safety with analysis of incidence of adverse events and tolerance. |
| Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 0 hours,12 hours and 35 days after the end of the infusion. | The presence of neutralizing antibodies to agalsidase beta activity was analyzed in serum samples from 24 volunteers (0h, 12h and 35 days), by biological activity neutralization method. The percentage of inhibition in the samples was calculated by comparing the activity value of 1 ng of agalsidase beta alone with that of agalsidase treated with the serum samples. Those samples with percentage inhibition \>50% were defined as positive. |
| Enzymatic Activity on Plasma Samples Measured With Fluorometric Method | Pre-infusion and 5 hours post administration (end of infusion) | Comparison between enzymatic activity of both formulations of agalsidase beta, assessing the difference between the 5 hour timepoint and the basal determination, to estimate their biological activity as part of the pharmacodynamic analysis. A fluorometric assay will be used. The enzymatic activity will be measured in mU/ml. The variation of enzymatic activity between the sample taken at the end of the infusion (5 hours) and pre-infusion will be analyzed. |
Countries
Argentina
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Agalsidase Beta from Biosidus Participants received a single infusion at a dose 1 mg/kg
Agalsidase beta from Biosidus 1 mg/kg: Patients received an infusion of 1 mg/kg of Agalsidase Beta from Biosidus. Final infusion dose is achieved with lyophilized drug at concentration 35 mg and 5 mg | 12 |
| Fabrazyme (Sanofi-Genzyme) Participants received a single infusion at a dose 1 mg/kg
Fabrazyme (agalsidase beta) 1 mg/kg: Patients received an infusion of 1 mg/kg of Fabrazyme. Final infusion dose is achieved with lyophilized drug at concentration 35 mg and 5 mg | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Agalsidase Beta from Biosidus | Fabrazyme (Sanofi-Genzyme) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Body Mass Index (BMI) | 23.32 Kg/m2 STANDARD_DEVIATION 1.56 | 22.4 Kg/m2 STANDARD_DEVIATION 1.7 | 22.8 Kg/m2 STANDARD_DEVIATION 1.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 12 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 174.5 Centimeters STANDARD_DEVIATION 6.6 | 169.5 Centimeters STANDARD_DEVIATION 9.3 | 172 Centimeters STANDARD_DEVIATION 8.2 |
| Region of Enrollment Argentina | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
| Weight | 71 Kilograms STANDARD_DEVIATION 5.7 | 64.5 Kilograms STANDARD_DEVIATION 7.9 | 67.6 Kilograms STANDARD_DEVIATION 7.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 7 / 12 | 9 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Area Under the Curve of Serum Concentration Between Times 0 and 12 Hours of Agalsidase Beta
Compare the area under the curve between times 0 and 12 hours of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T)
Time frame: 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Agalsidase Beta from Biosidus | Area Under the Curve of Serum Concentration Between Times 0 and 12 Hours of Agalsidase Beta | 418.21 mU*h/ml | Standard Deviation 84.81 |
| Fabrazyme (Sanofi-Genzyme) | Area Under the Curve of Serum Concentration Between Times 0 and 12 Hours of Agalsidase Beta | 472.15 mU*h/ml | Standard Deviation 100.47 |
Primary
Area Under the Curve of Serum Concentration, Resulting From the Extrapolation From Time 0 to Infinite Time
Compare the area under the curve of serum concentration, resulting from the extrapolation from time 0 to infinite time of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T)
Time frame: 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Agalsidase Beta from Biosidus | Area Under the Curve of Serum Concentration, Resulting From the Extrapolation From Time 0 to Infinite Time | 419.81 mU*h/ml | Standard Deviation 85.1 |
| Fabrazyme (Sanofi-Genzyme) | Area Under the Curve of Serum Concentration, Resulting From the Extrapolation From Time 0 to Infinite Time | 473.51 mU*h/ml | Standard Deviation 100.87 |
Primary
Maximum Serum Concentration of Agalsidase Beta (Cmax)
Compare the maximum serum concentration of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T)
Time frame: 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion
Population: Per protocol analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Agalsidase Beta from Biosidus | Maximum Serum Concentration of Agalsidase Beta (Cmax) | 95.51 mU/ml | Standard Deviation 24.9 |
| Fabrazyme (Sanofi-Genzyme) | Maximum Serum Concentration of Agalsidase Beta (Cmax) | 109.65 mU/ml | Standard Deviation 24.32 |
Primary
Time at Which Maximum Serum Concentration of Agalsidase Beta is Observed (Tmax)
Compare the time at which maximum serum concentration of agalsidase beta is observed of two formulations of agalsidase beta after intravenous infusion of 1 mg/kg: * Fabrazyme (Sanofi-Genzyme) (Reference Formulation, R) * Agalsidase beta from Biosidus SA (Test Formulation, T)
Time frame: 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Agalsidase Beta from Biosidus | Time at Which Maximum Serum Concentration of Agalsidase Beta is Observed (Tmax) | 3.83 h | Standard Deviation 1.53 |
| Fabrazyme (Sanofi-Genzyme) | Time at Which Maximum Serum Concentration of Agalsidase Beta is Observed (Tmax) | 3.36 h | Standard Deviation 1.21 |
Secondary
Enzymatic Activity on Plasma Samples Measured With Fluorometric Method
Comparison between enzymatic activity of both formulations of agalsidase beta, assessing the difference between the 5 hour timepoint and the basal determination, to estimate their biological activity as part of the pharmacodynamic analysis. A fluorometric assay will be used. The enzymatic activity will be measured in mU/ml. The variation of enzymatic activity between the sample taken at the end of the infusion (5 hours) and pre-infusion will be analyzed.
Time frame: Pre-infusion and 5 hours post administration (end of infusion)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Agalsidase Beta from Biosidus | Enzymatic Activity on Plasma Samples Measured With Fluorometric Method | 98.45 mU/ml |
| Fabrazyme (Sanofi-Genzyme) | Enzymatic Activity on Plasma Samples Measured With Fluorometric Method | 109.65 mU/ml |
Secondary
Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta
The presence of neutralizing antibodies to agalsidase beta activity was analyzed in serum samples from 24 volunteers (0h, 12h and 35 days), by biological activity neutralization method. The percentage of inhibition in the samples was calculated by comparing the activity value of 1 ng of agalsidase beta alone with that of agalsidase treated with the serum samples. Those samples with percentage inhibition \>50% were defined as positive.
Time frame: 0 hours,12 hours and 35 days after the end of the infusion.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Agalsidase Beta from Biosidus | Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 0 hours | 0 Participants with positive result |
| Agalsidase Beta from Biosidus | Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 12 hours after the end of the infusion | 0 Participants with positive result |
| Agalsidase Beta from Biosidus | Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 35 days after the end of the infusion | 0 Participants with positive result |
| Fabrazyme (Sanofi-Genzyme) | Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 0 hours | 0 Participants with positive result |
| Fabrazyme (Sanofi-Genzyme) | Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 12 hours after the end of the infusion | 0 Participants with positive result |
| Fabrazyme (Sanofi-Genzyme) | Number of Participants With Positive Results for the Presence of Neutralizing Antibodies Against Agalsidase Beta | 35 days after the end of the infusion | 0 Participants with positive result |
Secondary
Number of Patients With Adverse Events
Evaluation of the product safety with analysis of incidence of adverse events and tolerance.
Time frame: From infusion to 35 days after
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Agalsidase Beta from Biosidus | Number of Patients With Adverse Events | 5 Participants |
| Fabrazyme (Sanofi-Genzyme) | Number of Patients With Adverse Events | 7 Participants |