PK/PD Study of 2 Agalsidase Formulations in Single Dose of 1 mg/kg Administered to Healthy Volunteers as IV Infusion

Study Overview
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Brief Summary
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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
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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.

Official Title
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Comparative Pharmacokinetic and Pharmacodynamic Study Between 2 Agalsidase Beta Formulations at a Single Dose of 1 mg/kg of Agalsidase (Biosidus) and Fabrazyme (Sanofi Genzyme) as Intravenous Infusion in Male Healthy Volunteers

Conditions
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Fabry Disease

Intervention / Treatment
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* Biological: Agalsidase beta from Biosidus 1 mg/kg
* Biological: Fabrazyme (agalsidase beta) 1 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects between the ages of 18 and 40 Body mass index (BMI) between 19 and 25 kg/m². 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. 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) Volunteers who are well disposed to the study and have signed the approved informed consent prior to the start of the study Exclusion Criteria: History of clinically significant allergies (except for untreated asymptomatic seasonal allergies) 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 Volunteers who are receiving other drugs (prescription or over-the-counter) or who have within the 2 weeks prior to the study Volunteers with history of autoimmune diseases. Chronic disorders of the CNS, psychological and/or psychiatric disorders: bipolar disorder, severe depression, insomnia, changes in personality Active or chronic infections Having received live or inactivated viral or bacterial vaccines, within the fifteen days prior to visits 1 or 2 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. Known allergies to any of the components of the formulations Active smoker, of more than 10 cigarettes/day Current clinical evidence of severe digestive disorders, surgeries of the gastrointestinal tract (except for appendectomy) Current clinical evidence of kidney disease Current clinical evidence of liver disorders Current clinical evidence of respiratory and cardiac disease Presence of diabetes mellitus, thyroid dysfunction or other endocrine disorders Evidence of active gastroduodenal disease History of peripheral thrombotic phenomena Underlying neurological disease Presence of a current progressive chronic disease History of drug or alcohol abuse or addiction within the last three years Participation in a clinical study within the last three months 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. 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. 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) Significant abnormalities in the electrocardiogram Positive PCR test for COVID-19 Positive serology for HIV, hepatitis B or hepatitis C Abnormal clinical laboratory test results (that according to the principal investigator's judgement are considered clinically significant) Uncooperative volunteers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Agalsidase Beta from Biosidus<br>Participants received a single infusion at a dose 1 mg/kg | Biological: Agalsidase beta from Biosidus 1 mg/kg<br>* 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<br>|
| Active Comparator: Fabrazyme (Sanofi-Genzyme)<br>Participants received a single infusion at a dose 1 mg/kg | Biological: Fabrazyme (agalsidase beta) 1 mg/kg<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | 
| 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) | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | 
| 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) | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | 
| 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) | 0, 1, 3, 5, 5.5, 6, 7, 8, 10 and 12 hours from the beginning of the infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Pre-infusion and 5 hours post administration (end of infusion) | 
| Number of patients with adverse events | Evaluation of the product safety with analysis of incidence of adverse events and tolerance. | From infusion to 35 days after | 
| Immunogenicity of agalsidase beta | The titer of anti-agalsidase beta antibodies will be determined in both groups of volunteers, by biological activity neutralization method | 0 and 12 hours after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fabry Disease, agalsidase beta, phase 1