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    Clinical Trial Results:
    A Phase 1/2, Open Label, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Exploratory Efficacy Parameters of pegunigalsidase alfa (PRX-102) Administered by Intravenous Infusion Every 2 Weeks for 12 Weeks to Adult Fabry Patients. Please refer to PB-102-F02 study (EudraCT number 2013-002554-78) report for details.

    Summary
    EudraCT number
    		 2012-004786-40
    Trial protocol
    		 GB   ES  
    Global end of trial date
    06 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2020
    First version publication date
    03 Jan 2020
    Other versions
    Summary report(s)
    		 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    PB-102-F01 / PB-102-F02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01678898
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Protalix Ltd.
    Sponsor organisation address
    2 Snunit St, Carmiel, Israel, 20100
    Public contact
    Rainer Schuckelt, Cato Europe GmbH, 49 22343794411, r.schuckelt@cato-europe.com
    Scientific contact
    Raul CHertkoff, Protalix Ltd., 972 49028100, raul@protalix.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, pharmacokinetics and exploratory efficacy parameters of pegunigalsidase alfa (PRX-102) in adult Fabry patients who have successfully completed treatment with pegunigalsidase alfa in the core study PB-102-F01, and continued to receive treatment (at the same dose that was initially assigned to each patient) in the PB-102-F02 extension study. The extension study provides important additional long term information on safety, tolerability and clinical outcome in patients treated with different doses of pegunigalsidase alfa.
    Protection of trial subjects
    Since this study (F01 and F02) represents the first administration of pegunigalsidase alfa (PRX-102) to humans, the patients were infused sequentially and stepwise in order to evaluate tolerability. The first 6 patients were given the lowest dose (0.2 mg/kg) for at least 2 infusions each and if well tolerated, the next 6 patients were given the 1 mg/kg dose for at least 2 infusions each, and if well tolerated, the last 6 patients were given the highest dose (2 mg/kg). Specifically in the 2mg/kg treatment group, patients were provided with premedication as a preventive measure. Custom tailoring of infusion volume and rate were implemented for patients weighing over 100Kg in the 1mg/kg and 2mg/kg treatment groups.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    05 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Paraguay: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    18
    EEA total number of subjects
    3
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment efforts were conducted in North and South America, Europe and Australia for PB-102-F01 (3 months). Eighteen patients were eligible for enrollment, and 16 completed the study.

    Pre-assignment
    Screening details
    		 Eighteen (18) patients were eligible for enrollment after meeting all inclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 18
    Number of subjects completed
    		 18

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Pegunigalsidase alfa
    Arm description
    		 Safety analysis was performed on all 18 treated patients, and efficacy analysis was performed on the 16 patients who completed the study and received all infusions. Efficacy was analyzed on all 16 patients (9 males and 7 females), and additionally on phenotypically classic Fabry disease patients (9 males and 1 female).
    Arm type
    		 Dose range finding

    Investigational medicinal product name
    pegunigalsidase alfa
    Investigational medicinal product code
    Other name
    PRX-102, Alpha-galactosidase-A
    Pharmaceutical forms
    Concentrate and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each patient received one of three pegunigalsidase alfa (PRX-102) doses (0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg), as an intravenous infusion every 2 weeks for 12 weeks. All patients who completed study PB-102-F01 (12 weeks) were enrolled into extension study PB-102-F02 to receive the same dose they had received in study PB-102-F01, and continued to receive pegunigalsidase alfa (PRX-102) as an intravenous infusion every 2 weeks for an additional 38 weeks, i.e. for a total of 12 months of treatment.

    Number of subjects in period 1
    		Pegunigalsidase alfa
    Started
    18
    Completed
    16
    Not completed
    2
         Physician decision
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 17 17
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 11 11
    All vs Classic Fabry Patients
    The efficacy population included 16 patients; the study population was composed of 9 males and 7 females, however, only 10 patients (9 males and 1 female) met the definition of classic Fabry disease. Efficacy was analyzed in all patients and in patients with classic Fabry disease. The two patients (from the 1mg/kg group) who withdrew without completing the study also met the definition of phenotypic classic Fabry disease, and were only included in the safety population.
    Units: Subjects
        Classic Fabry Disease Patients
    		 12 12
        Non-Classic Fabry Disease Patients
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Efficacy group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy population in the study included 16 patients: 6 patients in the 0.2 mg/kg treatment group, 6 patients in the 1.0 mg/kg (after one patient withdrew due to an AE and one patient was discontinued from the study by the investigator), and 4 patients in the 2.0 mg/kg treatment group.

    Subject analysis set title
    Safety group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The safety population in the study included 18 patients: 6 patients in the 0.2 mg/kg treatment group, 8 patients in the 1.0 mg/kg (6 completed the study; 1 was discontinued by the investigator and 1 withdrew due to an AE), and 4 patients in the 2.0 mg/kg treatment groups.

    Subject analysis set title
    0.2 mg/kg cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Six patients were enrolled in the 0.2mg/kg treatment group and completed the study (12 months)

    Subject analysis set title
    1 mg/kg cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eight patients were enrolled in the 1.0 mg/kg treatment group, however only 6 patients completed the study (12 months), after one withdrew due to an AE and one patient was discontinued from the study by the investigator.

    Subject analysis set title
    2 mg/kg cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Four patients were enrolled in the 2.0 mg/kg treatment group and completed the study (12 months).

    Subject analysis set title
    Phenotypic Classic Fabry Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Of the 16 patients who completed the 12 months treatment period, 10 (9 males and 1 female) fit the description of phenotypic classic patients.

    Subject analysis sets values
    		 Efficacy group Safety group 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort Phenotypic Classic Fabry Patients
    Number of subjects
    16
    18
    6
    6
    4
    10
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    1
    1
    0
    1
    0
    1
        Adults (18-64 years)
    15
    17
    6
    5
    4
    9
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    7
    7
    2
    2
    3
    1
        Male
    9
    11
    4
    4
    1
    9
    All vs Classic Fabry Patients
    The efficacy population included 16 patients; the study population was composed of 9 males and 7 females, however, only 10 patients (9 males and 1 female) met the definition of classic Fabry disease. Efficacy was analyzed in all patients and in patients with classic Fabry disease. The two patients (from the 1mg/kg group) who withdrew without completing the study also met the definition of phenotypic classic Fabry disease, and were only included in the safety population.
    Units: Subjects
        Classic Fabry Disease Patients
    10
    12
    5
    4
    1
    10
        Non-Classic Fabry Disease Patients
    6
    6
    1
    2
    3
    0

    End points

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    End points reporting groups
    Reporting group title
    Pegunigalsidase alfa
    Reporting group description
    		 Safety analysis was performed on all 18 treated patients, and efficacy analysis was performed on the 16 patients who completed the study and received all infusions. Efficacy was analyzed on all 16 patients (9 males and 7 females), and additionally on phenotypically classic Fabry disease patients (9 males and 1 female).

    Subject analysis set title
    Efficacy group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The efficacy population in the study included 16 patients: 6 patients in the 0.2 mg/kg treatment group, 6 patients in the 1.0 mg/kg (after one patient withdrew due to an AE and one patient was discontinued from the study by the investigator), and 4 patients in the 2.0 mg/kg treatment group.

    Subject analysis set title
    Safety group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The safety population in the study included 18 patients: 6 patients in the 0.2 mg/kg treatment group, 8 patients in the 1.0 mg/kg (6 completed the study; 1 was discontinued by the investigator and 1 withdrew due to an AE), and 4 patients in the 2.0 mg/kg treatment groups.

    Subject analysis set title
    0.2 mg/kg cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Six patients were enrolled in the 0.2mg/kg treatment group and completed the study (12 months)

    Subject analysis set title
    1 mg/kg cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eight patients were enrolled in the 1.0 mg/kg treatment group, however only 6 patients completed the study (12 months), after one withdrew due to an AE and one patient was discontinued from the study by the investigator.

    Subject analysis set title
    2 mg/kg cohort
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Four patients were enrolled in the 2.0 mg/kg treatment group and completed the study (12 months).

    Subject analysis set title
    Phenotypic Classic Fabry Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Of the 16 patients who completed the 12 months treatment period, 10 (9 males and 1 female) fit the description of phenotypic classic patients.

    Primary: Safety - Adverse Events (AE)

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    End point title
    		 Safety - Adverse Events (AE) [1]
    End point description
    Reportings of adverse events reported by the patient and from monitoring with clinical laboratory, physical examination and ECG. For the complete analysis, please refer to the AEs section. Results represent the number of adverse events that were considered possibly, probably, or definitely related to treatment, experienced by 11/18 patients in the safety group.
    End point type
    Primary
    End point timeframe
    Patients were evaluated for AEs throughout the 12 months, from signing ICF up to 2 months after the last infusion.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a Phase 1/2 study with no formal statistical analysis required of pre-specified. Results of safety evaluations were summarized and described.
    End point values
    		 Safety group
    Number of subjects analysed
    18 [2]
    Units: events
        Safety - Adverse Events (AE)
    54
    Notes
    [2] - No statistical analyses was done for this end point.
    No statistical analyses for this end point

    Other pre-specified: Kidney Function Assessment - eGFR - mean change from baseline

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    End point title
    		 Kidney Function Assessment - eGFR - mean change from baseline
    End point description
    Estimated GFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The mean annualized eGFR slope of the phenotypically classic patients (n=9, after excluding one patient from the analysis due to intermittent treatment with doxycycline throughout the year) was 0.01 (±1.37). The results presented here represent the absolute mean change from baseline (visit 1) to 12 months.
    End point type
    Other pre-specified
    End point timeframe
    Levels of estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI equation, based on measured serum creatinine, were determined on day 1 and weeks 4, 8, 12, 26, 38 and 52, and used to determine the annualized slope of eGFR per patient.
    End point values
    		 Pegunigalsidase alfa Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    10
    Units: mL/min/1.73 m2
    arithmetic mean (standard error)
        Kidney Function assessment
    -0.8 ( 1.9 )
    0 ( 2.8 )
    No statistical analyses for this end point

    Other pre-specified: Plasma Gb3 levels

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    End point title
    		 Plasma Gb3 levels
    End point description
    Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
    End point type
    Other pre-specified
    End point timeframe
    Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months.
    End point values
    		 Pegunigalsidase alfa Efficacy group 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    16
    6
    6
    4
    9
    Units: ug/ml
    arithmetic mean (standard error)
        Biomarkers
    -22.2 ( 6.1 )
    -22.2 ( 6.1 )
    -16.8 ( 8.6 )
    -30.7 ( 11.2 )
    -16.2 ( 12.7 )
    -33.3 ( 7.6 )
    No statistical analyses for this end point

    Other pre-specified: Plasma Lyso-Gb3 Levels

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    End point title
    		 Plasma Lyso-Gb3 Levels
    End point description
    Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
    End point type
    Other pre-specified
    End point timeframe
    Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months.
    End point values
    		 Pegunigalsidase alfa Efficacy group 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    16
    6
    6
    4
    10
    Units: ng/ml
    arithmetic mean (standard error)
        Biomarkers
    -48.9 ( 5.7 )
    -48.9 ( 5.7 )
    -43.4 ( 12.2 )
    -59.9 ( 7.1 )
    -40.4 ( 7.5 )
    -57.6 ( 6.8 )
    No statistical analyses for this end point

    Other pre-specified: Kidney Gb3 accumulation – biopsies

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    End point title
    		 Kidney Gb3 accumulation – biopsies
    End point description
    Kidney biopsy was performed at baseline of study PB-102-F01 and following a total of 6 months treatment with pegunigalsidase alfa (at Month 3 visit of study PB-102-F02). Approximately 300 capillaries were scored in each specimen. The Barisoni Lipid Inclusion Scoring System (BLISS) was used as the quantitative scoring methodology for scoring Gb3 inclusions in kidney peritubular capillary (PTC) biopsy samples. The final score of each biopsy was the average number of inclusions per capillary. The scoring system was implemented by 3 pathologists/readers, who were blinded to patient, dose, and duration of treatment. A decrease in scoring from baseline to 6 Month is considered an indication for clinical improvement. Results are presented as percent change from baseline (visit 1) to month 6.
    End point type
    Other pre-specified
    End point timeframe
    Two kidney biopsies were performed: the first was before treatment, at visit 1 in PB-102-F01 study and the second was after a total of 6 months of treatment (i.e., at 3 months into study PB-102-F02).
    End point values
    		 Efficacy group Phenotypic Classic Fabry Patients
    Number of subjects analysed
    13
    8
    Units: percent
    arithmetic mean (standard error)
        Tissue disease involvement
    -67.8 ( 8.9 )
    -84.1 ( 3.4 )
    No statistical analyses for this end point

    Other pre-specified: Cardiac Fibrosis per MRI

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    End point title
    		 Cardiac Fibrosis per MRI
    End point description
    Cardiac MRI was performed to estimate left ventricular mass (LVM), left ventricular mass index (LVMi), ejection fraction (EF) and percentage and mass of the myocardial fibrotic area. Results represent the number of segments with fibrosis after 1 year of treatment.
    End point type
    Other pre-specified
    End point timeframe
    Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit.
    End point values
    		 Efficacy group Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    10
    Units: number
    number (not applicable)
        Cardiac assessment
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Cardiac MRI - Ejection Fraction

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    End point title
    		 Cardiac MRI - Ejection Fraction
    End point description
    Results are presented as mean percent change from baseline (visit 1) to 12 months.
    End point type
    Other pre-specified
    End point timeframe
    Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
    End point values
    		 Efficacy group Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    10
    Units: percent
    arithmetic mean (standard error)
        Cardiac MRI - Ejection Fraction
    -3.1 ( 3.6 )
    -7.3 ( 3.2 )
    No statistical analyses for this end point

    Other pre-specified: Cardiac MRI – LVM

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    End point title
    		 Cardiac MRI – LVM
    End point description
    Results are presented as mean percent change from baseline (visit 1) to 12 months.
    End point type
    Other pre-specified
    End point timeframe
    Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months.
    End point values
    		 Efficacy group Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    10
    Units: percent
    arithmetic mean (standard error)
        Cardiac MRI – LVM
    0 ( 2.5 )
    -2.6 ( 3.4 )
    No statistical analyses for this end point

    Other pre-specified: Cardiac MRI - LVMI

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    End point title
    		 Cardiac MRI - LVMI
    End point description
    Results are presented as mean percent change from baseline (visit 1) to 12 months.
    End point type
    Other pre-specified
    End point timeframe
    Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months
    End point values
    		 Efficacy group Phenotypic Classic Fabry Patients
    Number of subjects analysed
    16
    10
    Units: percent
    arithmetic mean (standard error)
        Cardiac MRI - LVMI
    0.4 ( 2.6 )
    -3.1 ( 3.1 )
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetics – AUC

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    End point title
    		 Pharmacokinetics – AUC
    End point description
    PK parameters were derived from the plasma concentration versus time profiles. Pegunigalsidase alfa PK parameters and profile indicate dose dependency: the PK results for all three dose levels demonstrated that mean values for AUC0-∞ (the area under the plasma concentration curve from 0 hours to infinity) increased with increasing dose on Day 1 and at Months 3, 6, and 12. The enzyme was found to be available throughout the 2-week infusion intervals with a plasma half-life of approximately 80 hours. Results reported represent the values following a single dosing of the study drug.
    End point type
    Other pre-specified
    End point timeframe
    PK parameters were determined on Day 1 and 3 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
    End point values
    		 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort
    Number of subjects analysed
    6
    6
    4
    Units: ng*hr/mL
    arithmetic mean (standard error)
        AUC
    70070 ( 26044 )
    390896 ( 136476 )
    619393 ( 158562 )
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetics - Terminal Half Life

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    End point title
    		 Pharmacokinetics - Terminal Half Life
    End point description
    PK parameters were derived from the plasma concentration versus time profiles. t1/2 = half life.
    End point type
    Other pre-specified
    End point timeframe
    PK parameters were determined on Day 1 and 3 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
    End point values
    		 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort
    Number of subjects analysed
    6
    6
    4
    Units: hour
    arithmetic mean (standard error)
        Terminal Half Life
    60.3 ( 19.6 )
    78.9 ( 10.3 )
    70.7 ( 18 )
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetics - Clearance of Drug (Cl)

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    End point title
    		 Pharmacokinetics - Clearance of Drug (Cl)
    End point description
    PK parameters were derived from the plasma concentration versus time profiles. Clearance of drug from plasma represents the volume of plasma cleared of the drug per unit time per Kg. Results reported represent the values following a single dosing of the study drug.
    End point type
    Other pre-specified
    End point timeframe
    PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
    End point values
    		 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort
    Number of subjects analysed
    6
    6
    4
    Units: ml/hr/kg
    arithmetic mean (standard error)
        Clearance of Drug (Cl)
    2.96 ( 0.81 )
    2.85 ( 0.66 )
    3.41 ( 0.68 )
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetics - Volume of Distribution (Vz)

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    End point title
    		 Pharmacokinetics - Volume of Distribution (Vz)
    End point description
    PK parameters were derived from the plasma concentration versus time profiles. Vz is the volume of distribution during the elimination phase. Results reported represent the values following a single dosing of the study drug.
    End point type
    Other pre-specified
    End point timeframe
    PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
    End point values
    		 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort
    Number of subjects analysed
    6
    6
    4
    Units: ml/kg
    arithmetic mean (standard error)
        Volume of Distribution (Vz)
    246 ( 68 )
    321 ( 71 )
    345 ( 105 )
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetics – Cmax

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    End point title
    		 Pharmacokinetics – Cmax
    End point description
    Pharmacokinetic (PK) parameters were derived from the plasma concentration versus time profiles. Cmax is the maximal plasma concentration of a drug after administration. Results reported represent the values following a single dosing of the study drug.
    End point type
    Other pre-specified
    End point timeframe
    PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion.
    End point values
    		 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort
    Number of subjects analysed
    6
    6
    4
    Units: ng/ml
    arithmetic mean (standard error)
        Cmax
    1858 ( 531 )
    11123 ( 2409 )
    16625 ( 4299 )
    No statistical analyses for this end point

    Other pre-specified: Safety - Anti-Drug Antibodies

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    End point title
    		 Safety - Anti-Drug Antibodies
    End point description
    Low incidence of treatment induced ADA (3 of 16) with reversible and transient effect on PK was observed. Three (3) patients developed treatment-induced IgG antibodies to pegunigalsidase alfa (PRX-102). Two (2) patients from the 0.2 mg/kg treatment group had titers as high as 4633 and 2198, respectively, and both were positive for neutralizing antibodies. One (1) patient from the 1.0 mg/kg treatment group had a titer as high as 237. This patient was negative for neutralizing antibodies. ADA response was transient and tolerization was observed. Results reported represent the number of patients who were ADA positive per group.
    End point type
    Other pre-specified
    End point timeframe
    Anti-pegunigalsidase alfa (PRX-102) antibodies, including neutralizing antibodies in patients having a positive IgG antibody response, were assessed at Visit 1, 2 (Month 1), and then every 2 months during the study, and 2 months after the last infusion.
    End point values
    		 Efficacy group 0.2 mg/kg cohort 1 mg/kg cohort 2 mg/kg cohort
    Number of subjects analysed
    16
    6
    6
    4
    Units: subjects
        Safety - Anti-Drug Antibodies
    3
    2
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the start of treatment throughout the 12 months of the study, including a follow up at the end of the study. all AE are reported under Clinical trial results 2013-002554-78
    Adverse event reporting additional description
    Any laboratory abnormality assessed as clinically significant by the investigator was recorded as an adverse event. A specific analysis was performed for events that occured during and up to 2h post infusion. Total AEs - 223; 169 not treatment related, 54 treatment related. Reported are the infusion related AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 All patients who received at least a single or partial treatment are included in this reporting group analysis

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 18 (11.11%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Renal Hematoma
    Additional description: One patient in the 1mg/kg group experienced a renal hematoma due to the kidney biopsy at baseline. The patient was treated and the renal hematoma was resolved. This event was considered unrelated to treatment.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
    Additional description: A 52 y.o. male experienced a bronchospasm related to the study drug 40 minutes following the first infusion initiation, was treated, recovered, and discontinued Per Protocol.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 18 (88.89%)
    Vascular disorders
    Hypotension
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Nervous system disorders
    Headache
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    6
    Dizziness
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    General disorders and administration site conditions
    Chest discomfort
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Infusion reaction
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Abdominal pain
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Sneezing
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Dyspnoea
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Chest pain
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Itching
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Sweating
    Additional description: Reported during infusion or up to 2h post infusion.
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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