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    Clinical Trial Results:
    A Phase 3, Open Label, Switch Over Study to Assess the Safety, Efficacy and Pharmacokinetics of pegunigalsidase alfa (PRX-102) 2 mg/kg Administered by Intravenous Infusion Every 4 Weeks for 52 weeks in Patients with Fabry Disease Currently Treated with Enzyme Replacement Therapy; Fabrazyme® (agalsidase beta) or Replagal™ (agalsidase alfa)

    Summary
    EudraCT number
    		 2017-001528-23
    Trial protocol
    		 GB   BE   ES   CZ   DK   IT  
    Global end of trial date
    01 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2022
    First version publication date
    06 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PB-102-F50
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03180840
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Protalix Ltd.
    Sponsor organisation address
    2 Snunit Street, Carmiel, Israel, 2161401
    Public contact
    Raul Chertkoff, Protalix Ltd., +972 4-902-8100, raul@protalix.com
    Scientific contact
    Sari Alon, Protalix Ltd., +972 4-902-8100, sari@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
    03 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, efficacy and pharmacokinetics of pegunigalsidase alfa (PRX-102) at a dosing regimen of 2.0 mg/kg every 4 weeks in patients with Fabry disease currently treated with currently commercially available ERT (agalsidase alfa or agalsidase beta).
    Protection of trial subjects
    The first administrations of pegunigalsidase alfa were performed under controlled conditions at the investigational site. Premedication, if used for the patient’s agalsidase alfa or agalsidase beta infusions before study entry, was continued for the first infusion with pegunigalsidase alfa, and then gradually tapered down at the Investigator’s discretion and according to the patient’s tolerability during the next infusions. Patients were allowed to receive the infusions in a home care set-up if the Investigator and Sponsor Medical Director/Monitor agreed that it was safe to do so and once the patient was clinically stable and there were no additional changes to premedication, infusion rate or observation time. In cases of clear clinical deterioration, the treatment could have been changed to 1.0 mg/kg every 2 weeks at the Investigator’s discretion and following discussion with the Sponsor Medical Director/Monitor.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jul 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    30
    EEA total number of subjects
    10
    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)
    0
    Adults (18-64 years)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients who were treated with agalsidase beta or agalsidase alfa for at least 3 years, and have been on a stable dose (> 80% labelled dose/kg) for at least 6 months.

    Pre-assignment
    Screening details
    		 A total of 30 patients (24 males and 6 females) were enrolled and switched from agalsidase alfa or agalsidase beta to pegunigalsidase alfa over a 52-week period, of whom 29 patients (23 males and 6 females) completed the study.

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Number of subjects completed
    		 30

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open Label

    Arms
    Arm title
    		 pegunigalsidase alfa
    Arm description
    		 pegunigalsidase alfa 2.0 mg/kg every 4 weeks for 12 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    pegunigalsidase alfa
    Investigational medicinal product code
    Other name
    PRX-102
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2.0 mg/kg administered by intravenous (IV) infusion every 4 weeks for 12 months

    Number of subjects in period 1
    		pegunigalsidase alfa
    Started
    30
    Completed
    29
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All treated patients

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.5 ( 11.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 24 24
    Previous ERT
    Previously treated with agalsidase beta or anti-agalsidase alfa
    Units: Subjects
        Agalsidase alfa
    		 7 7
        Agalsidase beta
    		 23 23
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population, defined as all patients who received at least one dose (partial or complete) of pegunigalsidase alfa in the study

    Subject analysis set title
    Efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Efficacy population, defined as all patients who received any dose of pegunigalsidase alfa 2.0 mg/kg in this study and who had at least one post-baseline visit with an efficacy evaluation

    Subject analysis set title
    Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Male subjects from safety population

    Subject analysis set title
    Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Female subjects from safety population

    Subject analysis sets values
    		 Safety population Efficacy population Male Female
    Number of subjects
    30
    29
    24
    6
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    30
    29
    24
    6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.5 ( 11.3 )
    ( )
    39.3 ( 12.2 )
    45.2 ( 5.3 )
    Gender categorical
    Units: Subjects
        Female
    6
    6
    6
    6
        Male
    24
    23
    24
    24
    Previous ERT
    Previously treated with agalsidase beta or anti-agalsidase alfa
    Units: Subjects
        Agalsidase alfa
    7
    5
    2
        Agalsidase beta
    23
    19
    4

    End points

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    End points reporting groups
    Reporting group title
    pegunigalsidase alfa
    Reporting group description
    		 pegunigalsidase alfa 2.0 mg/kg every 4 weeks for 12 months

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population, defined as all patients who received at least one dose (partial or complete) of pegunigalsidase alfa in the study

    Subject analysis set title
    Efficacy population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Efficacy population, defined as all patients who received any dose of pegunigalsidase alfa 2.0 mg/kg in this study and who had at least one post-baseline visit with an efficacy evaluation

    Subject analysis set title
    Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Male subjects from safety population

    Subject analysis set title
    Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Female subjects from safety population

    Primary: Number of participants experiencing adverse events (AEs)

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    End point title
    		 Number of participants experiencing adverse events (AEs) [1]
    End point description
    Results represent the number of treatment-emergent adverse events (TEAE) that were considered possibly, probably, or definitely related to treatment
    End point type
    Primary
    End point timeframe
    12 months
    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: No formal statistical analysis was specified for this study, the data was summarized using descriptive statistics.
    End point values
    		 Safety population
    Number of subjects analysed
    30
    Units: subjects
        At least 1 TEAE
    27
        At least 1 mild or moderate TEAE
    26
        At least 1 severe TEAE
    2
        At least 1 serious TEAE
    2
        At least 1 non-serious TEAE
    26
        At least 1 related TEAE
    9
        At least 1 related mild or moderate TEAE
    9
        At least 1 related severe TEAE
    0
        At least 1 related serious TEAE
    0
        At least 1 TEAE leading to withdrawal
    0
        At least 1 TEAE leading to death
    0
    No statistical analyses for this end point

    Other pre-specified: Estimated Glomerular Filtration Rate (eGFR)

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    End point title
    		 Estimated Glomerular Filtration Rate (eGFR)
    End point description
    eGFR was calculated based on the serum creatinine values according to the CKD-EPI formula. The absolute change in eGFR from baseline measurement at visit 1 to last measurement at Month 12 was summarized using descriptive statistics.
    End point type
    Other pre-specified
    End point timeframe
    12 Months
    End point values
    		 Efficacy population Male Female
    Number of subjects analysed
    29
    23
    6
    Units: mL/min/1.73 m^2
    arithmetic mean (standard error)
        Baseline
    99.44 ( 4.15 )
    100.68 ( 4.96 )
    94.69 ( 6.76 )
        Month 12
    100.65 ( 3.14 )
    103.24 ( 3.46 )
    91.15 ( 6.39 )
        Change from Baseline to Month 12
    -1.27 ( 1.39 )
    -0.64 ( 1.57 )
    -3.54 ( 3.12 )
    No statistical analyses for this end point

    Other pre-specified: Plasma Lyso-Gb3

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    End point title
    		 Plasma Lyso-Gb3
    End point description
    Globotriaosylsphingosine (Lyso-Gb3) is Fabry disease specific biomarker that can assess treatment outcome.
    End point type
    Other pre-specified
    End point timeframe
    12 Month
    End point values
    		 Efficacy population Male Female
    Number of subjects analysed
    29
    23
    6
    Units: nM
    arithmetic mean (standard error)
        Baseline
    19.36 ( 3.35 )
    23.27 ( 3.82 )
    4.35 ( 1.00 )
        Month 12
    22.23 ( 3.60 )
    27.05 ( 4.00 )
    4.52 ( 1.10 )
        Change from Baseline to Month 12
    3.01 ( 0.94 )
    3.79 ( 1.14 )
    0.17 ( 0.34 )
    No statistical analyses for this end point

    Other pre-specified: Quality of life by EQ VAS

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    End point title
    		 Quality of life by EQ VAS
    End point description
    The EQ VAS, of the EQ 5D 5L questionnaire, records the subject’s self-rated health on a vertical, visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ (score "100") and ‘Worst imaginable health state’ (score "0").
    End point type
    Other pre-specified
    End point timeframe
    12 Months
    End point values
    		 Efficacy population
    Number of subjects analysed
    29
    Units: Score
    arithmetic mean (standard error)
        Baseline
    78.3 ( 3.1 )
        Month 12
    82.1 ( 2.9 )
        Change from Baseline to Month 12
    3.0 ( 2.2 )
    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, Month 9 or 11, and month 12.
    End point values
    		 Safety population
    Number of subjects analysed
    30
    Units: ng/ml
    arithmetic mean (standard deviation)
        Pharmacokinetics
    35876.7 ( 11942.2 )
    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. AUC0-∞ is the area under the plasma concentration curve from 0 hours to infinity. 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, Month 9 or 11 and Month 12.
    End point values
    		 Safety population
    Number of subjects analysed
    30
    Units: ng*hr/ml
    arithmetic mean (standard deviation)
        Pharmacokinetics
    1797464.1 ( 822632.4 )
    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. 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, Month 9 or 11 and Month 12.
    End point values
    		 Safety population
    Number of subjects analysed
    30
    Units: hour
    arithmetic mean (standard deviation)
        Pharmacokinetics
    100.1 ( 58.3 )
    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 until 30 days following the final study dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    All Patients
    Reporting group description
    		 Analysis of AEs was performed on TEAEs, defined as AEs occurring after the start of the first infusion with pegunigalsidase alfa.

    Serious adverse events
    		 All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 30 (6.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 30 (90.00%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    17
    Contusion
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Neuralgia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    9
    Fatigue
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    6
    Chest discomfort
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Hypoacusis
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Myalgia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    7
    Gastroenteritis
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    4
    Sinusitis
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Gastroenteritis viral
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2

    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.
    Small number of subjects
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