Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function (BALANCE)

A Randomized, Double Blind, Active Control Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function in Patients With Fabry Disease Previously Treated With Agalsidase Beta

This was a randomized, double-blind, active control study of the enzyme replacement therapy (ERT) drug PRX-102 (pegunigalsidase alfa) in Fabry disease patients with impaired renal function. Patients who had been treated for approximately 1 year with agalsidase beta and who had been on a stable dose of that product for at least 6 months were randomized in a 2:1 ratio to either switch to PRX-102 or to continue treatment with agalsidase beta. Both treatments were delivered by intravenous infusions every two weeks, at a dosage of 1 mg/kg.

Study Overview

• Status: Completed
• Conditions: Fabry Disease
• Intervention / Treatment: Biological: PRX-102 (pegunigalsidase alfa); Biological: agalsidase beta

Detailed Description

This was a randomized, double-blind, active control study examining the safety and efficacy of pegunigalsidase alfa (PRX-102) in Fabry disease patients with impaired renal function. Participants had to have been taking the licensed ERT drug agalsidase beta (Fabrazyme®) for at least 1 year prior to study entry, and to have been on a stable dose of that product for at least the last 6 months. Since the disease expresses itself differently in males and females, gender could have an impact on the therapeutic effect; thus, there was additionally a requirement that no more than 50% of the patients could be female.

Following screening, eligible patients were randomized in a 2:1 ratio to either switch to PRX-102 or continue treatment with agalsidase beta, with randomization stratified according to whether the urine protein-to-creatinine ratio (UPCR), a measure of kidney function, was above or below a specified threshold. Both products were administered as an intravenous infusion every 2 weeks, at a dosage of 1 mg/kg, for up to 24 months. Both patients and study staff were blinded as to which treatment was being given.

Patients who completed the study were invited to continue in a long-term open-label extension study, PB-102-F60, in which all participants would receive PRX-102 1 mg/kg every 2 weeks.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Czech Republic
    • Prague, Czech Republic, Czechia, 12808
      • Vseobecna Fakultni Nemocnice V Praze
• Finland
  • Turku, Finland, 20520
    • Turku University Central Hospital
• France
  • Paris, France, 92380
    • Hopital Raymond Poincare
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
• Italy
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria "Federico II"
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum
• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital Klinisk Forskningspost
• Slovenia
  • Slovenj Gradec, Slovenia, 2380
    • General Hospital Slovenj Gradec
• Spain
  • Zaragoza, Spain, 50012
    • Hospital de Dia Quiron Zaragoza
• Switzerland
  • Zürich, Switzerland
    • Klinik und Poliklinik für Innere Medizin UniversitätsSpital Zürich
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • London, United Kingdom, NW3 2QG
    • The Royal Free Hospital
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust
  • Birmingham
    • Edgbaston, Birmingham, United Kingdom
      • Institute of Metabolism and Systems Research
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • UAB Medicine
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Orange, California, United States, 92868
      • University of California Irvine Center
    • San Diego, California, United States, 92093
      • University of California San Diego
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hosptials and Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49525
      • Infusion Associates
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75235
      • Renal Disease Research Institute, LLC - Dallas
    • Dallas, Texas, United States, 75226
      • Institute of Metabolic Disease, Baylor Healthcare
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Eccles Primary Children's Outpatient Services Building
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • O+O Alpan LLC
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3596
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Symptomatic adult Fabry disease patients, age 18-60 years

  1. Males: Plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than 30% mean normal levels and one or more of the characteristic features of Fabry disease

     i. neuropathic pain

     ii. cornea verticillata

     iii. clustered angiokeratoma

  2. Females:

     a. historical genetic test results consistent with Fabry pathogenic mutation and one or more of the described characteristic features of Fabry disease:

     i. neuropathic pain

     ii. cornea verticillata

     iii. clustered angiokeratoma

     b. or in the case of novel mutations a first degree male family member with Fabry disease with the same mutation, and one or more of the characteristic features of Fabry disease

     i. neuropathic pain

     ii. cornea verticillata

     iii. clustered angiokeratoma

• Screening eGFR by CKD-EPI equation 40 to 120 mL/min/1.73 m²
• Linear negative slope of eGFR based on at least 3 serum creatinine values over approximately 1 year (range of 9 to 18 months, including the value obtained at the screening visit) of ≥ 2 mL/min/1.73 m²/year
• Treatment with a dose of 1 mg/kg agalsidase beta per infusion every 2 weeks for at least one year and at least 80% of 13 (10.4) mg/kg total dose over the last 6 months.
• Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically accepted method of contraception, not including the rhythm method.

Exclusion Criteria:

• History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase beta
• Known non-pathogenic Fabry mutations
• History of renal dialysis or transplantation
• History of acute kidney injury in the 12 months prior to screening, including specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-specific conditions (e.g, ischemia, toxic injury); as well as extrarenal pathology (e.g., prerenal azotemia, and acute postrenal obstructive nephropathy)
• Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
• Patient with a screening eGFR value between 91-120 mL/min/1.73 m², having an historical eGFR value higher than 120 mL/min/1.73 m² (during 9 to 18 months before screening)
• Urine protein to creatinine ratio (UPCR) > 0.5 g/g and not treated with an ACE inhibitor or ARB
• Cardiovascular event (myocardial infarction, unstable angina) in the 6 month period before randomization
• Congestive heart failure NYHA Class IV
• Cerebrovascular event (stroke, transient ischemic attack) in the 6 month period before randomization
• Known history of hypersensitivity to Gadolinium contrast agent that is not managed by the use of pre-medication
• Female subjects who are pregnant, planning to become pregnant during the study, or are breastfeeding
• Presence of any medical, emotional, behavioral or psychological condition that, in the judgment of the Investigator and/or Medical Director, would interfere with the patient's compliance with the requirements of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PRX-102 (pegunigalsidase alfa); PRX-102 infusion every 2 weeks	Biological: PRX-102 (pegunigalsidase alfa); PRX-102 1 mg/kg every 2 weeks; Other Names: pegunigalsidase alfa; Recombinant human alpha galactosidase-A
Active Comparator: agalsidase beta; agalsidase beta infusion every 2 weeks	Biological: agalsidase beta; agalsidase beta 1 mg/kg every 2 weeks; Other Names: Fabrazyme

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)	The individual annualized mean change (slope) in eGFR (mL/min/1.73 m^2/year) is an estimate of the individual patient's annualized change in eGFR, which is derived from the eGFR assessments over time, for up to 24 months. The individual annualized mean change (slope) in eGFR is estimated for each patient with at least 4 eGFR observations. For patients with fewer than 4 eGFR observations, the slope will be missing.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Glomerular Filtration Rate (eGFR)	eGFR was calculated based on measured serum creatinine levels according to the CKD-EPI formula. The median values obtained at baseline and at Month 24 are reported. The change in eGFR from baseline measurement prior to first infusion to last measurement at Month 24 was summarized using descriptive statistics. The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24
Plasma Lyso-Gb3	Globotriaosylsphingosine (lyso-Gb3) is a Fabry disease-specific biomarker measured in the plasma. The median concentrations obtained at baseline and at Month 24, and the change from baseline to Month 24 in median concentration, are reported. The change in Lyso-Gb3 from baseline measurement prior to first infusion to last measurement at Month 24 was summarized using descriptive statistics. The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24
Short Form Brief Pain Inventory (BPI)	The Short Form Brief Pain Inventory ( BPI) questioner is self-completed by patients regarding pain severity and interference. Descriptive statistics summarize the findings for the change from baseline at Week 104 for "Pain at Its Worst in Last 24 Hours". The severity of various aspects of pain scored on a scale of 0 to 10 ( no pain / pain as bad as you can imagine). The change in BPI from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics. The change was calculated for each subject and the reported value is the mean (Standard Error) of these changes.	Baseline and Month 24
Mainz Severity Score Index (MSSI)	The Mainz Severity Score Index (MSSI) is an instrument that is specifically designed to measure the severity of Fabry disease signs/symptoms and to monitor the clinical course of the disease. The MSSI is administered by the investigator, and yields scores for general, neurological, cardiovascular, renal, and overall assessments. The overall score range from 0 to 76. An overall score of less than 20 points is considered mild signs and symptoms of Fabry disease, 20 to 40 is considered moderate, and greater than 40 is considered severe. The change in overall MSSI score from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics. The change was calculated for each subject and the reported value is the mean (Standard Error) of these changes.	Baseline and Month 24
Urine Protein/Creatinine Ratio (UPCR)	The UPCR provides an estimate of protein excretion in urine, and is used as an indicator of the extent of chronic kidney disease. It was classified into three categories: 1) UPCR ≤ 0.5 gr/gr, 2) 0.5 gr/gr < UPCR < 1 gr/gr, 3) 1 gr/gr ≤ UPCR. The results are presented as the percentage of patients (%) in each category at baseline and Month 24. There are no statistical analyses for this endpoint.	Baseline and Month 24
Left Ventricular Mass Index With Hypertrophy at Baseline	Left Ventricular Mass Index (LVMI) based on cardiac MRI for patients with hypertrophy at baseline (for males, hypertrophy is above 91 g/m^2 and for females, above 77 g/m^2). The change in LVMI from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics. The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24
Left Ventricular Mass Index Without Hypertrophy at Baseline	Left Ventricular Mass Index (LVMI) based on cardiac MRI for patients without hypertrophy at baseline (for males, hypertrophy is above 91 g/m^2 and for females, above 77 g/m^2). The change in LVMI from baseline measurement prior to first infusion to the last measurement at Month 24 was summarized using descriptive statistics. The change was calculated for each subject and the reported value is the median (full range) of these changes.	Baseline and Month 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PRX-102 pharmacokinetics	PRX-102 pharmacokinetics parameters	Day 1, 6 months, 12 months and 24 months
Anti-drug IgG antibodies		Every 2 weeks for 1 month, then every month for the first 6 months and every 3 month up to 24 months

Collaborators and Investigators

• Sponsor: Protalix
• Collaborators: Chiesi Farmaceutici S.p.A.
• Investigators: Study Director: Sari Aron, MSc, Protalix Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): October 1, 2021
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: June 2, 2016
• First Submitted That Met QC Criteria: June 6, 2016
• First Posted (Estimated): June 10, 2016

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 10, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Glomerular filtration rate; Proteinuria; Fabry Disease; PRX-102; pegunigalsidase alfa
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease
• Other Study ID Numbers: PB-102-F20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO