Safety, Efficacy, & PK of PRX-102 in Patients With Fabry Disease Administered Intravenously Every 4 Weeks (BRIGHT)

Phase 3 Open-Label Switch Over Study to Assess Safety, Efficacy & PK of Pegunigalsidase Alfa (PRX-102) 2mg/kg IV Every 4 Weeks for 52 Weeks in Fabry Disease Patients Currently Treated With Enzyme Replacement Therapy Fabrazyme® or Replagal™

This open-label switchover study will assess the safety, efficacy, and pharmacokinetics of pegunigalsidase alfa (PRX-102) 2 mg/kg administered every 4 weeks for 52 weeks in Fabry patients previously treated with ERT: agalsidase alfa or agalsidase beta for at least 3 years. Safety and efficacy exploratory endpoints will be evaluated throughout the study period and pharmacokinetics will be obtained on Day 1 and Week 52.

Study Overview

• Status: Completed
• Conditions: Fabry Disease
• Intervention / Treatment: Biological: Pegunigalsidase alfa

Detailed Description

This is an open-label switchover study to assess the safety, efficacy, and pharmacokinetics of pegunigalsidase alfa treatment of 2 mg/kg every 4 weeks in patients previously treated with enzyme-replacement therapy (ERT): agalsidase alfa or agalsidase beta, for at least 3 years and on a stable dose (>80% labelled dose/kg) for at least the last 6 months. Following screening, patients will be enrolled and switched from their current ERT to receive intravenous (IV) infusions of pegunigalsidase alfa 2 mg/kg every 4 weeks for 52 weeks (total of 14 infusions). At the time of enrollment, premedication, if used for the agalsidase alfa or agalsidase beta infusions before enrollment, will be continued using the same premedication regimen during the first infusion with pegunigalsidase alfa and then will be gradually tapered down at the Investigator's discretion during the next infusions based on protocol-specified criteria. First infusions of pegunigalsidase alfa will be administered under controlled conditions at the investigation site. Based on the protocol-specified criteria, patients will be able to receive their pegunigalsidase alfa infusions at a home care setup once the Investigator and Sponsor Medical Monitor agree that it is safe to do so. Safety and efficacy exploratory endpoints will be assessed throughout the 52-week study. In the case of clear clinical deterioration, the treatment may be changed to 1.0 mg/kg every 2 weeks at the Investigator's discretion and discussion with the Medical Monitor.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • UZ Antwerpen
• Czechia
  • Praha 2, Czechia, 120 00
    • Fakultní poliklinika Všeobecné fakultní nemocnice v Praze
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• Italy
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria "Federico II"
• Norway
  • Bergen, Norway, 5021
    • Helse Bergen HF Haukeland universitetssykehus
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • London, United Kingdom, NW3 2QG
    • The Royal Free Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Uab Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Michigan
    • Grand Rapids, Michigan, United States, 49525
      • Infusion Associates
  • Texas
    • Dallas, Texas, United States, 75226
      • Institute of Metabolic Disease
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital & Clinics
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • O & O Alpan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Key inclusion criteria:

Eligible subjects must fulfill the following inclusion criteria:

1. Age: 18-60 years
2. A documented diagnosis of Fabry disease

3. Males: plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than lower limit of normal according to the laboratory reference ranges and one or more of the characteristic features of Fabry disease

   1. Neuropathic pain
   2. Cornea verticillata
   3. Clustered angiokeratoma

4. Females: historical genetic test results consistent with Fabry mutations, or in the case of novel mutations a first-degree male relative with Fabry disease, and one or more of the characteristic features of Fabry disease

   1. Neuropathic pain
   2. Cornea verticillata
   3. Clustered angiokeratoma
5. Treatment with agalsidase alfa or agalsidase beta for at least 3 years and on a stable dose (>80% labelled dose/kg) for at least last 6 months
6. eGFR ≥ 30 mL/min/1.73m^2 by CKD-EPI equation at screening visit
7. Availability of at least 3 historical serum creatinine evaluations since starting agalsidase alfa or agalsidase beta treatment and not more than 2 years old
8. Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically accepted, highly effective method of contraception. These include combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, or sexual abstinence
9. Patients whose clinical condition, in the opinion of the Investigator, is suitable for treatment with ERT every 4 weeks.

Key exclusion criteria:

The presence of any of the following excludes a subject from study enrollment:

1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase alfa or agalsidase beta
2. History of renal dialysis or transplantation
3. Linear negative slope of eGFR of ≥ 2 mL/min/1.73m^2/year based on at least 4 serum creatinine values over approximately 2 years (including the value obtained at the screening visit)
4. 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 post renal obstructive nephropathy)
5. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
6. Urine protein to creatinine ratio (UPCR) at screening > 0.5 g/g or mg/mg or 500 mg/g and not treated with an ACE inhibitor or ARB
7. Females who are pregnant, planning to become pregnant during the study, or are breast feeding
8. Cardiovascular event (myocardial infarction, unstable angina) in the 6-month period before screening
9. Cerebrovascular event (stroke, transient ischemic attack) in the 6-month period before screening
10. 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pegunigalsidase alfa; Pegunigalsidase alfa 2 mg/kg intravenous infusion every 4 weeks	Biological: Pegunigalsidase alfa; Pegunigalsidase alfa 2 mg/kg every 4 weeks; Other Names: PRX-102; Recombinant human alpha galactosidase-A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03	Results represent the number of treatment-emergent adverse events (TEAE) that were considered possibly, probably, or definitely related to treatment.	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
estimated Glomerular Filtration Rate (eGFR)	Change in eGFR	Baseline and every 4 weeks throughout week 52
Frequency of pain medication use	Concomitant use of analgesics	All visits until week 52
Left Ventricular Mass Index	LVMI measured in g/m2 by echocardiogram	Baseline, week 24 and week 52
Plasma Lyso-Gb3	Biomarker of disease	Baseline, and 12, 24, 40, and 52 weeks
Plasma Gb3	Biomarker of disease	Baseline, and 12, 24, 40, and 52 weeks
Urine Lyso-Gb3	Biomarker of disease	Baseline, and 12, 24, 40, and 52 weeks
Protein/creatinine ratio	Biomarker of renal function	Baseline, and 12, 24, 40, and 52 weeks
Cardiac function assessment	Exercise tolerance (stress test)	Day 1 and week 52
Short-form Brief Pain Inventory (BPI)	Visual analog scale to measure pain	Day 1 and weeks 24 and 52
Mainz Severity Score Index (MSSI)	Monitoring of clinical improvement with treatment	Day 1 and week 52
Quality-of-Life EQ-5D-5L	Self-evaluation describing current patient health	Day 1 and 24 and 52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Glomerular Filtration Rate (eGFR)	eGFR was calculated based on the serum creatinine values that were assessed at Day 1, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 according to the CKD-EPI formula, baseline and Month 12 (week 52) reported. The change in eGFR from baseline measurement at Day 1 prior to first PRX-102 infusion to last measurement at Month 12 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 12 (week 52)
Plasma Lyso-Gb3	Globotriaosylsphingosine (Lyso-Gb3) is Fabry disease specific biomarker that can assess treatment outcome, for which was measured at Baseline, weeks 12, 24, 40 and 52. The mean Plasma Lyso-Gb3 concentrations at baseline and Month 12 (week 52) and the mean change from Baseline reported. The change from baseline to month 12 was calculated for each subject and the reported values is the mean (Standard Error) of these changes.	Baseline and month 12 (Week 52)
Quality of Life by EQ-VAS	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). The change from baseline to month 12 was calculated for each subject and the reported value is the mean (Standard Error) of these changes.	Baseline and 12 months (week 52)
Pharmacokinetics - Cmax	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.	Day 1, Month 9 or 11, and Month 12
Pharmacokinetics - AUC	PK parameters were derived from the plasma concentration versus time profiles. AUC is the area under the plasma concentration curve from 0 hour to infinity. Results reported represent the values following a single dosing of the study drug.	Day 1, Month 9 or 11, and Month 12.
Pharmacokinetics - Terminal Half Life	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.	Day 1, Month 9 or 11, and Month 12.

Collaborators and Investigators

• Sponsor: Protalix
• Collaborators: Chiesi Farmaceutici S.p.A.
• Investigators: Study Director: Sari Alon, Sr. Director Regulatory Affairs

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2017
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): August 1, 2020

Study Registration Dates

• First Submitted: May 29, 2017
• First Submitted That Met QC Criteria: June 7, 2017
• First Posted (Actual): June 8, 2017

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: Fabry Disease; pegunigalsidase alfa; Enzyme-Replacement Therapy
• 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-F50

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No