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

• ClinicalTrials.gov Identifier: NCT03180840
• Recruitment Status: Completed
• First Posted: June 8, 2017
• Results First Posted: January 5, 2023
• Last Update Posted: January 5, 2023
• Sponsor: Protalix
• Information provided by (Responsible Party): Protalix

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Fabry Disease	Biological: Pegunigalsidase alfa	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Switch over study in patients previously receiving either agalsidase alfa or agalsidase beta and switched to pegunigalsidase alfa (PRX-102) for the treatment of Fabry disease.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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™
• Actual Study Start Date: July 10, 2017
• Actual Primary Completion Date: August 1, 2020
• Actual Study Completion Date: August 1, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Other Outcome Measures:

1. Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: Baseline and Month 12 (week 52) ]
   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.
2. Plasma Lyso-Gb3 [ Time Frame: Baseline and month 12 (Week 52) ]

   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.

3. Quality of Life by EQ-VAS [ Time Frame: Baseline and 12 months (week 52) ]
   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.
4. Pharmacokinetics - Cmax [ Time Frame: Day 1, Month 9 or 11, and Month 12 ]
   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.
5. Pharmacokinetics - AUC [ Time Frame: Day 1, Month 9 or 11, and Month 12. ]
   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.
6. Pharmacokinetics - Terminal Half Life [ Time Frame: Day 1, Month 9 or 11, and Month 12. ]
   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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

UAB Medicine

Birmingham, Alabama, United States, 35294

United States, Georgia

Emory University School of Medicine

Atlanta, Georgia, United States, 30322

United States, Iowa

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States, 52242

United States, Michigan

Infusion Associates

Grand Rapids, Michigan, United States, 49525

United States, Texas

Institute of Metabolic Disease

Dallas, Texas, United States, 75226

United States, Utah

University of Utah Hospital & Clinics

Salt Lake City, Utah, United States, 84132

United States, Virginia

O & O Alpan

Fairfax, Virginia, United States, 22030

Belgium

UZ Antwerpen

Edegem, Belgium, 2650

Czechia

Fakultní poliklinika Všeobecné fakultní nemocnice v Praze

Praha 2, Czechia, 120 00

Denmark

Rigshospitalet

Copenhagen, Denmark, 2100

Italy

Azienda Ospedaliera Universitaria "Federico II"

Napoli, Italy

Norway

Helse Bergen HF Haukeland Universitetssykehus

Bergen, Norway, 5021

United Kingdom

Addenbrooke's Hospital

Cambridge, United Kingdom, CB2 0QQ

The Royal Free Hospital

London, United Kingdom, NW3 2QG

Sponsors and Collaborators

Protalix

Investigators

• Study Director: Sari Alon; Sr. Director Regulatory Affairs

  Study Documents (Full-Text)

Documents provided by Protalix:

Study Protocol  [PDF] July 25, 2018

Statistical Analysis Plan  [PDF] November 25, 2020

More Information

• Responsible Party: Protalix
• ClinicalTrials.gov Identifier: NCT03180840
• Other Study ID Numbers: PB-102-F50
• First Posted: June 8, 2017
• Results First Posted: January 5, 2023
• Last Update Posted: January 5, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Protalix:

Enzyme-Replacement Therapy; pegunigalsidase alfa; Fabry Disease

Additional relevant MeSH terms:

Fabry Disease; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders