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

Fabry Disease Clinical Trial

— BRIGHT  

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™

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03180840
• Other study ID #: PB-102-F50
• Status: Completed
• Phase: Phase 3
• Start date: July 10, 2017
• Est. completion date: August 1, 2020

Study information

• Verified date: September 2023
• Source: Protalix
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: August 1, 2020
• Est. primary completion date: August 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Biological:
• Pegunigalsidase alfa
Pegunigalsidase alfa 2 mg/kg every 4 weeks

Locations

Country	Name	City	State
Belgium	UZ Antwerpen	Edegem
Czechia	Fakultní poliklinika Všeobecné fakultní nemocnice v Praze	Praha 2
Denmark	Rigshospitalet	Copenhagen
Italy	Azienda Ospedaliera Universitaria "Federico II"	Napoli
Norway	Helse Bergen HF Haukeland Universitetssykehus	Bergen
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	The Royal Free Hospital	London
United States	Emory University School of Medicine	Atlanta	Georgia
United States	UAB Medicine	Birmingham	Alabama
United States	Institute of Metabolic Disease	Dallas	Texas
United States	O & O Alpan	Fairfax	Virginia
United States	Infusion Associates	Grand Rapids	Michigan
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Utah Hospital & Clinics	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Protalix	Chiesi Farmaceutici S.p.A.

Countries where clinical trial is conducted

United States,  Belgium,  Czechia,  Denmark,  Italy,  Norway,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Other	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)
Other	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)
Other	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
Other	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.
Other	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.
Primary	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