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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02795676

Acronym

BALANCE

Enrollment

Registered

2016-06-10

Start date

2016-06-30

Completion date

2022-07-31

Last updated

2023-09-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fabry Disease

Keywords

Glomerular filtration rate, Proteinuria, PRX-102, pegunigalsidase alfa, Fabry Disease

Brief summary

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.

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.

Interventions

BIOLOGICALPRX-102 (pegunigalsidase alfa)

PRX-102 1 mg/kg every 2 weeks

BIOLOGICALagalsidase beta

agalsidase beta 1 mg/kg every 2 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)	24 months	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.

Secondary

Measure	Time frame	Description
Plasma Lyso-Gb3	Baseline and Month 24	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.
Short Form Brief Pain Inventory (BPI)	Baseline and Month 24	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.
Mainz Severity Score Index (MSSI)	Baseline and Month 24	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.
Estimated Glomerular Filtration Rate (eGFR)	Baseline and Month 24	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.
Left Ventricular Mass Index With Hypertrophy at Baseline	Baseline and Month 24	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.
Left Ventricular Mass Index Without Hypertrophy at Baseline	Baseline and Month 24	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.
Urine Protein/Creatinine Ratio (UPCR)	Baseline and Month 24	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.

Countries

Czechia, Finland, France, Hungary, Italy, Netherlands, Norway, Slovenia, Spain, Switzerland, United Kingdom, United States

Participant flow

Recruitment details

Symptomatic adult Fabry patients who had been taking agalsidase beta for at least 1 year and on a stable dose for at least 6 months. No more than 50% could be female. Screening eGFR (CKD-EPI) 40 to 120 mL/min/1.73 m\^2; Screening linear eGFR slope more negative than -2 mL/min/1.73 m\^2/year based on at least 3 values over \ 1 year.

Pre-assignment details

Of the 78 randomized patients, 53 were assigned to the PRX-102 arm and 25 to the agalsidase beta arm. One PRX-102 patient withdrew consent before receiving the study product; accordingly, 77 patients were treated, 52 in the PRX-102 arm and 25 in the agalsidase beta arm.

Participants by arm

Arm	Count
PRX-102 (Pegunigalsidase Alfa) Pegunigalsidase alfa administered as an intravenous infusion every 2 weeks, at a dosage of 1 mg/kg	52
Agalsidase Beta Agalsidase beta administered as an intravenous infusion every 2 weeks, at a dosage of 1 mg/kg	25
Total	77

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	0
Overall Study	Withdrawal by Subject	3	1

Baseline characteristics

Characteristic	Total	PRX-102 (Pegunigalsidase Alfa)	Agalsidase Beta
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	77 Participants	52 Participants	25 Participants
Age, Continuous	44.3 years STANDARD_DEVIATION 10	43.9 years STANDARD_DEVIATION 10.2	45.2 years STANDARD_DEVIATION 9.6
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) Black or African American	3 Participants	1 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	72 Participants	49 Participants	23 Participants
Region of Enrollment Czechia	1 Participants	1 Participants	0 Participants
Region of Enrollment Finland	1 Participants	0 Participants	1 Participants
Region of Enrollment France	3 Participants	3 Participants	0 Participants
Region of Enrollment Hungary	1 Participants	0 Participants	1 Participants
Region of Enrollment Italy	3 Participants	2 Participants	1 Participants
Region of Enrollment Netherlands	5 Participants	4 Participants	1 Participants
Region of Enrollment Norway	2 Participants	1 Participants	1 Participants
Region of Enrollment Slovenia	2 Participants	2 Participants	0 Participants
Region of Enrollment Spain	3 Participants	2 Participants	1 Participants
Region of Enrollment United Kingdom	5 Participants	4 Participants	1 Participants
Region of Enrollment United States	51 Participants	33 Participants	18 Participants
Sex: Female, Male Female	30 Participants	23 Participants	7 Participants
Sex: Female, Male Male	47 Participants	29 Participants	18 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 52	0 / 25
other Total, other adverse events	47 / 52	24 / 25
serious Total, serious adverse events	8 / 52	6 / 25

Outcome results

Primary

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.

Time frame: 24 months

Population: The Intent to Treat (ITT) population includes all randomized patients who received at least one dose of the assigned study medication with at least 4 eGFR observations.~For 1 patient with fewer than 4 eGFR observations, the slope was missing.

Arm	Measure	Value (MEDIAN)
PRX-102 (Pegunigalsidase Alfa)	Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)	-2.514 mL/min/1.73 m^2/year
Agalsidase Beta	Annualized Change (Slope) in Estimated Glomerular Filtration Rate (eGFR)	-2.155 mL/min/1.73 m^2/year

95% CI: [-2.444, 1.726]Regression, Linear

Secondary

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.