Trial Outcomes & Findings for A Study of REPLAGAL® in Treatment-naive Chinese Participants With Fabry Disease (NCT NCT04974749)

Results Overview

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this investigational product (IP) or medicinal product. Serious AE was any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality/birth defect, and was an important medical event. A TEAE was defined as any event emerging at or after the initiation of treatment with an IP or any existing event that worsened in either intensity or frequency following exposure to the IP until the end of the safety follow-up period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

20 participants

Primary outcome timeframe

From start of study drug administration up to 14 days after end of treatment (EOT) [up to Week 54]

Results posted on

2024-10-08

Participant Flow

Participants took part in the study at 6 investigative sites in China from 1 May 2022 to 3 January 2024.

A total of 20 participants with Fabry disease were enrolled in this study to receive REPLAGAL for 52 weeks.

Participant milestones

Participant milestones
Measure	REPLAGAL Participants received REPLAGAL 0.2 milligrams per kilogram (mg/kg) body weight, intravenous (IV) infusion, every other week (EOW) from Day 1 (Week 0) up to Week 52.
Overall Study STARTED	20
Overall Study COMPLETED	17
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	REPLAGAL Participants received REPLAGAL 0.2 milligrams per kilogram (mg/kg) body weight, intravenous (IV) infusion, every other week (EOW) from Day 1 (Week 0) up to Week 52.
Overall Study Withdrawal by Subject	2
Overall Study Gestation	1

Baseline Characteristics

A Study of REPLAGAL® in Treatment-naive Chinese Participants With Fabry Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Age, Continuous	30.1 years STANDARD_DEVIATION 14.90 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	20 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Height	160.47 centimeters (cm) STANDARD_DEVIATION 9.271 • n=5 Participants
Weight	53.88 kilograms (kg) STANDARD_DEVIATION 10.370 • n=5 Participants
Body Mass Index (BMI)	20.87 kilograms per meter square (kg/m^2) STANDARD_DEVIATION 3.674 • n=5 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to 14 days after end of treatment (EOT) [up to Week 54]

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this investigational product (IP) or medicinal product. Serious AE was any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality/birth defect, and was an important medical event. A TEAE was defined as any event emerging at or after the initiation of treatment with an IP or any existing event that worsened in either intensity or frequency following exposure to the IP until the end of the safety follow-up period.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Serious Treatment-emergent Adverse Events (TEAEs)	2 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to 14 days after EOT (up to Week 54)

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this investigational product or medicinal product. A TEAE was defined as any event emerging at or after the initiation of treatment with an IP or any existing event that worsened in either intensity or frequency following exposure to the IP until the end of the safety follow-up period.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With TEAEs	20 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to Week 52

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

An IRR was defined as an event that began either during or within 24 hours after the start of the infusion, and was judged as related to treatment with the IP. An IRR could be serious or non-serious. Adverse events that were considered IRRs were noted as such in the participant's source documentation. Other AEs which occurred prior to the infusion, along with AEs associated with protocol-defined testing and assessments (example, laboratory testing and physical examinations), which were performed prior to the infusion, were not considered as IRRs.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Infusion-related Reactions (IRRs)	5 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 52

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

Number of participants with positive ADA to REPLAGAL were reported.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Positive Anti-drug Antibodies (ADA) to REPLAGAL	6 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 52

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

Number of participants with positive NAb to REPLAGAL were reported.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Positive Neutralizing Antibodies (NAb) to REPLAGAL	5 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to Week 52

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

Laboratory assessment included parameters of serum chemistry, hematology, and urinalysis. Clinically meaningful laboratory parameters assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in laboratory parameters were reported.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Clinically Meaningful Changes in Laboratory Parameters	0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to Week 52

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

Vital sign assessment included pulse, blood pressure, respiratory rate, and temperature. Clinically meaningful vital signs assessment was based on investigator interpretation. Number of participants with clinically meaningful abnormalities in vital signs were reported.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Clinically Meaningful Changes in Vital Signs	0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to Week 52

Population: Safety Analysis Set included all participants in the ITT Set who received at least 1 dose of REPLAGAL.

ECG parameters included assessment of heart rate, sinus rhythm, atrial or ventricular hypertrophy, and assessment of PR, QRS, QT, and corrected QT intervals. Clinically meaningful ECG assessment was based on investigator interpretation. Number of participants with clinically meaningful abnormalities in 12-lead ECG were reported.

Outcome measures

Outcome measures
Measure	REPLAGAL n=20 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Number of Participants With Clinically Meaningful Changes in Electrocardiogram (ECG) Parameters	0 Participants

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Modified Intent-to-treat (mITT) Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints.

Renal function was assessed by eGFR using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for ≥18 years participants, eGFR = 141 x min (Scr/κ,1)\^(α) x max(Scr/κ,1)\^(-1.209) x 0.993\^(Age) x 1.018 (if female) x 1.159 (if black) where: Scr is serum creatinine (milligram per deciliter \[mg/dL\]); κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Scr/κ or 1; max indicates the maximum of Scr /κ or 1. For \<18 years participants, Counahan-Barratt equation was used for calculation of eGFR. eGFR = (0.43 × height in centimeter \[cm\])/Scr where, Scr is serum creatinine (mg/dL). Renal function as assessed by eGFR was expressed using the unit: milliliters/minute/1.73 meter square (mL/min/1.73m\^2).

Outcome measures

Outcome measures
Measure	REPLAGAL n=19 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Renal Function as Assessed by Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52	4.1 mL/min/1.73m^2 Standard Deviation 12.48

SECONDARY outcome

Timeframe: Baseline, Weeks 8, 16, 28, and 40

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

The eGFR was calculated by CKD-EPI formula for ≥18 years participants, eGFR = 141 x min (Scr/κ,1)\^(α) x max(Scr/κ,1)\^(-1.209) x 0.993\^(Age) x 1.018 (if female) x 1.159 (if black) where: Scr is serum creatinine (mg/dL); κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Scr/κ or 1; max indicates the maximum of Scr /κ or 1. For \<18 years participants, Counahan-Barratt equation was used for calculation of eGFR. eGFR = (0.43 × height in cm)/Scr where, Scr is serum creatinine (mg/dL).

Outcome measures

Outcome measures
Measure	REPLAGAL n=19 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40 Week 8	-1.2 mL/min/1.73m^2 Standard Deviation 15.66
Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40 Week 16	-0.4 mL/min/1.73m^2 Standard Deviation 13.67
Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40 Week 28	5.1 mL/min/1.73m^2 Standard Deviation 11.25
Change From Baseline in eGFR Values at Weeks 8, 16, 28, and 40 Week 40	0.3 mL/min/1.73m^2 Standard Deviation 13.17

SECONDARY outcome

Timeframe: Baseline, Weeks 16 and 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

LVMI was measured by echocardiography at the clinical sites, and LVMI was derived using the following formula: LVM \[grams\] = 0.8×\[1.04×{(LVDd + IVSTd + PWTd)\^3 - LVDd\^3}\] + 0.6, where: LVDd is left ventricular internal diameter (diastolic) (cm), IVSTd is intraventricular septum thickness (diastolic) (cm), and PWTd is posterior wall thickness (diastolic) (cm). LVM indexed to height (LVMI) = LVM/height\^2.7 (g/m\^2.7), where height was measured in meter.

Outcome measures

Outcome measures
Measure	REPLAGAL n=19 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Change From Baseline in Left Ventricular Mass Index (LVMI) at Weeks 16 and 52 Week 16	-0.4696 grams per meter (g/m)^2.7 Standard Deviation 6.81928
Change From Baseline in Left Ventricular Mass Index (LVMI) at Weeks 16 and 52 Week 52	-1.7261 grams per meter (g/m)^2.7 Standard Deviation 9.87836

SECONDARY outcome

Timeframe: Baseline, Weeks 16 and 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

LVEF is the central measure of left ventricular systolic function. LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). This was measured by echocardiography at the clinical sites.

Outcome measures

Outcome measures
Measure	REPLAGAL n=19 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Weeks 16 and 52 Week 16	-1.1 percent of LVEF Standard Deviation 7.29
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Weeks 16 and 52 Week 52	0.8 percent of LVEF Standard Deviation 3.28

SECONDARY outcome

Timeframe: Baseline, Weeks 8, 16, 28, 40, and 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

The change from baseline in urine protein/creatinine ratio was derived from early morning spot urine samples collected at the specified time points.

Outcome measures

Outcome measures
Measure	REPLAGAL n=19 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Change From Baseline in Urine Protein/Creatinine Ratio Week 8	0.0759 gram per gram Standard Deviation 0.17486
Change From Baseline in Urine Protein/Creatinine Ratio Week 16	0.1061 gram per gram Standard Deviation 0.21743
Change From Baseline in Urine Protein/Creatinine Ratio Week 28	0.0711 gram per gram Standard Deviation 0.16049
Change From Baseline in Urine Protein/Creatinine Ratio Week 40	0.0830 gram per gram Standard Deviation 0.16333
Change From Baseline in Urine Protein/Creatinine Ratio Week 52	0.0627 gram per gram Standard Deviation 0.16508

SECONDARY outcome

Timeframe: Baseline, Weeks 8, 16, 28, 40, and 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Overall number analyzed is the number of participants with pain at baseline. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

The BPI short form is a numeric rating scale that assesses the severity of pain (severity scale), its impact on daily functioning (Pain Interference scale). BPI short form pain severity scale has been reported here. Pain severity scale has 4 questions that assess pain intensity (worst, least, average, right now) on 10-point rating scales (0=No pain to 10=Pain as bad as you can imagine). The pain severity score is calculated as the average of questions, with a total score ranging from 0 to 10 with higher scores indicating more pain. A negative change from baseline indicates better outcome.

Outcome measures

Outcome measures
Measure	REPLAGAL n=7 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score Week 8	-1.607 score on a scale Standard Deviation 2.8572
Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score Week 16	-2.214 score on a scale Standard Deviation 2.4041
Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score Week 28	-1.833 score on a scale Standard Deviation 2.6957
Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score Week 40	-1.375 score on a scale Standard Deviation 2.8007
Change From Baseline in Brief Pain Inventory (BPI) Short Form Pain Severity Total Score Week 52	-0.958 score on a scale Standard Deviation 3.3370

SECONDARY outcome

Timeframe: Baseline, Weeks 8, 16, 28, 40, and 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Overall number analyzed is the number of participants with pain at baseline. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

The BPI short form is a numeric rating scale that assesses the severity of pain (severity scale), its impact on daily functioning (Pain Interference scale). BPI short form pain interference scale has been reported here. Pain interference scale has 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life) on 10-point rating scales as (0=Does not interfere to 10=Completely interferes). The pain interference score is calculated as the average of questions, with a total score ranging from 0 to 10 with higher scores indicating more interference. A negative change from baseline indicates better outcome.

Outcome measures

Outcome measures
Measure	REPLAGAL n=7 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Change From Baseline in BPI Short Form Pain Interference Total Score Week 8	-2.286 score on a scale Standard Deviation 3.6636
Change From Baseline in BPI Short Form Pain Interference Total Score Week 16	-3.571 score on a scale Standard Deviation 3.9812
Change From Baseline in BPI Short Form Pain Interference Total Score Week 28	-4.738 score on a scale Standard Deviation 4.3221
Change From Baseline in BPI Short Form Pain Interference Total Score Week 40	-3.810 score on a scale Standard Deviation 3.8222
Change From Baseline in BPI Short Form Pain Interference Total Score Week 52	-3.643 score on a scale Standard Deviation 5.7020

SECONDARY outcome

Timeframe: Baseline, Weeks 8, 16, 28, 40, and 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Number analyzed is the number of participants with data available for analysis at the specified timepoint.

Plasma lyso-Gb3 determinations were performed at the central laboratory using a validated liquid chromatography-tandem mass spectrometry bioanalytical assay.

Outcome measures

Outcome measures
Measure	REPLAGAL n=19 Participants Participants received REPLAGAL 0.2 mg/kg body weight, IV infusion, EOW from Day 1 (Week 0) up to Week 52.
Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level Week 8	-36.236 percent change Standard Deviation 24.7056
Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level Week 16	-38.147 percent change Standard Deviation 24.7376
Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level Week 28	-37.764 percent change Standard Deviation 25.8314
Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level Week 40	-35.565 percent change Standard Deviation 27.7874
Percent Change From Baseline in Plasma Globotriaosylsphingosine (Lyso-Gb3) Level Week 52	-37.072 percent change Standard Deviation 27.5659

SECONDARY outcome

Timeframe: Baseline up to Week 52

Population: mITT Set included all enrolled participants who had received at least 1 dose of investigational product and completed at least 1 post-baseline efficacy assessment of the endpoints. Overall number analyzed is the number of participants with age \<18 years old.

Hearing loss was assessed in participants with the age \<18 years old by audiology testing. Audiology testing included pure tone conduction and bone conduction for each ear using 4 different pure tone frequencies (500 hertz \[Hz\], 1000 Hz, 2000 Hz, and 4000 Hz). Any changes in threshold were to be categorized as conductive, sensorineural, or unknown.