Fabry Disease
Conditions
Keywords
Fabry disease, Enzyme-Replacement Therapy, pegunigalsidase alfa, PRX-102, alpha galactosidase-A
Brief summary
This is an open label switch over study to assess the safety and efficacy of PRX-102 (pegunigalsidase alfa). Patients treated with agalsidase alfa for at least 2 years and on a stable dose (\>80% labelled dose/kg) for at least 6 months. Patients will be screened and evaluated over 3 months while continuing on agalsidase alfa. Following the screening period, the patient will be enrolled and switched from their agalsidase alfa treatment to receive intravenous (IV) infusions of PRX-102 1 mg/kg every two weeks for 12 months. No more than 25% of treated patients will be female.
Detailed description
Dosage and administration details: pegunigalsidase alfa individual dose for each patient was prepared according to the patient's weight. Pegunigalsidase alfa administrated at 1 mg/kg, intravenously over 3 hours, every 2 weeks. After the first 2 months of treatment with pegunigalsidase alfa, infusion time may be reduced gradually to 1.5 hours pending patient tolerability.
Interventions
BIOLOGICALPRX-102 (pegunigalsidase alfa)
PRX-102 1 mg/kg every 2 weeks
Sponsors
Chiesi Farmaceutici S.p.A.
Protalix
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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 laboratory range and one or more of the characteristic features of Fabry disease i. Neuropathic pain ii. Cornea verticillata iii. 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 i. Neuropathic pain ii. Cornea verticillata iii. Clustered angiokeratoma 5. Treatment with agalsidase alfa for at least 2 years and on a stable dose (\>80% labelled dose/kg) for at least 6 months 6. eGFR ≥ 40 ml/min/1.73 m2 by CKD-EPI equation 7. Availability of at least 2 historical serum creatinine evaluations since starting agalsidase alfa treatment and not more than 2 years 8. Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically acceptable method of contraception, not including the rhythm method
Exclusion criteria
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase alfa 2. History of renal dialysis or transplantation 3. 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) 4. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening 5. Urine protein to creatinine ratio (UPCR) \> 0.5 g/g and not treated with an ACE inhibitor or ARB 6. Known history of hypersensitivity to Gadolinium contrast agent that was not managed by the use of premedication; 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. Congestive heart failure NYHA Class IV 10. Cerebrovascular event (stroke, transient ischemic attack) in the 6 month period before screening 11. Presence of any medical, emotional, behavioral or psychological condition that, in the judgment of the Investigator and/or Medical Monitor would interfere with the patient's compliance with the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 12 months | Results represent the number of treatment-emergent adverse events (TEAE) that were considered possibly, probably, or definitely related to treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Annualised Change in eGFR (Slope) | Pre-switch, Post-switch | The annualized change in eGFR (slope) per patient was calculated with all available eGFR values using a linear regression. The mean pre-switch slope is the eGFR slope during screening period and pre-infusion visit 1 (while on Replagal®). The mean post-switch slope is the eGFR slope during PRX-102 treatment, calculated based on eGFR vales at weeks 4, 8, 12, 16, 20, 26, 30, 34, 38, 42, 46, 52 after visit 1. The mean change in eGFR slope from pre- to post-switch is the mean difference between the two slopes. eGFR was calculated based on the serum creatinine values according to the CKD-EPI formula. |
| Plasma Lyso-Gb3 | Baseline and month 12 (week 52) | Plasma Lyso-Gb3 is Fabry disease specific biomarker that can assess treatment outcome which was measured at Baseline and weeks 12, 26, 38, 52. Baseline and Month 12 (week 52) reported. |
| eGFR | Baseline and Month 12 (week 52) | eGFR was calculated based on the serum creatinine values that were assessed at weeks 4, 8, 12, 16, 20, 26, 30, 34, 38, 42, 46, 52 according to the CKD-EPI formula, baseline and Month 12 (week 52) reported. The absolute change in eGFR from baseline measurement at visit 1 prior to first PRX-102 infusion to last measurement at Month 12 was summarized using descriptive statistics. |
| Left Ventricular Mass Index (g/m^2) by MRI | 12 months | Left ventricular mass was determined based on cardiac MRI data and the LVMI was indexed to patient's body surface area (g/m\^2). In male patients the normal range for LVMI was 57-91 g/m\^2, in female patients 47-77 g/m\^2. |
| Quality of Life EQ VAS | 12 months | 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). |
| Number of Participants According to Protein/Creatinine Ratio (UPCR) | 12 months | Urine Protein to Creatinine Ratio (UPCR), assessed by spot urine test, at Month 12 (Week 52).Number of Participants According to Protein/Creatinine Ratio (UPCR) level |
Countries
Australia, Canada, Czechia, Netherlands, Norway, Slovenia, United Kingdom
Participant flow
Recruitment details
A total of 22 adult patients were planned to be included in the study; no more than 25% were planned to be female patients. In practice, 15 males and 7 females (32%) received treatment in this study; 20 patients (13 males and 7 females) completed the 12 month treatment duration.
Participants by arm
| Arm | Count |
|---|---|
| PRX-102 PRX-102 infusion 1 mg/kg every 2 weeks | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | PRX-102 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 44.0 years STANDARD_DEVIATION 11 |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race White | 22 Participants |
| Region of Enrollment Australia | 2 participants |
| Region of Enrollment Canada | 2 participants |
| Region of Enrollment Czechia | 8 participants |
| Region of Enrollment Netherlands | 1 participants |
| Region of Enrollment Norway | 2 participants |
| Region of Enrollment Slovenia | 1 participants |
| Region of Enrollment United Kingdom | 6 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 22 |
| other Total, other adverse events | 21 / 22 |
| serious Total, serious adverse events | 4 / 22 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events 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
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 TEAE leading to death | 0 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 TEAE | 21 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 mild or moderate TEAE | 19 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 severe TEAE | 4 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 SAE | 4 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 TEAE unrelated or unlikely related | 19 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 TEAE related to study treatment | 5 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 SAE related to study treatment | 2 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | At least 1 TEAE leading to discontinuation | 2 participants |
Other Pre-specified
eGFR
eGFR was calculated based on the serum creatinine values that were assessed at weeks 4, 8, 12, 16, 20, 26, 30, 34, 38, 42, 46, 52 according to the CKD-EPI formula, baseline and Month 12 (week 52) reported. The absolute change in eGFR from baseline measurement at visit 1 prior to first PRX-102 infusion to last measurement at Month 12 was summarized using descriptive statistics.
Time frame: Baseline and Month 12 (week 52)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | eGFR | Month 12 (week 52) eGFR | 76.91 mL/min/1.73m^2 | Standard Error 5.22 |
| PRX-102 | eGFR | Baseline eGFR | 79.46 mL/min/1.73m^2 | Standard Error 4.92 |
| PRX-102 | eGFR | Change in eGFR from Baseline to Month 12 (week 52) | -2.56 mL/min/1.73m^2 | Standard Error 2.14 |
| PRX-102 Male | eGFR | Month 12 (week 52) eGFR | 74.27 mL/min/1.73m^2 | Standard Error 7.15 |
| PRX-102 Male | eGFR | Baseline eGFR | 75.87 mL/min/1.73m^2 | Standard Error 6.62 |
| PRX-102 Male | eGFR | Change in eGFR from Baseline to Month 12 (week 52) | -1.60 mL/min/1.73m^2 | Standard Error 2.75 |
| PRX-102 Female | eGFR | Baseline eGFR | 86.14 mL/min/1.73m^2 | Standard Error 6.72 |
| PRX-102 Female | eGFR | Change in eGFR from Baseline to Month 12 (week 52) | -4.34 mL/min/1.73m^2 | Standard Error 3.54 |
| PRX-102 Female | eGFR | Month 12 (week 52) eGFR | 81.80 mL/min/1.73m^2 | Standard Error 7.09 |
Other Pre-specified
Left Ventricular Mass Index (g/m^2) by MRI
Left ventricular mass was determined based on cardiac MRI data and the LVMI was indexed to patient's body surface area (g/m\^2). In male patients the normal range for LVMI was 57-91 g/m\^2, in female patients 47-77 g/m\^2.
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Left Ventricular Mass Index (g/m^2) by MRI | Baseline | 86.9 g/m^2 | Standard Error 6.9 |
| PRX-102 | Left Ventricular Mass Index (g/m^2) by MRI | Change from Baseline | 4.1 g/m^2 | Standard Error 2.8 |
| PRX-102 | Left Ventricular Mass Index (g/m^2) by MRI | Month 12 (Week 52) | 89.4 g/m^2 | Standard Error 6.1 |
| PRX-102 Male | Left Ventricular Mass Index (g/m^2) by MRI | Baseline | 97.6 g/m^2 | Standard Error 8.9 |
| PRX-102 Male | Left Ventricular Mass Index (g/m^2) by MRI | Month 12 (Week 52) | 98.3 g/m^2 | Standard Error 7.8 |
| PRX-102 Male | Left Ventricular Mass Index (g/m^2) by MRI | Change from Baseline | 2.4 g/m^2 | Standard Error 3.4 |
| PRX-102 Female | Left Ventricular Mass Index (g/m^2) by MRI | Change from Baseline | 7.1 g/m^2 | Standard Error 5 |
| PRX-102 Female | Left Ventricular Mass Index (g/m^2) by MRI | Baseline | 66.9 g/m^2 | Standard Error 5.8 |
| PRX-102 Female | Left Ventricular Mass Index (g/m^2) by MRI | Month 12 (Week 52) | 74.1 g/m^2 | Standard Error 7.2 |
Other Pre-specified
Mean Annualised Change in eGFR (Slope)
The annualized change in eGFR (slope) per patient was calculated with all available eGFR values using a linear regression. The mean pre-switch slope is the eGFR slope during screening period and pre-infusion visit 1 (while on Replagal®). The mean post-switch slope is the eGFR slope during PRX-102 treatment, calculated based on eGFR vales at weeks 4, 8, 12, 16, 20, 26, 30, 34, 38, 42, 46, 52 after visit 1. The mean change in eGFR slope from pre- to post-switch is the mean difference between the two slopes. eGFR was calculated based on the serum creatinine values according to the CKD-EPI formula.
Time frame: Pre-switch, Post-switch
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Mean Annualised Change in eGFR (Slope) | post-switch | -1.19 mL/min/1.73m^2/year | Standard Error 1.77 |
| PRX-102 | Mean Annualised Change in eGFR (Slope) | Change in eGFR slope from pre- to post-switch | 4.70 mL/min/1.73m^2/year | Standard Error 2.26 |
| PRX-102 | Mean Annualised Change in eGFR (Slope) | pre-switch | -5.9 mL/min/1.73m^2/year | Standard Error 1.34 |
| PRX-102 Male | Mean Annualised Change in eGFR (Slope) | pre-switch | -6.36 mL/min/1.73m^2/year | Standard Error 1.89 |
| PRX-102 Male | Mean Annualised Change in eGFR (Slope) | post-switch | -1.73 mL/min/1.73m^2/year | Standard Error 2.64 |
| PRX-102 Male | Mean Annualised Change in eGFR (Slope) | Change in eGFR slope from pre- to post-switch | 4.63 mL/min/1.73m^2/year | Standard Error 3.48 |
| PRX-102 Female | Mean Annualised Change in eGFR (Slope) | pre-switch | -5.03 mL/min/1.73m^2/year | Standard Error 1.65 |
| PRX-102 Female | Mean Annualised Change in eGFR (Slope) | Change in eGFR slope from pre- to post-switch | 4.83 mL/min/1.73m^2/year | Standard Error 1.09 |
| PRX-102 Female | Mean Annualised Change in eGFR (Slope) | post-switch | -0.21 mL/min/1.73m^2/year | Standard Error 1.47 |
Other Pre-specified
Number of Participants According to Protein/Creatinine Ratio (UPCR)
Urine Protein to Creatinine Ratio (UPCR), assessed by spot urine test, at Month 12 (Week 52).Number of Participants According to Protein/Creatinine Ratio (UPCR) level
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PRX-102 | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Moderately increased | 2 Subjects |
| PRX-102 | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Protein Undetectable | 9 Subjects |
| PRX-102 | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Severely increased | 5 Subjects |
| PRX-102 | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Normal to Mildly increased | 4 Subjects |
| PRX-102 Male | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Moderately increased | 0 Subjects |
| PRX-102 Male | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Normal to Mildly increased | 2 Subjects |
| PRX-102 Male | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Protein Undetectable | 7 Subjects |
| PRX-102 Male | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Severely increased | 4 Subjects |
| PRX-102 Female | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Normal to Mildly increased | 2 Subjects |
| PRX-102 Female | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Protein Undetectable | 2 Subjects |
| PRX-102 Female | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Severely increased | 1 Subjects |
| PRX-102 Female | Number of Participants According to Protein/Creatinine Ratio (UPCR) | Moderately increased | 2 Subjects |
Other Pre-specified
Plasma Lyso-Gb3
Plasma Lyso-Gb3 is Fabry disease specific biomarker that can assess treatment outcome which was measured at Baseline and weeks 12, 26, 38, 52. Baseline and Month 12 (week 52) reported.
Time frame: Baseline and month 12 (week 52)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Plasma Lyso-Gb3 | Month 12 (Week 52) | 24.20 nM | Standard Error 5.1 |
| PRX-102 | Plasma Lyso-Gb3 | Baseline | 38.51 nM | Standard Error 9.68 |
| PRX-102 | Plasma Lyso-Gb3 | Change from Baseline | -14.31 nM | Standard Error 5.13 |
| PRX-102 Male | Plasma Lyso-Gb3 | Month 12 (Week 52) | 32.25 nM | Standard Error 6.89 |
| PRX-102 Male | Plasma Lyso-Gb3 | Baseline | 51.81 nM | Standard Error 13.6 |
| PRX-102 Male | Plasma Lyso-Gb3 | Change from Baseline | -19.55 nM | Standard Error 7.55 |
| PRX-102 Female | Plasma Lyso-Gb3 | Baseline | 13.81 nM | Standard Error 2.31 |
| PRX-102 Female | Plasma Lyso-Gb3 | Change from Baseline | -4.57 nM | Standard Error 1.42 |
| PRX-102 Female | Plasma Lyso-Gb3 | Month 12 (Week 52) | 9.24 nM | Standard Error 1.08 |
Other Pre-specified
Quality of Life 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).
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Quality of Life EQ VAS | Change from Baseline | 5.1 Score | Standard Error 3.3 |
| PRX-102 | Quality of Life EQ VAS | Month 12 | 76.9 Score | Standard Error 4.5 |
| PRX-102 | Quality of Life EQ VAS | Baseline | 71.8 Score | Standard Error 4.3 |
| PRX-102 Male | Quality of Life EQ VAS | Change from Baseline | 4.8 Score | Standard Error 4.9 |
| PRX-102 Male | Quality of Life EQ VAS | Baseline | 66.8 Score | Standard Error 5.3 |
| PRX-102 Male | Quality of Life EQ VAS | Month 12 | 71.5 Score | Standard Error 5.4 |
| PRX-102 Female | Quality of Life EQ VAS | Month 12 | 86.7 Score | Standard Error 7 |
| PRX-102 Female | Quality of Life EQ VAS | Baseline | 81.6 Score | Standard Error 6.1 |
| PRX-102 Female | Quality of Life EQ VAS | Change from Baseline | 5.6 Score | Standard Error 3 |