Fabry Disease
Conditions
Keywords
Enzyme-Replacement Therapy, pegunigalsidase alfa, Fabry Disease
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.
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.
Interventions
BIOLOGICALPegunigalsidase alfa
Pegunigalsidase alfa 2 mg/kg every 4 weeks
Sponsors
Chiesi Farmaceutici S.p.A.
Protalix
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | Month 12 | 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 |
|---|---|---|
| Plasma Lyso-Gb3 | 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. |
| Quality of Life by EQ-VAS | 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. |
| Estimated Glomerular Filtration Rate (eGFR) | 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. |
| Pharmacokinetics - AUC | 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. |
| Pharmacokinetics - Terminal Half Life | 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. |
| Pharmacokinetics - Cmax | 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. |
Countries
Belgium, Czechia, Denmark, Italy, Norway, United Kingdom, United States
Participant flow
Recruitment details
Patients who were treated with agalsidase beta or agalsidase alfa for at least three years and have been on a stable dose (\>80% labelled dose/kg) for at least 6 months.
Pre-assignment details
Screening details: A total of 52 patients were screened of whom 30 patients (24 males and 6 females) were enrolled and switched from agalsidase alfa or agalsidase beta to pegunigalsidase alfa over a 52-week period, of whom 29 patients (23 males and 6 females) completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Pegunigalsidase Alfa Pegunigalsidase alfa 2 mg/kg intravenous infusion every 4 weeks
Pegunigalsidase alfa: Pegunigalsidase alfa 2 mg/kg every 4 weeks | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pegunigalsidase Alfa |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age, Continuous | 40.5 years STANDARD_DEVIATION 11.3 |
| Previous Enzyme Replacement Therapy (ERT) Agalsidase alfa | 7 Participants |
| Previous Enzyme Replacement Therapy (ERT) Agalsidase beta | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment Belgium | 2 participants |
| Region of Enrollment Czechia | 3 participants |
| Region of Enrollment Denmark | 1 participants |
| Region of Enrollment Italy | 3 participants |
| Region of Enrollment Norway | 1 participants |
| Region of Enrollment United Kingdom | 2 participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 30 |
| other Total, other adverse events | 27 / 30 |
| serious Total, serious adverse events | 2 / 30 |
Outcome results
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.
Time frame: Month 12
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 TEAE | 27 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 mild or moderate TEAE | 26 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 severe TEAE | 2 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 serious TEAE | 2 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 non-serious TEAE | 26 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 related TEAE | 9 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 related mild or moderate | 9 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 related severe TEAE | 0 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 related serious TEAE | 0 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 TEAE leading to withdrawal | 0 participants |
| PRX-102 | Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 | At least 1 TEAE leading to death | 0 participants |
Other Pre-specified
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.
Time frame: Baseline and Month 12 (week 52)
Population: Any subjects who have at least one post-baseline observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Estimated Glomerular Filtration Rate (eGFR) | Month 12 (week 52) | 100.65 mL/min/1.73m^2 | Standard Error 3.14 |
| PRX-102 | Estimated Glomerular Filtration Rate (eGFR) | Baseline | 99.44 mL/min/1.73m^2 | Standard Error 4.15 |
| PRX-102 | Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline to Month 12 (week 52) | -1.27 mL/min/1.73m^2 | Standard Error 1.39 |
| Males | Estimated Glomerular Filtration Rate (eGFR) | Month 12 (week 52) | 103.24 mL/min/1.73m^2 | Standard Error 3.46 |
| Males | Estimated Glomerular Filtration Rate (eGFR) | Baseline | 100.68 mL/min/1.73m^2 | Standard Error 4.96 |
| Males | Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline to Month 12 (week 52) | -0.64 mL/min/1.73m^2 | Standard Error 1.57 |
| Females | Estimated Glomerular Filtration Rate (eGFR) | Baseline | 94.69 mL/min/1.73m^2 | Standard Error 6.76 |
| Females | Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline to Month 12 (week 52) | -3.54 mL/min/1.73m^2 | Standard Error 3.12 |
| Females | Estimated Glomerular Filtration Rate (eGFR) | Month 12 (week 52) | 91.15 mL/min/1.73m^2 | Standard Error 6.39 |
Other Pre-specified
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.
Time frame: Day 1, Month 9 or 11, and Month 12.
Population: All subjects who received at least one dose or PRX-102 and for whom a sufficient number of evaluable samples were available to determine at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PRX-102 | Pharmacokinetics - AUC | 1797464.1 ng*hr/mL | Standard Deviation 822632.4 |
Other Pre-specified
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.
Time frame: Day 1, Month 9 or 11, and Month 12
Population: All subjects who received at least one dose of PRX-102 and for whom a sufficient number of evaluable samples were available to determine at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PRX-102 | Pharmacokinetics - Cmax | 35876.7 ng/mL | Standard Deviation 11942.2 |
Other Pre-specified
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.
Time frame: Day 1, Month 9 or 11, and Month 12.
Population: All subjects who received at least one dose of PRX-102 and for whom a sufficient number of evaluable samples were available to determine at least 1 PK parameter
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PRX-102 | Pharmacokinetics - Terminal Half Life | 100.1 hour | Standard Deviation 58.3 |
Other Pre-specified
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.
Time frame: Baseline and month 12 (Week 52)
Population: Any subjects who have at least one post-baseline observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Plasma Lyso-Gb3 | Month 12 (week 52) | 22.23 nM | Standard Error 3.6 |
| PRX-102 | Plasma Lyso-Gb3 | Baseline | 19.36 nM | Standard Error 3.35 |
| PRX-102 | Plasma Lyso-Gb3 | Change from Baseline to Month 12 (week 52) | 3.01 nM | Standard Error 0.94 |
| Males | Plasma Lyso-Gb3 | Month 12 (week 52) | 27.05 nM | Standard Error 4 |
| Males | Plasma Lyso-Gb3 | Baseline | 23.27 nM | Standard Error 3.82 |
| Males | Plasma Lyso-Gb3 | Change from Baseline to Month 12 (week 52) | 3.79 nM | Standard Error 1.14 |
| Females | Plasma Lyso-Gb3 | Baseline | 4.35 nM | Standard Error 1 |
| Females | Plasma Lyso-Gb3 | Change from Baseline to Month 12 (week 52) | 0.17 nM | Standard Error 0.34 |
| Females | Plasma Lyso-Gb3 | Month 12 (week 52) | 4.52 nM | Standard Error 1.1 |
Other Pre-specified
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.
Time frame: Baseline and 12 months (week 52)
Population: Any subjects who have at least one post-baseline observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRX-102 | Quality of Life by EQ-VAS | Baseline | 78.3 scores on a scale | Standard Error 3.1 |
| PRX-102 | Quality of Life by EQ-VAS | Month 12 (week 52) | 82.1 scores on a scale | Standard Error 2.9 |
| PRX-102 | Quality of Life by EQ-VAS | Change from Baseline to Month 12 (week 52) | 3.0 scores on a scale | Standard Error 2.2 |