Clinical trial NCT05710692: Study to Evaluate the Safety, PK, PD, and Efficacy of PRX-102 in Japanese Patients With Fabry Disease
Official title: A Multicenter Open-Label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Pegunigalsidase Alfa (PRX-102) in Japanese Patients With Fabry Disease (RISE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Fabry Disease
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
Collaborators: name: ICON plc
First posted: 2023-02-02
Enrollment: 18
Sex: ALL
Minimum age (years): 13
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this study is to evaluate the safety and efficacy of pegunigalsidase alfa in Japanese patients (adults and adolescents) affected by Fabry disease. It is planned of a total of approximately 18-20 male and female Fabry disease patients between the ages of 13 and 60 years to be part of the study. The study is conducted in Japan.

Detailed description: Investigators are doing this study to find out if treatment with pegunigalsidase alfa will prevent or reduce the development of health problems caused by Fabry disease and thereby improve patients' health and quality of life.

pegunigalsidase alfa (PRX-102) is a drug made using genetic engineering techniques and manufactured using cultured tobacco cells. It is given by intravenous infusion every 2 weeks, at a dosage of 1 milligram per kilogram (mg/kg) of body weight.

The study consists of a main study that is divided into two stages, each of which will last one year, followed by an optional extension study. In the optional extension stage, the participants may receive PRX-102 intravenous infusion every 2 weeks, at a dosage of 1 milligram per kilogram (mg/kg) of body weight or every 4 weeks at a dosage of 2 milligrams per kilogram (mg/kg) of body weight.

There are three groups (cohorts) in this study, with adults enrolled in either Cohort A or B and adolescents in Cohort C. Whether an adult is assigned to Cohort A or Cohort B depends on their kidney function and treatment history.

This study will start with a screening visit of up to 4 weeks. It will be followed up by infusion visits every 2 weeks or 4 weeks. For subjects not continuing in the extension stage, a follow-up call is to be made 30 days after the last study drug infusion.

Eligibility criteria: Inclusion criteria (all subjects)

* Must have been born in Japan and have their biological parents and all 4 grandparents of Japanese descent
* A documented diagnosis of Fabry disease, as determined by the following:
* Males: Plasma and/or leukocyte alpha-galactosidase-A activity (by activity assay) that is ≤ 5% of mean normal laboratory levels or, if the enzymatic activity is above the 5% limit but still under the normal level, a confirmed disease-causing mutation of the GLA gene
* Females: Historical genetic test results consistent with Fabry mutations or, in the case of novel mutations, a first-degree male relative with Fabry disease
* All subjects: At least one of the following characteristic features of Fabry disease: neuropathic pain, cornea verticillata, and/or clustered angiokeratoma
* Estimated glomerular filtration rate (eGFR) at screening ≥40 mL/min/1.73 m2. For adults, this will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine equation (2009); and for adolescents, it will be calculated using the Creatinine Cystatin C-based Chronic Kidney Disease in Children (CKiD) equation.
* Clinical condition that in the opinion of the Investigator requires treatment with ERT

Additional inclusion criteria for subjects in Cohort A

* Aged ≥18 to ≤60 years
* Treatment with agalsidase beta for at least the last 12 months prior to screening, with the dose stable (defined as having received at least 80% of the labelled dose) for at least the last 6 months
* Diagnosis of kidney impairment, defined as a linear slope of eGFR more negative or equal to -2 mL/min/1.73 m2/year. The historical eGFR slope will be calculated based on at least 3 serum creatinine values obtained over the past 9 to 24 months prior to screening, using the CKD-EPI Creatinine equation (2009). This criterion will be confirmed at screening by calculating the screening eGFR slope using historical and screening serum creatinine values. Both historical and screening eGFR slopes will be used for the diagnosis of kidney impairment.

Additional inclusion criterion for subjects in Cohort B

- Aged ≥18 to ≤60 years

Additional inclusion criteria for subjects in Cohort C

* Aged ≥13 to \<18 years
* If they previously received or are currently receiving ERT treatment, the subjects must be negative for anti-drug antibodies for PRX-102

Exclusion Criteria:

* Administration of ERT for Fabry disease within 14 days before baseline, substrate reduction therapy for Fabry disease within 3 days before baseline, or chaperone therapy for Fabry disease within 3 days before baseline
* History of type I hypersensitivity reactions (anaphylactic or anaphylactoid life-threatening reaction) to other ERT treatment for Fabry disease or to any component of the study drug
* Cohort A only: eGFR value of \>90 to ≤120 mL/min/1.73 m2 at screening and a historical eGFR value \>120 mL/min/1.73 m2 in the past 9 to 24 months before screening, indicating absence of renal impairment
* Urine protein to creatinine ratio (UPCR) \>0.5 g/g (0.5 mg/mg or 500 mg/g) if not treated with an ACE inhibitor or ARB
* Initiation of treatment, or a change in dose to ongoing treatment, with an angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the 4 weeks prior to screening.
* Currently taking another investigational drug for any condition
* Carry only known non-pathogenic Fabry mutations
* History of renal dialysis or kidney 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 renal vasculitis); non-specific conditions (e.g., ischemia, toxic injury); as well as extrarenal pathology (e.g., prerenal azotaemia, and acute postrenal obstructive nephropathy
* History of (or current) malignancy requiring treatment; the one exception is a prior history of resected basal cell carcinoma
* Severe cardiomyopathy or significant unstable cardiac disease within 6 months prior to screening
* A positive test for Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) within 3 months prior to screening, using a validated molecular assay or validated antigen assay
* Females: Pregnant or lactating, or of childbearing potential with a fertile male partner and unwilling to use a highly reliable method of contraception from the informed consent signature until 30 days after the last study treatment
* Presence of any medical, emotional, behaevioral, or psychological condition that in the judgment of the Investigator could interfere with the subject's compliance with the requirements of the study
* Previous treatment with cellular therapy or gene therapy for any condition

Primary outcomes:
measure: Incidence of Treatment Emergent Adverse Events (TEAEs)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Incidence of Infusion Related Reactions (IRRs)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Incidence of Injection site reactions (ISRs)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change of laboratory tests' results
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in in body weight in kilograms
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in height in centimeters
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in Tanner stage
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change from baseline of 12-lead ECG quantitative parameters: Mean Heart Rate, PR Interval, QRS Duration, QT Interval, QTc Interval, and ST Segment
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Incidence of treatment-emergent Anti-Drug Antibodies (ADAs)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: ADA status change from baseline
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Incidence of premedication use at each visit and change of infusion premedications from baseline
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change from baseline of Maximum plasma concentration (Cmax), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Time to maximum plasma concentration (tmax), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Area under the plasma concentration-time curve from time 0 to time t (AUC0 t), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Area under the curve from time 0 to 2 weeks (AUC0-2wk), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Area under the curve from time 0 to infinity (AUC0-∞), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Terminal half-life (t1/2), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Area under the curve over a dosing interval (AUCτ), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Observed drug concentration at the end of the dosing interval (Cτ), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Clearance (Cl), pharmacokinetic parameter
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
measure: Change from baseline of Volume of distribution (Vz), pharmacokinetic parameters
timeFrame: Assessments will be done over three two-week periods, starting at Baseline (Week 0), V7 (Week 12), and V27 (Week 52)
Secondary outcomes:
Other outcomes:
measure: Change in eGFR
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in annualized eGFR slope
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in urine albumin levels
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in urine protein levels
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Incidence of changes in echocardiogram results
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Incidence of changes in Holter ECG
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change of cardiac biomarkers
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Adults only: Response of the heart to external stress induced by exercise measured with Stress test (Bruce protocol)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Adults only: change of Cardiac MRI
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Adults only: change of Brain MRI
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in plasma level of Gb3 concentration (nM)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in plasma level of lyso-Gb3 (nM)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change in urine level of lyso-Gb3 (nM)
timeFrame: 12 Months, 24 Months and through study completion (an average of 4.5 years)
measure: Change from baseline of Mainz Severity Score Index (MSSI) scores
timeFrame: 12 Months, 24 Months and at the end of study
measure: Incidence of change from baseline in the number of different pain medications
timeFrame: 12 Months, 24 Months and at the end of study
measure: Incidence of Fabry Clinical Events
timeFrame: 12 Months, 24 Months and at the end of study
measure: Adults only: change in Gastrointestinal Symptom Rating Scale (GSRS) scores
timeFrame: 12 Months, 24 Months and at the end of study
measure: Adults only: change in Brief Pain Inventory - Short Form (BPI-SF) scores
timeFrame: 12 Months, 24 Months and at the end of study
measure: Adults only: change of quality of life assessed using EQ-5D-5L questionnaire
timeFrame: 12 Months, 24 Months and at the end of study
measure: Cohort C only: Change in Gastrointestinal Symptoms (PedsQL-GI) Questionnaire scores
timeFrame: 12 Months, 24 Months and at the end of study
measure: Cohort C only: change in Fabry-Specific Pediatric Health and Pain Questionnaire (FPHPQ) scores
timeFrame: 12 Months, 24 Months and at the end of study
measure: Cohort C only: change in PedsQL Pediatric Pain Questionnaire (PedsQL-PPQ) scores
timeFrame: 12 Months, 24 Months and at the end of study
measure: Cohort C only: change of quality of life assessed using EQ-5D-Y Questionnaire
timeFrame: 12 Months, 24 Months and at the end of study
Locations:
city: Chikushino
country: Japan
facility: Fukuoka University Chikushi Hospital
state: Fukuoka
city: Sendai
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Nishihara
country: Japan
facility: University of the Ryukyu Hospital
state: Okinawa
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital, 3-1-3 Hongo, Bunkyo-ku, Tokyo
state: Tokyo
city: Minato-ku
country: Japan
facility: Tokyo Jikei University Hospital
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Asahikawa City
country: Japan
facility: Asahikawa Medical University Hospital
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
Study officials:
References: