Study to Evaluate the Safety, PK, PD, and Efficacy of PRX-102 in Japanese Patients With Fabry Disease

JRCT ID: jRCT2031230079

Registered date:17/05/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Fabry disease
• Date of first enrollment: 25/08/2023
• Target sample size: 18
• Study type: Interventional

Intervention(s)

Subjects enrolled in the three cohorts will receive an intravenous (IV) infusion of PRX-102 at a dose of 1 mg/kg every 2 weeks, for up to one year (Stage I).
Subjects who complete Stage I will continue to receive PRX-102 for up to one more year. Cohort A subjects will continue to receive the same dosing as in Stage I. Cohort B and Cohort C subjects who have reached the age of 18 years may switch to PRX-102 2 mg/kg every 4 weeks (Stage II), depending on the results of PK and safety data obtained during Stage I.
Subjects who complete Stages I and II will be offered the opportunity to take part in an optional extension study in which they may continue to receive treatment with PRX-102 until either the product becomes commercially available in Japan or the Sponsor decides to terminate the study (extension study). During the extension study, Cohort A subjects who will have by now completed 24 months on the 1 mg/kg regimen may switch to PRX-102 2 mg/kg every 4 weeks, depending on the results of PK and safety data obtained during Stage I. The same option may be offered to Cohort C subjects who reach the age of 18 while the extension study is in progress.

Outcome(s)

Primary Outcome

1. Incidence of Treatment Emergent Adverse Events (TEAEs)
2. Incidence of Infusion Related Reactions (IRRs)
3. Incidence of Injection site reactions (ISRs)
4. Change of laboratory tests' results
5. Change in in body weight in kilograms
6. Change in height in centimeters
7. Change in Tanner stage
8. Change from baseline of 12-lead ECG quantitative parameters
9. Incidence of Anti-Drug Antibodies (ADAs) against PRX-102
10. ADA status change from baseline
11. Incidence of premedication use at each visit and change of infusion premedications from baseline
12. Change from baseline of Maximum plasma concentration (Cmax)
13. Change from baseline of Time to maximum plasma concentration (tmax)
14. Change from baseline of Area under the plasma concentration-time curve from time 0 to time t (AUC0 t)
15. Change from baseline of Area under the curve from time 0 to 2 weeks (AUC0-2wk)
16. Change from baseline of Area under the curve from time 0 to infinity (AUCinf)
17. Change from baseline of Terminal half-life (t1/2)
18. Change from baseline of Area under the curve over a dosing interval (AUCtau)
19. Change from baseline of Observed drug concentration at the end of the dosing interval (Ctau)
20. Change from baseline of Clearance (Cl)
21. Change from baseline of Volume of distribution (Vz)

Key inclusion & exclusion criteria

• Age minimum: >= 13age old
• Age maximum: <= 60age old
• Gender: Both

Include criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrolment in the study:
All subjects
1. Must have been born in Japan and have their biological parents and all 4 grandparents of Japanese descent
2. A documented diagnosis of Fabry disease, as determined by the following:
- Males: Plasma and/or leukocyte alfa-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
3. Estimated glomerular filtration rate (eGFR) at screening =>40 mL/min/1.73 m^2. 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.
4. Clinical condition that in the opinion of the Investigator requires treatment with ERT
5. A female subject (including an adolescent in Cohort C, if applicable) must meet one of the following criteria:
- If of childbearing potential, she must:
a. Have a negative serum pregnancy test result at screening, AND
b. Agree to undergo a urine pregnancy test at baseline and every 12 weeks thereafter up to the final treatment, AND
c. Agree to use one of the following highly reliable methods of contraception from the day of the informed consent signature until 30 days after the last infusion received. The following methods are acceptable:
- Placement of an intrauterine device (IUD) or intrauterine releasing system (IUS)
- Combined (both estrogen and progestogen) hormonal contraception (oral) associated with inhibition of ovulation, supplemented with a barrier method (preferably male condom)
- Bilateral tubal occlusion
- Sexual abstinence, defined as refraining from heterosexual intercourse during the entire study period
- Partner vasectomy, provided that the partner is the sole sexual partner and has received medical verification of the surgical success
Be of non-childbearing potential, defined as one of the following:
- Post-menopausal (12 consecutive months of amenorrhea), OR
- Permanently sterile following hysterectomy, bilateral salpingectomy, or bilateral oophorectomy (supporting evidence required)
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 m~2/year. The historical 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). It is preferable if all 3 samples assessed were done at the same center using the same laboratory; however, the results of samples that were assessed by different laboratories will be accepted. 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
Before the start of treatment, the Investigator will decide whether or not pregnancy testing and contraception counselling are necessary. Since over the course of the study, pre-pubertal girls may reach menarche and adolescents of either gender may become sexually active, the Investigator must periodically check on the status of these issues and implement pregnancy testing and/or contraception counselling if required.

Exclude criteria

The presence of any of the following will exclude a prospective subject from study enrolment:
1. Administration of previous treatment 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
2. History of severe 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
3. Cohort A only: eGFR value of >90 to =<120 mL/min/1.73 m^2 at screening, and a historical eGFR value >120 mL/min/1.73 m^2 in the past 9 to 24 months before screening, indicating absence of renal impairment
4. 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
5. 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
6. Currently taking another investigational drug for any condition
7. Carry only known non-pathogenic Fabry mutations
8. History of renal dialysis or kidney transplantation
9. 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 azotemia, and acute postrenal obstructive nephropathy
10. History of (current) malignancy requiring treatment; the one exception is a prior history of resected basal cell carcinoma
11. Severe cardiomyopathy or significant unstable cardiac disease within 6 months prior to screening
12. 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
13. 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 study participation ends
14. Presence of any medical, emotional, behavioral, or psychological condition that in the judgment of the Investigator could interfere with the subject compliance with the requirements of the study
15. Previous treatment with cellular therapy or gene therapy for any condition

Related Information

• Primary Sponsor: Simona Amore
• Secondary ID(s): NCT05710692