Safety, Efficacy, & PK of PRX-102 in Patients With Fabry Disease Administered Intravenously Every 4 Weeks

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.

• Pegunigalsidase alfa (Biological), also known as PRX-102, Recombinant human alpha galactosidase-A: Pegunigalsidase alfa 2 mg/kg every 4 weeks

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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.

Sex: All, ages: 18 Years to 60 Years

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.

Participant flow

Outcome results

• Number of Participants With Treatment-related Adverse Events (TEAE) as Assessed by CTCAE v4.03 (Primary), Number, participants: PRX-102 27
• Estimated Glomerular Filtration Rate (eGFR) (Other pre specified), Mean, mL/min/1.73m^2: Efficacy Population 99.44 +/- 4.15; Males 100.68 +/- 4.96; Females 94.69 +/- 6.76
• Plasma Lyso-Gb3 (Other pre specified), Mean, nM: Efficacy Population 19.36 +/- 3.35; Males 23.27 +/- 3.82; Females 4.35 +/- 1.00
• Quality of Life by EQ-VAS (Other pre specified), Mean, scores on a scale: Efficacy Population 78.3 +/- 3.1
• Pharmacokinetics - Cmax (Other pre specified), Mean, ng/mL: Safety Population 35876.7 +/- 11942.2
• Pharmacokinetics - AUC (Other pre specified), Mean, ng*hr/mL: Safety Population 1797464.1 +/- 822632.4
• Pharmacokinetics - Terminal Half Life (Other pre specified), Mean, hour: Safety Population 100.1 +/- 58.3

Adverse events

Time frame: Adverse events were collected from the start of treatment until 30 days following the final study dose, an average of 13 months.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Small number of subjects.

• Results publication: Azimpour K, Dorling P, Koulinska I, Kunduri S, Lan Z, Poritz J, Tremblay G, Raad-Faherty A. Health State Utility Values in Fabry Disease: Insights from the Pegunigalsidase Alfa Clinical Trials. Adv Ther. 2025 Mar;42(3):1421-1434. doi: 10.1007/s12325-024-03095-2. Epub 2025 Jan 23. PMID 39847314

• Study Protocol (PDF, 2018-07-25)
• Statistical Analysis Plan (PDF, 2020-11-25)