Dose-ranging Study of PRX-102 in Adult Fabry Disease Patients

• ClinicalTrials.gov Identifier: NCT01678898
• Recruitment Status: Completed
• First Posted: September 5, 2012
• Results First Posted: January 27, 2020
• Last Update Posted: January 27, 2020
• Sponsor: Protalix
• Information provided by (Responsible Party): Protalix

Study Description

Brief Summary:

This is the first human treatment with PRX-102, an enzyme being developed as a long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (alpha galactosidase deficiency). The safety, tolerability, and exploratory efficacy will be evaluated in this study of increasing doses. Patients will be treated with infusions every two weeks for 12 months.

Condition or disease	Intervention/treatment	Phase
Fabry Disease	Drug: PRX-102	Phase 1; Phase 2

Detailed Description:

Under the PB-102-F01 study protocol, patients will be enrolled into one of three PRX-102 dosing groups (0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg) and receive PRX-102 as an intravenous infusion every 2 weeks for 12 weeks (3 months). Patients who finish the PB-102-F01 study will be enrolled in the PB-102-F02 extension study and receive the same dose they had received in the PB-102-F01 study for an additional 38 weeks (9 months).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Open Label, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Exploratory Efficacy Parameters of PRX-102 Administered by Intravenous Infusion Every 2 Weeks for 12 Months to Adult Fabry Patients
• Actual Study Start Date: October 2012
• Actual Primary Completion Date: March 6, 2016
• Actual Study Completion Date: March 6, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: 0.2 mg/kg; PRX-102 0.2 mg/kg every 2 weeks	Drug: PRX-102; Other Name: plant cell expressed recombinant human alpha-galactosidase-A
Experimental: 1 mg/kg; PRX-102 1 mg/kg every 2 weeks	Drug: PRX-102; Other Name: plant cell expressed recombinant human alpha-galactosidase-A
Experimental: 2 mg/kg; PRX-102 2 mg/kg every 2 weeks	Drug: PRX-102; Other Name: plant cell expressed recombinant human alpha-galactosidase-A

Outcome Measures

Primary Outcome Measures :

1. Adverse Events [ Time Frame: 12 months ]
   Reportings of adverse events reported by the patient and from monitoring with clinical laboratory, physical examination and ECG. Results represent the number of AEs that were considered possibly, probably, or definitely related to treatment.

Other Outcome Measures:

1. Plasma Gb3 Concentrations [ Time Frame: Plasma Gb3 concentration (ug/mL) was measured at baseline and every 3 months up to 12 months. ]
   Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
2. Kidney Function - Change in eGFR [ Time Frame: eGFR is performed at baseline (day 1) weeks 4, 8, 12, 26, 38 and 52 (12 months) ]
   Estimated glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Levels of eGFR calculated by the CKD-EPI equation, based on measured serum creatinine on day 1, weeks 4, 8, 12, 26, 38 and 52 are used to determine the annualized slope of eGFR per patient over a 12 months period. The absolute mean change from baseline (visit 1) to 12 months is then derived from the eGFR slope.
3. Plasma Lyso-Gb3 Levels [ Time Frame: Plasma Lyso-Gb3 concentration (ng/mL) was measured at baseline and every 3 months up to 12 months. ]
   Results are presented as mean percent change from baseline (visit 1) to 12 months +/- standard error.
4. Change in Kidney Gb3 Accumulation [ Time Frame: Visit 1 (day 1) in PB-102-F01 study and after a total of 6 months of treatment (i.e., at 3 months into study PB-102-F02). ]
   Kidney biopsy was performed at baseline of study PB-102-F01 and following 6 months treatment with PRX-102. Approximately 300 capillaries were scored in each specimen. A quantitative Barisoni Lipid Inclusion Scoring System (BLISS) was used for scoring Gb3 inclusions in kidney peritubular capillary (PTC) biopsy samples.The scoring system was implemented by 3 blinded pathologists/readers.The BLISS scoring methodology consists of counting the number of Gb-3 inclusions per capillary previously annotated.The final score of each biopsy was the average number of inclusions per capillary. A decrease in scoring from baseline to 6 Month is considered an indication for clinical improvement.
5. Cardiac Fibrosis Per MRI [ Time Frame: Cardiac MRI was performed in order to assess myocardial fibrosis at baseline, 6 months and 12 months visit. ]

   Cardiac MRI was performed to estimate the percentage and mass of the myocardial fibrotic area.

   Results represent the number of subjects with fibrosis after 1 year of treatment.

6. Cardiac MRI - Ejection Fraction [ Time Frame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months. ]
   Results are presented as mean percent change from baseline (visit 1) to 12 months.
7. Cardiac MRI - LVM [ Time Frame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months. ]
   Results are presented as mean percent change from baseline (visit 1) to 12 months.
8. Cardiac MRI - LVMI [ Time Frame: Cardiac MRI was performed 3 times: at baseline (visit 1), 6 months and 12 months. ]
   Cardiac MRI with computer-calculated left ventricular mass index were conducted at baseline, 6 month, and 12 months. Results are presented as mean percent change from baseline (visit 1) to 12 months. LVMI is calculated by dividing the left ventricular mass by body surface area.
9. Pharmacokinetics - AUC [ Time Frame: PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion. ]
   PK parameters were derived from the plasma concentration versus time profiles. Results reported represent the averaged values following a single dosing of the study drug.
10. Pharmacokinetics - Terminal Half Life [ Time Frame: PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion. ]
    PK parameters were derived from the plasma concentration versus time profiles. Results reported represent the averaged values following a single dosing of the study drug.
11. Pharmacokinetics - Clearance of Drug (Cl) [ Time Frame: PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion. ]

    PK parameters were derived from the plasma concentration versus time profiles. Clearance of drug from plasma represents the volume of plasma cleared of the drug per unit time per Kg.

    Results reported represent the averaged values following a single dosing of the study drug.

12. Pharmacokinetics - Volume of Distribution (Vz) [ Time Frame: PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion. ]
    PK parameters were derived from the plasma concentration versus time profiles. Vz is the volume of distribution during the elimination phase. Results reported represent the averaged values following a single dosing of the study drug.
13. Pharmacokinetics - Cmax [ Time Frame: PK parameters were determined on Day 1 and 3, 6, and 12 months at these time points: pre-infusion (baseline); 1 h after the beginning of the infusion; at the end of the infusion; 1, 4, 8, 24, 48±3, 72±3, 96±3 h and 2 weeks ± 3 days post-infusion. ]

    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 averaged values following a single dosing of the study drug.

14. Number of Participants With Anti-Drug Antibodies [ Time Frame: Anti-pegunigalsidase alfa (PRX-102) antibodies, including neutralizing antibodies in patients having a positive IgG antibody response, were assessed at Visit 1, 2 (Month 1), and then every 2 months during the study, and 2 months after the last infusion. ]
    Results reported represent the number of participants who were tested positive for anti-pegunigalsidase alfa (PRX-102) antibodies, including neutralizing antibodies in patients having a positive IgG antibody response per group, at Visit 1, 2 (Month 1), and then every 2 months during the study, and 2 months after the last infusion.
15. Change in Short Form Brief Pain Inventory (BPI) [ Time Frame: The Short Form Brief Pain Inventory (BPI) is assessed at baseline, 3-month, 6-month, and 12-month visits. ]
    Pain severity (worst, least, average, and right now) is summarized at baseline, 3-month, 6-month and 12-month of the study. The Short Form Brief Pain Inventory (BPI) is based on a 10-point scale, where 0=no pain and 10=pain as bad as you can imagine. A reduction in pain severity score indicated an improvement. The changes from baseline for individual scores and composite scores (a mean severity score) was assessed. The mean change in score from baseline at the 12-month visit is reflected.
16. Urine Creatinine Level [ Time Frame: Urine creatinine level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits using spot urine tests. ]
    Proteinuria is assessed using spot urine tests at baseline, 3-month, 6-month, 9-month, and 12-month visits. The percent changes of urine creatinine level at the 12-month visit from baseline is reflected.
17. Urine Protein/Creatinine Ratio [ Time Frame: Protein/.creatinine ratio is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits ]
    Proteinuria is assessed using spot urine tests at baseline, 3-month, 6-month, 9-month, and 12-month visits. The percent changes of urine protein/creatinine ratio at the 12-month visit from baseline is reflected.
18. Total Urine Protein Level [ Time Frame: Total urine protein level is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    Proteinuria is assessed using spot urine tests at baseline, 3-month, 6-month, 9-month, and 12-month visits. The percent changes of total urine protein level at the 12-month visit from baseline is reflected.
19. Brain MRI [ Time Frame: Brain MRI is performed at baseline and 12-month visit. ]
    Qualitative assessments regarding evidence of stroke using brain MRI were summarized at baseline and 12-month visits. Number is subjects with evidence of stoke on the brain MRI at the 12-month visit is reflected.
20. Change in Mainz Severity Score Index (MSSI) [ Time Frame: The MSSI is performed at baseline, 6-month, and 12-month ]
    The Mainz Severity Score Index (MSSI) is useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI scoring system is composed of four sections that cover the general, neurological,cardiovascular and renal signs and symptoms of Fabry disease. Each section includes a group of signs and symptoms that are associated with Fabry disease. The minimal score is 0, and the maximum score for the general section is 18. A higher score indicates more severe clinical manifestations of the disease.The MSSI is performed at baseline, 6-month, and 12-month. The overall mean reduction of the total general score at 12-month from baseline is reflected.
21. Gastrointestinal Symptoms Questionnaire - Severity of Abdominal Pain [ Time Frame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    A qualitative assessments regarding abdominal pain and diarrhea at baseline, 3-month, 6-month, 9-month, and 12-month visits. The subjects were asked to report the severity of their abdominal pain as no pain, mild, moderate, severe or really severe. The number of subjects who reported no or mild abdominal pain at the 12-month visit are reflected.
22. Gastrointestinal Symptoms Questionnaire - Frequency of Abdominal Pain [ Time Frame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    A qualitative assessments regarding abdominal pain and diarrhea at baseline, 3-month, 6-month, 9-month, and 12-month visits. The subjects were asked to report their frequency of abdominal pain as never, rarely, monthly, weekly, or daily. The numbers of subjects who reported never or rarely having abdominal pain at the 12-month visit are reflected.
23. Gastrointestinal Symptoms Questionnaire - Frequency of Diarrhea [ Time Frame: The Gastrointestinal Symptoms Questionnaire is assessed at baseline, 3-month, 6-month, 9-month, and 12-month visits. ]
    A qualitative assessments regarding abdominal pain and diarrhea at baseline, 3-month, 6-month, 9-month, and 12-month visits. The subjects were asked to report their frequency of diarrhea as never, rarely, monthly, weekly, or daily. The number of subjects who reported never or rarely having diarrhea at the 12-month visit is reflected.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Symptomatic adult Fabry patients (≥18 yrs)
• Males: plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than lower limit of normal (LLN in plasma=3.2 nmol/hr/ml, LLN in leucocytes=32 nmol/hr/mg/protein)
• Females: historical genetic test results consistent with Fabry mutations
• Globotriaosylceramide (Gb3) concentration in urine > 1.5 times upper normal limit
• Patients who have never received enzyme replacement therapy (ERT) in the past, or patients who have not received ERT in the past 6 months and have a negative anti alpha galactosidase antibody test
• eGFR ≥ 60 mL/min/1.73m2
• The patient signs informed consent
• 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:

• Participation in any trial of an investigational drug within 30 days prior to study screening
• Chronic kidney disease stages 3-5 (CKD 3-5) (Appendix 7)
• History of dialysis or renal transplantation
• Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
• Severe myocardial fibrosis by MRI (≥2 late-enhancement [LE] positive left ventricular segments) (Weidemann et al. 2009)
• History of clinical stroke
• Pregnant or nursing
• Presence of HIV and/or HBsAg and/or Hepatitis C infections
• Known allergies to ERT
• Known allergy to Gadolinium based contrast agents
• 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

Contacts and Locations

Locations

United States, California

UC Davis Medical Center, MIND Institute Department of Pediatrics, Section of Genetics

Sacramento, California, United States, 95817

United States, Georgia

Department of Human Genetics, Emory University School of Medicine

Atlanta, Georgia, United States, 30322

United States, Iowa

University of Iowa Health Clinics

Iowa City, Iowa, United States, 52242

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Maryland

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States, 21205

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Texas

Research Baylor Institute of Metabolic Disease

Dallas, Texas, United States, 75226

United States, Virginia

O & O Alpan LLC

Fairfax, Virginia, United States, 22030

Australia

Royal Melbourne Hospital

Victoria Park, Australia, 3050

Paraguay

Hematology and Clinical Research Private Institute

Asuncion, Paraguay

Serbia

Clinical Center of Serbia

Belgrade, Serbia

Spain

Hospital de Dia Quiron Zaragoza

Zaragoza, Spain, 50012

United Kingdom

The Royal Free Hospital

London, United Kingdom, NW3 2QG

Sponsors and Collaborators

Protalix

Investigators

• Study Director: Einat Almon, PhD; Protalix

More Information

Publications of Results:

Schiffmann R, Goker-Alpan O, Holida M, Giraldo P, Barisoni L, Colvin RB, Jennette CJ, Maegawa G, Boyadjiev SA, Gonzalez D, Nicholls K, Tuffaha A, Atta MG, Rup B, Charney MR, Paz A, Szlaifer M, Alon S, Brill-Almon E, Chertkoff R, Hughes D. Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial. J Inherit Metab Dis. 2019 May;42(3):534-544. doi: 10.1002/jimd.12080. Epub 2019 Apr 8.

• Responsible Party: Protalix
• ClinicalTrials.gov Identifier: NCT01678898
• Obsolete Identifiers: NCT01769001
• Other Study ID Numbers: PB-102-F01 & PB-102-F02
• First Posted: September 5, 2012
• Results First Posted: January 27, 2020
• Last Update Posted: January 27, 2020
• Last Verified: January 2020

Keywords provided by Protalix:

Fabry disease; Alpha galactosidase deficiency; Metabolic storage disease

Additional relevant MeSH terms:

Fabry Disease; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders