To evaluate the safety and efficacy of PRX-102 compared to agalsidase beta in Fabry disease patients with impaired renal function.
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy parameter is the comparison of the mean annualized change
(slope) in estimated glomerular filtration rate (eGFRCKD-EPI) between treatment
groups.
Secondary outcome
* Left Ventricular Mass Index (g/ m2) by MRI
* Plasma Lyso-Gb3
* Plasma Gb3
* Urine Lyso-Gb3
* Protein/Creatinine ratio spot urine test
* Frequency of pain medication use
* Exercise tolerance (Stress Test)
* Short Form Brief Pain Inventory (BPI)
* Mainz Severity Score Index (MSSI)
* Quality of life EQ-5D-5L
Background summary
Fabry disease is a progressive lysosomal storage disease that is seriously
debilitating and ultimately life-threatening. It is caused by X-linked
deficiency of the enzyme alpha galactosidase-A (alpha-GAL-A), and affects both
males and females. The disease is characterized by subnormal or absent activity
of alpha-GAL-A. Clinical onset of the disease typically occurs during childhood
or adolescence (Schaefer et al. 2009) and will progress to end- stage renal
disease, cardiac complications and cerebrovascular problems in the fourth or
fifth decade of life (Wilcox et al. 2008). Although Fabry disease is a X-linked
disorder, females are also affected and develop manifestations of the disease
due to lack of cross-correction between cells with normal alpha-GAL-A activity
(mutated X chromosome is inactivated) and cells with enzyme deficiency
(non-mutated X chromosome is inactivated). The clinical abnormalities in
females are more variable, and of later onset compared to males (Schiffmann
2009).
Fabry disease is regarded as a rare disease and it is estimated that 1 in
40,000 males has the disease, whereas the estimated prevalence in the general
population is 1 in 117,000 (Meikle et al. 1999).
Protalix has developed PRX-102, a chemically modified recombinant human
alpha-GAL-A expressed in plant cell culture. As a result of this modification,
PRX-102 exhibits more stabilized homo dimer with active enzyme over longer
period, extended circulation residence time and enhanced bioavailability of the
enzyme relative to the commercial drug. Therefore, PRX-102 provides continuous
presence of enzyme over the 2 week dosing interval.
Study objective
To evaluate the safety and efficacy of PRX-102 compared to agalsidase
beta in Fabry disease patients with impaired renal function.
Study design
This is a randomized, double blind, active control study of PRX-102 in Fabry
disease patients with impaired renal function. Patients treated for
approximately 1 year with agalsidase beta and on a stable dose for at least 6
months will be screened and then randomized to continue treatment with 1 mg/kg
agalsidase beta or to treatment with 1 mg/kg of PRX-102. The identity of the
enzyme will be blinded to the patient and the investigator. Patients will
receive intravenous infusions every two weeks.
Patients will be randomized in a 2:1 ratio of PRX-102 to agalsidase beta.
Randomization will be stratified by urine protein to creatinine ratio (UPCR) of
< or * 1 g/g by spot urine sample.
At the time of randomization, premedication, if used for the agalsidase beta
infusions before study entry will be continued and gradually tapered at the
investigator*s discretion during the first 3 months of the study. The first
infusions of blinded agalsidase beta or PRX-102 will be administered under
controlled conditions at the investigation site. The patient can receive their
infusions at their pre-defined infusion facility or as part of a home setup
once the investigator and Sponsor Medical Director agree that it is safe to do
so.
An interim analysis will be conducted at 12 months and the final analysis at 24
months of treatment.
Intervention
Pegunigalsidase alfa (PRX-102) 1 mg/kg or agalsidase beta 1 mg/kg,
intravenously over 3 hours, every 2 weeks.
After the first 3 months of treatment infusion time may be reduced gradually to
1.5 hours pending patient tolerability, PI evaluation, and Medical
Monitor/Director approval.
Study burden and risks
PRX-102 has been given to 16 people for a duration of more than a year, but the
specific side effects are not yet well known. The safety profile of PRX-102
however does not seem very different from other enzymes used to treat Fabry
disease.
It is possible that the symptoms will not improve during the study or may even
worsen. Please see the Investigators Brochure and/or Informed Consent form for
an overview of all possible side effects.
2 Snunit St Science Park
Carmiel 20100
IL
2 Snunit St Science Park
Carmiel 20100
IL
Listed location countries
Age
Inclusion criteria
1. Symptomatic adult Fabry disease patients, age 18-60 years
a. Plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than 30% mean normal levels
b. One or more of the described characteristic features of Fabry disease:
i. neuropathic pain,
ii. cornea verticillata,
iii. clustered angiokeratoma
2. Screening eGFR by CKD-EPI equation 40 to 90 mL/min/1.73 m2
3. Linear negative slope of eGFR of * 2 mL/min/1.73 m2 based on at least 3 serum creatinine values over approximately 1 year (range of 9 to 18 months, including the value obtained at the screening visit)
4. Treatment with a dose of 1 mg/kg agalsidase beta per infusion every 2 weeks for at least one year and at least 80% of 13 (10.4) mg/kg total dose over the last 6 months
5. Female patients and male patients whose co-partners are of child-bearing potential agree to use a medically accepted method of contraception, not including the rhythm method.
Exclusion criteria
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase beta
2. History of renal dialysis or transplantation
3. 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 postrenal obstructive nephropathy)
4. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated or dose changed in the 4 weeks prior to screening
5. Urine protein to creatinine ratio (UPCR) > 0.5 g/g and not treated with an ACE inhibitor or ARB
6. Cardiovascular event (myocardial infarction, unstable angina) in the 6 month period before randomization
7. Congestive heart failure NYHA Class IV
8. Cerebrovascular event (stroke, transient ischemic attack) in the 6 month period before randomization
9. Known history of hypersensitivity to Gadolinium contrast agent
10. Female subjects who are pregnant, planning to become pregnant during the study, or are breastfeeding
11. 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-000378-38-NL |
| ClinicalTrials.gov | NCT02795676 |
| CCMO | NL59184.018.16 |