To evaluate the safety and efficacy of PRX-102 in patients with Fabry disease currently treated with agalsidase alfa
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
SAFETY ENDPOINTS:
Change from baseline in:
* Clinical laboratory tests
* Physical examination
* Assessment of the injection site
* Electrocardiogram
* Treatment-emergent adverse events
* Ability to taper off infusion premedication throughout the first 2 months of
the study
* Requirement for use of premedication overall to manage infusion reactions
* Treatment-emergent anti-PRX-102 antibodies
Secondary outcome
EFFICACY ENDPOINTS:
* Mean annualised change in estimated glomerular filtration rate (eGFRCKD-EPI)
* Left Ventricular Mass Index (g/m2) preferably by MRI (echocardiogram can be
used as an alternative)
* 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 and will progress to end- stage renal disease, cardiac
complications and cerebrovascular problems in the fourth or fifth decade of
life. 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.
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.
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 in patients with Fabry disease
currently treated with agalsidase alfa
Study design
This is an open label switch over study to assess the safety and efficacy of
PRX-102. Patients treated with agalsidase alfa for at least 2 years and on a
stable dose (>80% labelled dose/kg) for at least 6 months. Patients will be
evaluated for 3 months with this dose while on agalsidase alfa every other week
infusion (Study Part A), during which safety and efficacy data will be
collected for baseline data generation. They will then be switched from their
agalsidase alfa treatment to receive intravenous (IV) infusions of PRX-102 1
mg/kg every two weeks for 12 months (Study Part B). No more than 25% of treated
patients will be female.
At the time of enrolment, premedication, if used for the agalsidase alfa
infusions before study entry, will be continued during Study Part A and after
first infusion with PRX-102 treatment (Study Part B) premedication will be
gradually tapered at the investigator*s discretion during the first 2 months.
The first infusions of PRX-102 will be administered under controlled conditions
at the investigation site. The patient can receive their PRX-102 infusions at
their pre-study infusion facility or as part of a home care setup once the
investigator and Sponsor Medical Director agree that it is safe to do so.
Intervention
During the first 3 months, Study Part A, patients will be on agalsidase alfa
every other week infusion according to their previous dose and rate of
infusion. At Study Part B patients will be switched to PRX-102 1 mg/kg,
intravenously to be administered over 3 hours, every 2 weeks. After the first 3
months of treatment with PRX-102, infusion time may be reduced gradually to 1.5
hours pending patient tolerability, investigator evaluation, and Sponsor
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.
Snunit St Science Park 2
Carmiel 20100
IL
Snunit St Science Park 2
Carmiel 20100
IL
Listed location countries
Age
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 laboratory range and one or more of the characteristic features of Fabry disease;i. Neuropathic pain;ii. Cornea verticillata;iii. 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;i. Neuropathic pain;ii. Cornea verticillata;iii. Clustered angiokeratoma;5. Treatment with agalsidase alfa for at least 2 years and on a stable dose (>80% labelled dose/kg) for at least 6 months;6. eGFR * 40 ml/min/1.73 m2 by CKD-EPI equation;7. Availability of at least 2 historical serum creatinine evaluations since starting agalsidase alfa treatment and not more than 2 years;8. 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
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase alfa;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. Known history of hypersensitivity to Gadolinium contrast agent that is not managed by the use of premedication;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. Congestive heart failure NYHA Class IV;10. Cerebrovascular event (stroke, transient ischemic attack) in the 6 month period before screening;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 | EUCTR2016-001318-11-NL |
| ClinicalTrials.gov | NCT03018730 |
| CCMO | NL60570.018.17 |