In May 2020, the companies filed an application with the U.S. Food and Drug Administration (FDA) seeking the accelerated approval of PRX-102, given at a dose of 1 mg/kg every other week, for the treatment of adults with Fabry.
Accelerated, or conditional, approval is granted to a medication whose immediate availability fulfills an unmet medical need, provided early evidence of its benefits outweigh potential risks. Full approval typically depends on further verification of its clinical benefits in a confirmatory trial.
After granting it priority review, the agency rejected the application in April 2021 due to issues with facility inspections and manufacturing processes, partially caused by travel restrictions during the COVID-19 pandemic. The decision was not associated with concerns related to the therapy’s safety or effectiveness shown in clinical trials.
Protalix and Chiesi have requested a meeting with the FDA to discuss the regulatory path toward PRX-102’s approval in the U.S. The companies plan to file a similar regulatory application with the European Medicines Agency later this year to seek the therapy’s approval in the EU.
How PRX-102 works
People with Fabry disease are unable to make sufficient amounts of alpha-galactosidase A (Gal A), an enzyme responsible for breaking down a fatty molecule called globotriaosylceramide (Gb3). Gal A deficiency leads to the toxic accumulation of Gb3, mainly in blood vessels walls, causing damage to organs such as the kidneys, heart, and blood vessels in the brain.
Made with Protalix’s plant-based ProCellEx platform, PRX-102 delivers a modified version of Gal A directly into the bloodstream (intravenously). This version is meant to be more active and last longer in the body than others.
If successful, it may potentially reduce dosing frequency to once a month relative to currently available ERTs — Sanofi Genzyme’s Fabrazyme (agalsidase beta) and Takeda’s Replagal (agalsidase alpha) — that need to be given every two weeks. All existing ERTs are administered directly into the bloodstream.
PRX-102 in clinical trials
Two-year data from a Phase 1/2 clinical trial (NCT01678898) and its extension study (NCT01981720), involving 11 adults with Fabry disease, showed that 1 mg/kg of PRX-102, given every other week, safely and effectively lowered levels of disease biomarkers, improved kidney function, and slowed disease progression.
These promising, early findings supported the launch of three international Phase 3 clinical trials — BRIDGE (NCT03018730), BALANCE (NCT02795676), and BRIGHT (NCT03180840) — to compare PRX-102 with existing ERTs for Fabry.
The completed, switch-over BRIDGE study tested PRX-102 in 22 adults with Fabry who were previously treated with Replagal for at least two years. Participants continued on Replagal for three months of evaluations before switching to 1 mg/kg of PRX-102, given every two weeks for up to a year.
Final results showed that one year of treatment with PRX-102 was safe, and effectively slowed kidney function decline relative to that seen during Replagal’s use, meeting the trial’s main goal. This also meant that fewer patients showed moderately progressing or fast-progressing kidney disease, with 60% of patients achieving stable disease status.
PRX-102 also was found to lower the levels of lyso-Gb3 — a biomarker of Fabry disease — particularly in men, further supporting the therapy’s potential to lessen disease burden.
The most common moderate adverse events reported with PRX-102 included common cold, headache, and shortness of breath. Four patients (20%) developed persistent antibodies against the delivered Gal A enzyme, which were found to suppress its activity in two of these individuals, rendering the treatment less effective.
The ongoing BALANCE trial is assessing whether PRX-102 works better than Fabrazyme at preventing kidney function decline in 78 adults who were previously treated with Fabrazyme for a year. Fabrazyme was the first ERT approved for Fabry in several countries, including the U.S. and some European nations.
Participants were randomly assigned to either continue on the approved therapy or to switch to PXR-102 (1 mg/kg), both administered twice a month for up to two years.
Interim data showed that PRX-102 was at least as effective as Fabrazyme at slowing kidney disease progression among participants who had completed a minimum of one year of treatment. BALANCE is set to end in May 2022, and final data are expected by June 2022.
In the completed switch-over BRIGHT study (NCT03180840), 30 adults who had been stable on Fabrazyme or Replagal for at least three years were switched to 2 mg/kg of PRX-102, given every four weeks, for up to one year.
Top-line data showed that PRX-102’s once-a-month regimen was well-tolerated and effectively maintained lyso-Gb3 levels, kidney function, and quality of life throughout the study. In addition, 75% of patients reported a reduction or stabilization in pain severity.
Notably, 10 patients (33.3%) were positive for anti-Gal A antibodies at the study’s start, and four of them became negative for such antibodies after switching to PRX-102. No other participant developed antibodies against delivered Gal A after one year of PRX-102 treatment, further supporting the therapy’s favorable safety profile.
Protalix also is sponsoring two open-label extension studies to assess the long-term safety and effectiveness of PRX-102 given with the every-other-week regimen (NCT03566017) and the once-a-month regimen (NCT03614234) in patients who complete PRX-102 trials.
A total of 18 BRIDGE participants and 29 BRIGHT patients entered those extension studies. Patients completing the BALANCE trial also are expected to join. Participants will be followed for up to three or four years or until the therapy becomes commercially available, whichever occurs first.
In October 2020, Protalix and Chiesi launched an expanded access program (NCT04552691) in the U.S. to provide pre-approval access to PRX-102 for people with Fabry disease who, in the opinion of their physician, lack satisfactory treatment options and/or are unable to participate in ongoing clinical trials.
Last updated: Sept. 20, 2021
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