FDA Rejects Quick Approval of PRX-102, Plant-based ERT for Adults

The U.S. Food and Drug Administration (FDA) has rejected Protalix BioTherapeutics and Chiesi Global Rare Diseases’ request for accelerated approval of PRX-102 (pegunigalsidase alfa) as the first plant-based, every-other-week enzyme replacement therapy (ERT) for adults with Fabry disease.

This decision was not related to any concerns with the safety or effectiveness of PRX-102 shown in clinical testing, Protalix stated in an updated press release offering basic details of the FDA’s decision.

Rather, the agency was unable to conduct a required “inspection of Protalix’s manufacturing facility in Carmiel, Israel,” due to travel restrictions in place during the COVID-19 pandemic.

Issues with manufacturing processes likewise were seen at a third-party site in Europe, under a review of records given “in lieu of a pre-licensing inspection.” Details will be sent to that facility directly by the FDA, the release stated.

Also weighing on accelerated approval for PRX-102 was the “recent” conversion of Fabrazyme (agalsidase beta, by Sanofi Genzyme) “to full approval which must be addressed in the context of any potential resubmission seeking accelerated approval of PRX‑102,” the release noted. Both these potential and approved treatments for Fabry advise every-other-week patient dosing at 1 mg/kg.

This may be a reference to the U.S. agency wanting more data from an ongoing Phase 3 trial, called BRIGHT, testing Protalix’s ERT as a once-monthly intravenous infusion formulation. PRX-102’s application did not request its approval in this form.

“While disappointing, we remain confident in the strength of our data and in the depth of our program,” Dror Bashan, Protalix’s president and CEO, said in an earlier press release Wednesday.

“Based on extensive clinical data including results from the Phase 3 BRIDGE clinical trial of PRX-102 for the proposed treatment of Fabry disease, we continue to feel strongly that PRX‑102 is an important option for the treatment of Fabry disease in adult patients, and we are continuing with our efforts to make this therapy available to patients,” said Giacomo Chiesi, Chiesi’s head.

Protalix and Chiesi “are continuing to coordinate closely with the FDA to address and quickly resolve the deficiencies contained in the CRL,” Chiesi said. The companies are requesting type A meetings with U.S. regulators, or meetings “immediately necessary” for advancement of a “stalled drug development program.”

A similar regulatory request is still expected to be filed this year with the European Medicines Agency, which gave the treatment orphan drug designation, Protalix stated in its earlier release.

The FDA decision comes about eight months after the agency accepted and granted priority review to a biologics license application for PRX-102, under its accelerated approval pathway program. This pathway is for medications whose immediate availability fulfills an unmet medical need, provided early evidence supports its benefits. In November, the FDA extended its review date from Jan. 27 to April 27.

PRX-102, infused directly into the bloodstream, was developed by Protalix in collaboration with Chiesi, which under a license agreement will market the treatment globally.

Like other ERTs, PRX-102 delivers a lab-made alpha-galactosidase A — the missing enzyme in Fabry disease — directly into patients’ bloodstream. This helps cells break down the fatty molecule globotriaosylceramide (Gb3), preventing its toxic accumulation in various tissues and organs, including the kidneys, heart, and blood vessels in the brain.

Made with Protalix’s plant-based ProCellEx platform, PRX-102 has been chemically modified to last longer in the body, potentially requiring less frequent dosing than existing ERTs.

It also was seen in trials to lead to fewer neutralizing antibodies, which limit an ERT’s effectiveness, than Fabrazyme — the first ERT developed specifically for Fabry disease, which was given FDA accelerated approval in 2003. As such, PRX-102 may more effectively limit kidney toxicity.

Its regulatory application included a comprehensive set of preclinical, clinical, and manufacturing data to support the therapy’s approval, at a twice monthly dose of 1 mg/kg.

This included safety and efficacy results from three completed trials — a Phase 1/2 trial (NCT01678898), its extension study (NCT01981720), and the BRIDGE Phase 3 study (NCT03018730) — as well as safety findings from PRX‑102 ongoing trials in patients receiving the every-other-week regimen.

The open-label Phase 1/2 trial and its extension showed that PRX-102 remained active in the patients’ blood for up to two years, lowering the levels of disease biomarkers, improving kidney function, and slowing disease progression.

The international and open-label, switch-over BRIDGE study evaluated PRX-102’s safety and effectiveness in 22 adults who had been treated with Takeda’s Replagal (agalsidase alpha) for at least two years, and were on a stable dose for at least six months. Enrolled patients continued on Replagal for three months of evaluations before switching to Protalix’s investigational therapy.

Replagal is an approved ERT for Fabry patients in countries that include those of the European Union, Canada, and the U.K.; it is not approved in the U.S.

Final BRIDGE trial data showed that one year of treatment with PRX-102 safely and effectively slowed the progression of kidney disease relative to that seen with Replagal’s use, with 60% of patients achieving stable disease status. It also lowered the levels of disease biomarkers, especially in men.

Safety data from the BALANCE Phase 3 study (NCT02795676), which is testing PRX-102 in up to 78 patients previously treated with Fabrazyme, were also included. BALANCE is due to conclude in May 2022.

PRX-102’s Phase 3 development program includes one other, fully enrolled Phase 3 trial, BRIGHT (NCT03180840), that is testing the safety, pharmacokinetics, and effectiveness of PRX-102 — at a more convenient dose of 2 mg/kg, given every four weeks for up to one year — in 30 Fabry patients previously treated with a stable dose of a commercially available ERT every other week for at least three years. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body.

BRIGHT’s top-line data showed that a once-a-month regimen was well tolerated and effectively maintained a stable clinical presentation. Levels of biomarkers that included Gb3, kidney function, and quality of life also remained stable throughout the study, while three quarters of patients reported reduction or stabilization in pain severity.

Final data from this trial, due to conclude in December, is expected later this year. An open-label extension study (NCT03614234) that enrolled all 29 patients who completed BRIGHT runs up to January 2023.

Protalix and Chiesi launched an expanded access program (NCT04552691) for the U.S. in October, providing pre-approval access to PRX-102 to patients who, in the opinion of their physician, lack satisfactory treatment options and/or could not participate in ongoing Fabry trials. This program is also ongoing.

Protalix’s share value was reported to have dropped by around 38% in immediate response to the FDA announcement.