On the heels of the marketing OK in Europe, Protalix Biotherapeutics Inc. and the Chiesi Group’s global rare diseases unit scored approval of Elfabrio (pegunigalsidase alfa-iwxj) from the U.S. FDA for adults with Fabry disease.

A modified stabilized version of the recombinant human alpha-galactosidase A (alpha-gal-A) protein, the enzyme replacement therapy (ERT) Elfabrio was previously known as PRX-102. U.S. regulators’ green light was based on tests of safety, tolerability, and efficacy in a clinical program that involved more than 140 patients with up to 7.5 years of follow-up treatment. Enrolled were ERT-naïve as well as ERT-experienced patients.

Fabry disease is an X-linked, inherited condition that results from deficient activity of the lysosomal alpha-gal-A enzyme, which leads to buildup of globotriaosylceramide in the lysosomes. The affliction occurs in one person per 40,000 to 60,000. Symptoms range from episodes of pain and impaired peripheral sensation to organ failure.

Clinical efforts with Elfabrio included a head-to-head trial that met its primary endpoint, with Elfabrio turning up non-inferior efficacy to Fabrazyme (agalsidase beta, Sanofi SA) in controlling estimated glomerular filtration rate (eGFR) decline. Elfabrio proved generally well-tolerated, too, with the majority of adverse events mild or moderate in severity. Another competitor in the Fabry space is Galafold (migalastat, Amicus Therapeutics Inc.), an alpha-gal-A pharmacological chaperone that gained FDA clearance in August 2018. Elfabrio’s label carries a warning about hypersensitivity reactions, including anaphylaxis. “Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during Elfabrio administration,” gatekeepers said.

Elfabrio’s path has not been without hitches, albeit mild. In late April 2021, the FDA smacked Protalix with a complete response letter (CRL) regarding the BLA seeking accelerated approval. The CRL reported no concerns relating to the potential safety or efficacy in the data package, but noted that an inspection of Protalix's manufacturing facility in Carmiel, Israel, was required, and the agency could not get around to such a look-see during the review cycle.

By April of last year, the Protalix situation had improved dramatically, with phase III results in hand from the Fabry disease study called Balance. The trial was a 24-month, randomized, double-blind, active control experiment in patients with deteriorating renal function. Enrolled were 78 patients previously given Fabrazyme for at least one year with an eGFR slope at screening worse than -2 mL/min/1.73 m2/year. Subjects were randomized on a 2-to-1 ratio for switching to Elfabrio or continuing on Fabrazyme. A total of 77 patients were treated: 52 with Elfabrio and 25 with Fabrazyme. Results met the predefined criteria for noninferiority of the primary endpoint of kidney function in a head-to-head, active comparison on the intent-to-treat plus the per protocol analysis sets. Combined with previous phase III results from the studies called Bright and Bridge, as well as data from a phase I/II effort and its long-term extension, the company went back to the FDA, which accepted the BLA for Elfabrio in December of last year, setting a PDUFA date of May 9, 2023.

Protalix expanded its tie-up with Parma, Italy-based Chiesi in the summer of 2018, when the parties made known an exclusive license and supply agreement that granted to Chiesi the U.S. rights for development and commercialization of Elfabrio. The previous year, Protalix disclosed the arrangement with Chiesi for development and commercialization outside the U.S. 

In mid-February, the FDA gave its nod to Chiesi’s ERT Lamzede (velmanase alfa-tycv) for non-central nervous system manifestations of alpha-mannosidosis (AM) in adult and pediatric patients. An ultra-rare, progressive lysosomal storage disorder, AM is caused by deficiency in the enzyme alpha-mannosidase. Lamzede is the first ERT to win approval in the indication, characterized by an inability to properly break down certain groups of complex sugars in the body’s cells.

Shares of Protalix (NYSE:PRX) were trading at $2.88, down 4 cents.