Pegunigalsidase Alfa (Elfabrio)

Pegunigalsidase alfa is a third distinct enzyme-replacement drug for Fabry disease, approved by the FDA in 2023 after being grown not in animal or human cells like every other enzyme on this site, but in genetically engineered plant-cell culture, then chemically PEGylated to extend how long it circulates in the bloodstream. Its own pivotal trial didn't compare it against placebo — Fabry disease already had two approved enzymes by the time it entered testing — but head-to-head against the first one, agalsidase beta, in patients whose kidney function was still declining despite years on that older drug. A 2021 rejection over an unrelated factory inspection delayed approval by two years, and a fight over a more convenient dosing schedule was still unresolved in Europe as this page was reviewed.

A third Fabry enzyme, grown in plant cells instead of animal cells

This site's agalsidase beta page describes Fabry disease — a rare, X-linked disorder in which deficient alpha-galactosidase A activity lets a fatty molecule, globotriaosylceramide (GL-3), build up in blood vessels throughout the body — and Fabrazyme's 2003 approval as the first US treatment for it, followed by the oral chaperone migalastat (Galafold) in 2018. Pegunigalsidase alfa, developed by the Israeli biotech Protalix BioTherapeutics under the internal name PRX-102 and commercialized with Chiesi Global Rare Diseases as Elfabrio, became a third distinct FDA-approved option on 9 May 2023 (BLA 761161). What sets it apart isn't just being a later entrant: Protalix manufactures it using ProCellEx, a proprietary plant-cell expression system grown in cultured carrot cells, the same underlying platform behind taliglucerase alfa (Elelyso), a Gaucher disease enzyme this site's velaglucerase & taliglucerase page covers as the first plant-cell-expressed drug the FDA ever approved. Pegunigalsidase alfa goes a step further than taliglucerase by also being covalently bound to polyethylene glycol (PEGylated) — a chemical modification, unrelated to the plant-cell platform itself, that shields the enzyme from rapid clearance and extends its initial circulating half-life to roughly 80 hours, several times longer than an unmodified enzyme like Fabrazyme.

BALANCE: a head-to-head trial against agalsidase beta, not placebo

Because two Fabry enzymes already had FDA approval by the time pegunigalsidase alfa reached late-stage testing, its pivotal trial could no longer ethically withhold treatment behind a placebo the way Fabrazyme's 2001 trial did. Instead, the phase 3 BALANCE trial enrolled 77 adults with Fabry disease whose kidney function (estimated glomerular filtration rate, or eGFR) was already declining faster than a pre-specified threshold despite having been treated with agalsidase beta for at least a year — a population chosen specifically because their existing therapy wasn't fully controlling their disease. Patients were randomized 2:1 to switch to pegunigalsidase alfa (52 patients) or continue agalsidase beta (25 patients), both at 1 mg/kg every two weeks, for two years. The primary endpoint was the annualized rate of eGFR decline: the difference between the two groups was -0.36 mL/min/1.73m² per year, and the trial met its pre-specified non-inferiority margin, meaning pegunigalsidase alfa slowed kidney-function decline at least as well as continuing agalsidase beta rather than proving it worked better (Wallace EL, et al., "Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study," J Med Genet 2024;61(6):520-530, DOI: 10.1136/jmg-2023-109445).¹ Pegunigalsidase alfa also produced fewer treatment-emergent adverse events and fewer mild-to-moderate infusion-related reactions than agalsidase beta over the two years — a real, if modest, tolerability advantage rather than a superior effect on the kidney-function measure the trial was actually powered to detect.

Two companion trials rounded out the approval package: BRIDGE, a smaller open-label study switching patients from agalsidase alfa (the version never approved in the US) to pegunigalsidase alfa, in which mean annualized eGFR decline improved from -5.90 to -1.19 mL/min/1.73m² per year after the switch; and BRIGHT, an open-label study testing a less frequent, 2 mg/kg every-four-weeks dosing schedule in patients already stable on a biweekly enzyme, described further below.

A 2021 rejection over a factory inspection, not the data

Protalix and Chiesi first submitted the BLA for pegunigalsidase alfa with a PDUFA target action date of 27 January 2021, but on 28 April 2021 the FDA issued a Complete Response Letter declining to approve it at that time. The letter did not raise any concern about the drug's safety or efficacy data; it stated instead that the FDA needed to complete an on-site inspection of Protalix's manufacturing facility in Carmiel, Israel before it could approve the application, and that COVID-19 travel restrictions had prevented that inspection from happening during the review cycle — the same category of pandemic-era inspection delay that separately held up cipaglucosidase alfa's approval by roughly a year around the same period. Once travel restrictions eased enough for FDA inspectors to complete the required visit, and after Protalix and Chiesi resubmitted the application with the completed BALANCE, BRIDGE and BRIGHT trial data, the FDA approved Elfabrio on 9 May 2023 — a real, clinically-supported drug held back for two years by a factory visit that pandemic travel rules made impossible to schedule, not by any problem with the enzyme itself.

A 2026 fight over less-frequent dosing, so far only in Europe

The BRIGHT trial tested whether patients already stable on a biweekly enzyme could switch to a less frequent, higher-dose regimen — 2 mg/kg of pegunigalsidase alfa once every four weeks instead of 1 mg/kg every two weeks — a real convenience question for a chronic infused therapy, not a change to the underlying drug. Protalix and Chiesi sought that additional dosing option from the European Medicines Agency, but its Committee for Medicinal Products for Human Use (CHMP) issued a negative opinion on the every-four-weeks schedule; the companies formally sought re-examination of that decision in November 2025, the CHMP reversed course with a positive opinion on 30 January 2026, and the European Commission granted final approval for the every-four-weeks regimen on 9 March 2026, with the UK's MHRA separately approving the same additional schedule that May. As of this review, that less-frequent dosing option remains an EU and UK approval only; the FDA-approved US label continues to specify the original 1 mg/kg every-two-weeks regimen.

Current status

Elfabrio remains FDA-approved and currently marketed in the US by Chiesi Global Rare Diseases, manufactured by Protalix, for adults with confirmed Fabry disease — it carries a boxed warning for hypersensitivity reactions including anaphylaxis, consistent with every infused enzyme-replacement drug on this site, with roughly 14% of clinical-trial patients experiencing a hypersensitivity reaction and 3% experiencing anaphylaxis. Fabry disease patients now have three distinct FDA-approved treatment options (the infused enzymes Fabrazyme and Elfabrio, plus — for patients with a genetically amenable mutation — the oral chaperone Galafold), a genuinely more competitive landscape than existed when Fabrazyme was the only approved treatment through the 2009-2012 shortage described on this site's agalsidase beta page. Protalix's own financial disclosures through 2025 and early 2026 show Elfabrio's underlying product-sales growth moderating to roughly flat once one-time regulatory milestone payments (including a reported $25 million tied to the every-four-weeks EU approval) are excluded, with analysts attributing at least part of that slowdown to competition from the oral migalastat alternative in patients whose mutation qualifies for it — a real commercial headwind for an infused enzyme competing against a once-daily pill in that subset of patients.