FDA Approves Enzyme Replacement Therapy Pegunigalsidase Alfa for Fabry Disease


To date, the enzyme replacement therapy had been studied in a comprehensive clinical development program that comprised more than 140 patients with Fabry disease with up to 7.5 years of follow up treatment.

Giacomo Chiesi, head, Chiesi Global Rare Diseases

Giacomo Chiesi

The FDA has approved pegunigalsidase alfa (Chiesi Global Rare Diseases/Protalix), a pegylated enzyme replacement therapy (ERT), for the treatment of adults with Fabry disease. It will be marketed under the brand name Elfabrio.1

After resubmitting a biologics license application (BLA), the approval was based on data from 3 phase 3 trials: BALANCE (NCT02795676), BRIDGE (NCT03018730), and BRIGHT (NCT03180840), along with a phase 1/2 trial. Altogether, the clinical program comprised of more than 140 individuals with the disease with up to 7.5 years of follow up treatment. Efficacy for the therapy was shown in both ERT-naïve and ERT-experienced patients.

"While much progress has been made in the treatment of Fabry disease, there is still a need for new treatment options,” Giacomo Chiesi, head, Chiesi Global Rare Diseases, said in a statement.1 "We established Chiesi Global Rare Diseases to deliver innovative therapies and solutions for people affected by rare diseases. With the FDA approval of ELFABRIO, we can now offer people living with Fabry disease an alternative treatment option."

Pegunigalsidase alfa is a recombinant human a-galactosidase-A enzyme expressed in plant-cell culture with an initial half-life of 78.9 (±10.3) hours. The safety label of the newly approved therapy states that clinicians should consider pretreating Fabry with antihistamines, antipyretics, and/or corticosteroids before administration. It also notes that patients should immediately discontinue pegunigalsidase alfa if a severe hypersensitivity reaction or severe IAR occurs. If a mild or moderate hypersensitivity reaction or IAR occurs, the label recommends slowing the infusion rate or temporarily withholding the dose.

The BLA was originally accepted and granted priority review in August 202 based on a phase 1/2 trial, which included the related extension study, interim clinical data from the phase 3 BRIDGE switch-over study, and safety data. The FDA subsequently issued a complete response letter requesting an inspection of Protalix’s manufacturing facility but did not report concerns related to the safety and efficacy of the therapy.

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The phase 3 BRIDGE trial was an open-label, single-arm study designed to assess the safety and efficacy of the therapy in adults with Fabry, aged 24 to 60 years, who previously were receiving a stable dose of agalsidase alfa (Replagal; Shire), an approved ERT, for at least 2 years. At the conclusion of the study, patients showed substantial improvement in renal function as measured by mean annualized estimated Glomerular Filtration Rate (eGFR slope) in both male and female patients who were switched from agalsidase alfa to pegunigalsidase alfa.2

Results from BRIDGE showed that the mean annualized eGFR slope of the study participants improved from —5.90 ml/min/1.73m2/year while on agalsidase alfa to —1.19 mL/min/1.73m2/year on pegunigalsidase alfa in all patients. Male patients improved from —6.36 mL/min/1.73m2/year to —1.73 mL/min/1.73m2/year and female patients improved from —5.03 mL/min/1.73m2/year to —0.21 mL/min/1.73m2/year.

The 12-month open-label, switch-over BRIGHT study included 30 patients with Fabry disease previously treated a commercially available ERT such as agalsidase alfa or agalsidase beta for at least 3 years prior and were on a stable dose administered every 2 weeks. After receiving treatment with pegunigalsidase alfa 2 mg/kg every 4 weeks, no patients developed treatment-induced anti-drug antibodies (ADA). No Fabry clinical events were reported during the study either. Plasma lyso-Gb3 concentrations remained stable during the study with a mean change of 3.01 nM from baseline (19.36 nM) to week 52 (22.23 nM). During the 52-week treatment period, mean absolute change of Estimated Glomerular Filtration Rate (eGFR) values remained stable, with a mean change from baseline of –1.27 mL/min/1.73 m2.

"We are extremely pleased to receive FDA approval of ELFABRIO for the treatment of adult patients with Fabry disease," Dror Bashan, president and chief executive officer, Protalix, said in a statement.1 "This approval is a testament to the dedication of the Protalix and Chiesi teams to deliver this much needed new therapeutic option to patients in need. The totality of clinical data suggests that ELFABRIO has the potential to be a long-lasting therapy."

1. Chiesi Global Rare Diseases and Protalix BioTherapeutics announce FDA approval of Elfabrio (pegunigalsidase alfa-iwxj) for the treatment of Fabry disease. News release. Chiesi Global Rare Diseases. May 10, 2023. Accessed May 10, 2023. https://www.prnewswire.com/news-releases/chiesi-global-rare-diseases-and-protalix-biotherapeutics-announce-fda-approval-of-elfabrio-pegunigalsidase-alfa-iwxj-for-the-treatment-of-fabry-disease-301820680.html?tc=eml_cleartime
2. Protalix BioTherapeutics announces positive topline results from the BRIDGE phase 3 open-label, switch-over clinical trial evaluating pegunigalsidase alfa for the treatment of Fabry disease. News release. Carmiel, Israel. Protalix BioTherapeutics. Published May 11, 2020. Accessed May 10, 2023. https://www.biospace.com/article/releases/protalix-biotherapeutics-announces-positive-topline-results-from-the-bridge-phase-iii-open-label-switch-over-clinical-trial-evaluating-pegunigalsidase-alfa-for-the-treatment-of-fabry-disease/
Protalix BioTherapeutics and Chiesi Global Rare Diseases announce positive topline results from BRIGHT phase 3 open-label, switch-over clinical trial evaluating pegunigalsidase alfa 2 mg/kg every 4 weeks for treatment of Fabry disease. News release. Protalix BioTherapeutics. February 23, 2021. Accessed May 10, 2023. https://www.prnewswire.com/il/news-releases/protalix-biotherapeutics-and-chiesi-global-rare-diseases-announce-positive-topline-results-from-bright-phase-iii-open-label-switch-over-clinical-trial-evaluating-pegunigalsidase-alfa-2-mgkg-every-four-weeks-for-treatment-of-fabr-301233318.html
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