Fabry disease is a rare X-linked, lysosomal storage disorder that can cause renal failure or stroke.
On May 10, 2023, the FDA approved pegunigalsidase alfa-iwxj (Elfabrio; Chiesi Global Rare Diseases and Protalix Biotherapeutics) in the United States for the treatment of adults with Fabry disease.1 Pegunigalsidase alfa- iwxj is a recombinant human α-Galactosidase-A (α-Gal-A) enzyme expressed in plant cell culture, designed to be a pegylated enzyme replacement therapy. Pegunigalsidase alfa- iwxj was produced with plant cell–based platform technology (ProCellEx; Protalix Biotherapeutics) to offer a long half-life. It is delivered via intravenous infusion, supplying a functional version of α-Gal-A directly into a patient’s bloodstream.
In 2021, the FDA rejected an accelerated approval request for pegunigalsidase alfa-iwxj (named PRX-102 at that time).2 The rejection was due to issues with the manufacturing process and facility inspections. There were no issues concerning the safety or efficacy of PRX-102. In 2022, a second biologics license application for pegunigalsidase alfa-iwxj was submitted. This major US submission came shortly after an approval by the European Commission. The US approval of pegunigalsidase alfa-iwxj was largely based on results from phase 3 trials BALANCE (NCT02795676), BRIDGE (NCT03018730), and BRIGHT (NCT03180840), and a phase 1/2 trial.3 Pegunigalsidase alfa-iwx’s safety, tolerability, and efficacy have been studied in more than 140 patients with up to 7.5 years of follow-up treatment.
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Overview of Fabry Disease
Fabry disease is an X-linked disorder that occurs in both females and males and is caused by a mutation in a-GLA, leading to a deficient or absent α-Gal-A enzyme.4 Fabry disease is a rare disorder with a global prevalence estimated to range from 1 in 40,000 to 1 in 170,000 individuals.5 The clinical manifestations of Fabry disease include abdominal symptoms, pain, renal failure, and increased risk of stroke.4 Fabry disease is classified as either classic, occurring in childhood, or later onset, with symptoms presenting in adulthood. Treatment options for Fabry disease in the US include enzyme replacement therapy agalsidase beta (Fabrazyme; Sanofi Genzyme ) and the chaperone therapy migalastat (Galafold; Amicus Therapeutics), as well as adjunctive therapies to manage the complications associated with the disease.6
Efficacy
BRIDGE Trial
In the phase 3 BRIDGE trial, 22 patients aged 24 to 60 years were enrolled in an open-label, single-arm study to assess the safety and efficacy of pegunigalsidase alfa-iwx. Participants with Fabry disease were required to have been treated with agalsidase alfa for 2 years prior to switching to pegunigalsidase alfa-iwxj.3 The 20 patients who completed the study demonstrated an improvement in mean annualized eGFR slope, which increased from –5.9 mL/min/1.73 min2/year to –1.19 mL/min/1.73 min2/year.
BRIGHT Trial
The phase 3 BRIGHT study was an open-label switchover study that included 30 patients who were previously treated with either agalsidase beta or agalsidase alfa for 3 years prior to study entry. Following 52 weeks of treatment with pegunigalsidase alfa-iwx, participants had a mean decrease in eGFR of –1.27 mL/min/1.73 min2.
BALANCE Trial
In the phase 3, double-blind, active-controlled BALANCE trial, investigators enrolled 77 adults who were previously treated with enzyme replacement therapy.7 To qualify for the study, patients must have been treated with agalsidase beta for a minimum of 1 year prior to trial entry. Patients were randomly assigned 2:1 to receive either pegunigalsidase alfa-iwxj at 1 mg/kg or agalsidase beta every 2 weeks for 104 weeks. Fifty-two participants were randomly assigned to receive pegunigalsidase alfa-iwx, and 25 were randomly assigned to receive agalsidase beta. Sixty-one percent were men. The median baseline estimated glomerular filtration rate (eGFR) was 75 mL/min/1.73 min2. The annualized rate of change in eGFR (eGFR slope) was the primary efficacy end point of this trial. At the conclusion of 104 weeks, patients who received pegunigalsidase alfa-iwxj had a mean eGFR slope of –2.4 mL/min/1.73 min2/year; patients who received agalsidase beta had a mean eGFR slope of –2.3 mL/min/1.73 min2/year.
Morgan Loh, PharmD, is adjunct faculty at the Massachusetts College of Pharmacy and Health Science in Boston and a global regulatory affairs postdoctoral fellow at Alexion Pharmaceuticals, Inc.
Julia Settler, PharmD, MBA, is a first-year global medical communications–global medical affairs fellow at Alexion Pharmaceuticals, Inc.
Safety
Pegunigalsidase alfa-iwx’s label displays a warning for hypersensitivity reactions, including anaphylaxis. According to the prescribing information, in clinical trials, 14% of patients treated with pegunigalsidase alfa-iwxj had hypersensitivity reactions, with 3% who experienced anaphylaxis in the initial infusion and were positive for anti–pegunigalsidase alfa-iwxj IgE antidrug antibodies (ADA).7 This hypersensitivity risk may be higher in some patients with preexisting ADA from prior enzyme replacement therapies. Anaphylaxis was reported as a type 1 hypersensitivity reaction occurring within 5 to 40 minutes of infusion initiation. Signs and symptoms of a hypersensitivity reaction were headache, nausea, vomiting, throat tightness, facial and oral edema, truncal rash, tachycardia, hypotension, rigors urticaria, intense pruritus, moderate upper airway obstructions, macroglossia, and mild lip edema. Treatment given included administration of epinephrine, antihistamines, and/or systemic corticosteroids. Prior to administration of pegunigalsidase alfa-iwx, premedication with antihistamines, antipyretics, and/or corticosteroids should be considered.7
Other warnings and precautions on the label include infusion-associated reactions (IARs) and membranoproliferative glomerulonephritis. Monitoring for clinical or pharmacodynamic responses should be considered, especially in patients who demonstrate hypersensitivity reactions during treatment with pegunigalsidase alfa-iwxj or with preexisting ADA. According to the prescribing information, if a mild to moderate hypersensitivity reaction or a mild to moderate IAR occurs, holding the infusion for 15 to 30 minutes or slowing the infusion rate by 25% to 50% should be considered.7 If symptoms continue, stop the infusion and proceed with monitoring the patient. Reinitiation of the infusion could be considered within 7 to 14 days at 25% to 50% of the rate at which the reaction occurred, with the appropriate premedication. If symptoms alleviate after holding, the infusion can be resumed at a 25% to 50% reduced rate, as tolerated. At the next infusion, the infusion rate should be increased in increments of 25% every third infusion as tolerated until the initial rate at which the reaction occurred is reached. The patient should be closely monitored for the entire administration.7
The most common adverse reactions reported with pegunigalsidase alfa-iwxj were infusion-associated reactions (32%), nasopharyngitis (21%), headache (21%), diarrhea (19%), fatigue and nausea (17%), back pain (15%), pain in extremity (15%), and sinusitis (15%).7
Cost
The estimated annual cost of pegunigalsidase alfa-iwxj for an adult patient is approximately $430,000, supplied in a single-dose vial at 1 mg/kg via intravenous infusion every 2 weeks.8 Chiesi offers prescription co-pay and infusion assistance co-pay programs.9 These programs help alleviate costs by allowing patients to pay as little as $0 for the medication and/or infusion administration. According to a Chiesi Total Care fact sheet, to be eligible, patients must have commercial insurance, have a valid prescription, be enrolled in Chiesi Total Care, and be a resident of the United States or one of its territories.9
Conclusion
Pegunigalsidase alfa-iwxj offers a potential long-lasting therapy to individuals with Fabry disease, a multisystemic lysosomal storage disorder that mainly affects the kidneys, heart, and nervous system.
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