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. 2025 Jan;39(1):153-165.
doi: 10.1007/s40259-024-00690-1. Epub 2024 Nov 30.

Relevance of Neutralizing Antibodies for the Pharmacokinetics of Pegunigalsidase Alfa in Patients with Fabry Disease

Malte Lenders  1 , Elise Raphaela Menke  2 , Michael Rudnicki  3 , Markus Cybulla  4 , Eva Brand  2
Affiliations

Relevance of Neutralizing Antibodies for the Pharmacokinetics of Pegunigalsidase Alfa in Patients with Fabry Disease

Malte Lenders et al. BioDrugs. 2025 Jan.

Abstract

Background: Pegunigalsidase alfa is a newly approved drug for the treatment of Fabry disease, designed to increase the plasma half-life and reduce immunogenicity of infused α-galactosidase A (AGAL). We provide the first comprehensive pharmacokinetic and immunogenic data apart from industry-initiated studies.

Methods: Pharmacokinetics of pegunigalsidase alfa, amino acid, and polyethylene glycol (PEG)-specific antibodies and immune complexes were measured in treated patients (11 switched, two naïve). Measurements were performed in serum samples drawn directly before and after infusions over three to ten consecutive infusions. Only three patients started directly with 1.0 mg/kg body weight.

Results: No infusion-associated reactions were reported under pegunigalsidase alfa during the observation. Patients without pre-existing neutralizing anti-AGAL antibodies showed high enzymatic AGAL peak activities and sustained AGAL serum concentrations until the next infusion, which was not observed in those with neutralizing anti-AGAL antibodies. Nine (69.2%) patients presented with pre-existing anti-PEG antibodies (IgG or IgM), which seemed to have no impact on pharmacokinetics during the observation. No new anti-PEG or anti-AGAL antibody formation was observed after treatment initiation. Three (75.0%) patients with pre-existing neutralizing anti-AGAL antibodies showed a titer increase and one (25.0%) patient a decrease. In patients with anti-AGAL antibodies (n = 4) immune-complex formation was detected.

Conclusion: The pharmacokinetics of pegunigalsidase alfa show different profiles depending on the presence of pre-existing neutralizing antibodies, with reduced plasma half-life and peak enzyme activity after infusion in patients with antibodies. The clinical significance of a reduced pegunigalsidase alfa half-life and the formation of immune complexes in antibody-positive patients needs to be analyzed in future studies.

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Conflict of interest statement

Declarations. Funding: Open Access funding enabled and organized by Projekt DEAL. This study received funding from Chiesi GmbH, Germany (investigator initiated non-interventional studies: DJUS21002971, DJUS13008931, DJUS13011311). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of the article, or the decision to submit it for publication. Conflict of interest: ML received research/travel grants and/or speaker honoraria from Amicus Therapeutics, Sanofi, Chiesi, Sumitomo Pharma, and Takeda. EB received research grants and/or speaker honoraria from Amicus Therapeutics, Sanofi, Chiesi, Takeda, and Eleva. MR received speaker honoraria, congress support, and research grants from Sanofi, Chiesi, and Amicus Therapeutics. MC received speaker honoraria/travel grants from Takeda, Amicus Therapeutics, Idorsia, and Alexion. ERM has nothing to declare. Availability of data and material: The original contributions presented in the study are included in the article and Online Resources; further inquiries can be directed to the corresponding author. Ethics approval: All investigations were performed after approval by the Medical Association of Westphalian-Lippe and the Ethics Committee of the Medical Faculty of the University of Muenster (project no. 2011-347-f, date of report: 7 July 2011) and in accordance with the Declaration of Helsinki. Consent for publication: Written informed consent was obtained from all included patients for analysis and publication. Code availability: Not applicable Authors’ contribution: All authors have contributed to the article by participating in the conception and design (ML), acquisition of data (ML, ERM, MR, MC, EB) or formal analysis (ML, ERM) and interpretation of data (ML, EB), drafting the article (ML, EB) or revising it critically for important intellectual content (ERM, MR, MC). All authors read and approved the final version of the manuscript.

Figures

Fig. 1
Fig. 1
Individual pegunigalsidase alfa serum profiles after infusion over time and anti-PEG antibody detection in patients without neutralizing anti-drug antibodies. A–C Male patients (P1 to P3), D–I female patients (P4 to P9). Blood samples were drawn immediately before and after the infusions to allow monitoring α-galactosidase A (AGAL) activities between consecutive visits. Individual total amounts of infused enzyme during visits are provided within brackets. F Patient missed one infusion (V2), which allowed us to measure the residual AGAL activity 28 days after the first infusion (V1). The dotted black lines highlight the upper limit of normal AGAL activity in serum at 10.8 ng/ml serum
Fig. 2
Fig. 2
Individual pegunigalsidase alfa serum profiles after infusion over time and anti-PEG antibody detection in patients with pre-existing neutralizing anti-drug antibodies. A–D Male patients (P10 to P13). Blood samples were drawn immediately before and after the infusions allows monitoring α-galactosidase A (AGAL) activities between consecutive visits. Individual total amounts of infused enzyme during visits are provided within brackets. Anti-AGAL antibodies are measured by ELISAs (µg/ml) against agalsidase beta and pegunigalsidase alfa. Inhibition assays, providing the neutralizing antibodies total inhibitory capacities (mg), were measured against pegunigalsidase alfa. The dotted black lines highlight the upper limit of normal AGAL activity in serum at 10.8 ng/ml serum
Fig. 3
Fig. 3
Individual and overall pegunigalsidase alfa plasma peak activities. A Individual peak α-galactosidase A (AGAL) activities directly measured after infusions in dependence of the total infused amount of pegunigalsidase alfa. Black-labeled patients are negative for neutralizing anti-AGAL antibodies. Red-labeled patients are positive for neutralizing anti-AGAL antibodies. B Individual remaining AGAL activities directly measured before the next infusions in dependence of the total infused amount of pegunigalsidase alfa. Only patients negative for neutralizing anti-AGAL antibodies are shown, since residual activities in patients with neutralizing anti-AGAL antibodies were not detectable. C Overall peak activities after and directly before the next infusion in patients treated with pegunigalsidase alfa or directly after the infusions with agalsidase alfa or beta. The dotted black lines highlight the upper limit of normal AGAL activity in serum at 10.8 ng/ml serum
Fig. 4
Fig. 4
Comparison of area under the curve values dependent on the total amount of infused α-galactosidase A (AGAL). ADA neutralizing anti-AGAL anti-drug antibody neutralizing anti-AGAL
Fig. 5
Fig. 5
Immune complex detection in serum samples from patients with pre-existing neutralizing anti- α-galactosidase A (AGAL) antibodies. Serum samples were drawn immediately before infusions
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