Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa

Lenders, Malte; Pollmann, Solvey; Terlinden, Melina; Brand, Eva

doi:10.1016/j.omtm.2022.07.009

Cited by 15 publications

(14 citation statements)

References 18 publications

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“…Two of these patients, both men, had pre-existing ADAs at baseline with neutralizing activity and remained ADA-positive during pegunigalsidase alfa treatment. The pre-existing ADAs against pegunigalsidase alfa occurred due to cross-reactivity to the enzyme components of the amino acid sequence shared between pegunigalsidase alfa and agalsidase alfa, as agalsidase alfa is not PEGylated nor has plant glycans [ 26 ]. The other 5 developed ADAs transiently (n = 3) or persistently (n = 2), with none having neutralizing enzymatic activity in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Pegunigalsidase alfa is modified with polyethylene glycol (PEG), producing PEGylated protein subunits cross-linked into homodimers. As a result of PEGylation, pegunigalsidase alfa has a plasma half-life of about ~ 80 h compared to ~ ≤ 2 h for other currently available ERTs, and carries the theoretical potential for reduced immunogenicity due to epitope masking as suggested by in vitro studies [ 26 ]. In ERT-naïve patients, pegunigalsidase alfa treatment resulted in decreased Gb3 kidney deposition, decreased plasma lyso-Gb3, and reduced decline of kidney function with benefits sustained for up to 6 years of follow-up [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

Linhart,

Dostálová,

Nicholls

et al. 2023

Orphanet J Rare Dis

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Background Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). Objective/methods BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. Results Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. Conclusion Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

Linhart,

Dostálová,

Nicholls

et al. 2023

Orphanet J Rare Dis

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“…The drug (Elfabrio, Chiesi) was approved by both the EMA and FDA in May 2023 for the treatment of adult Fabry patients (1.0 mg/kg body weight, intravenously every 2 weeks). Preliminary studies on PRX-102 suggested less immunogenicity compared to agalsidase-alfa and agalsidase-beta ( 12 ) and in this respect, we recently demonstrated that pre-existing anti-drug antibodies against agalsidase-alfa and agalsidase-beta showed about 30% less affinity (less inhibitory capacity) for PRX-102 ( 13 ).…”

Section: Introductionmentioning

confidence: 90%

“…Enzyme uptake assays were performed as recently described ( 13 ). In short, AGAL-deficient EA.hy926 cells were seeded on 96-well plates with a density of 2 x 10 5 cells/ml and grown until confluence.…”

Section: Methodsmentioning

confidence: 99%

Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease

Lenders,

Feidicker,

Brand

et al. 2023

Front. Immunol.

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Polyethylene glycol (PEG)ylated drugs are used for medical treatment, since PEGylation either decreases drug clearance or/and shields the protein from undesirable immunogenicity. PEGylation was implemented in a new enzyme replacement therapy for Fabry disease (FD), pegunigalsidase-alfa (PRX-102). However, exposure to PEG via life-style products and vaccination can result in the formation of anti-PEG antibodies. We demonstrate the de novo formation of functional anti-PEG antibodies in a healthy male after the second mRNA-based vaccination against SARS-CoV-2. Consequently, we analyzed the frequency and inhibitory function of anti-PEG and anti-α-Galactosidase A (AGAL) antibodies in 102 FD patients (46.9% males). We identified 29 out of 87 (33.3%) patients with low anti-PEG titers. Sera from patients without anti-AGAL antibodies [n=70] showed a higher rescued AGAL activity of agalsidase-beta and PRX-102 [both p<0.0001] compared to those with anti-AGAL antibodies [n=15]. Sera from anti-AGAL antibody-negative and -positive patients had less inhibitory effects on PRX-102 (rescued activity: 89 ± 6% versus 85 ± 7% and 49 ± 26% versus 25 ± 32%; both p<0.0001). Enzyme stability assays demonstrated that AUCs in anti-AGAL-negative sera (n=20) were 7.6-fold higher for PRX-102, while AUCs of both enzymes in anti-AGAL-positive sera (n=6) were decreased. However, AUC for PRX-102 was 33% of non-anti-AGAL-positive sera treated PRX-102 and 5-fold higher compared to agalsidase-beta. Anti-PEG antibodies had no significant effects on serum half-life of PRX-102, probably due to low titers. Conceivably, therapy efficacy may be superior under next-generation PRX-102 therapy compared to current enzyme replacement therapies in terms of reduced inhibitory effects of anti-AGAL and minor inhibitory effects of anti-PEG antibodies.

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“…Pegunigalsidase alfa (Elfabrio, Chiesi Farmaceutici) ist ein pegyliertes α-Gal-A-Enzym mit deutlich verlängerter Plasmahalbwertszeit und weniger Antigenität, sodass es in geringerem Maß zur Bildung von "anti drug antibodies" (ADA) und zu weniger allergischen Nebenwirkungen kommt [6]. Es konnte gezeigt werden, dass bereits vorhandene ADAs weniger Affinität zu Pegunigalsidase alfa haben [7]. Die Umstellung einer bestehenden Enzymersatztherapie auf Pegunigalsidase alfa war sicher und wurde gut toleriert [8]…”

Section: Second-generation-enzymersatztherapieunclassified

Morbus Fabry

Kurschat

2023

Nephrologie aktuell

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Morbus Fabry ist eine seltene lysosomale Speichererkrankung, die zur Ablagerung von Sphingolipiden in vielen Organen führt und unbehandelt mit einer verkürzten Lebenserwartung verbunden ist. Patient*innen mit M. Fabry haben eine krankheitsverursachende Mutation im GLA-Gen auf dem X-Chromosom, die eine reduzierte oder fehlende Aktivität des Enzyms α-Galaktosidase A (α-Gal A) bedingt. In Europa geht man von einer Prävalenz von ca. 1:40 000 aus. Typische Symptome sind u. a. eine Niereninsuffizienz bis zur Dialysepflichtigkeit, eine LV-Hypertrophie (LV: linksventrikulär) oft ohne Hypertonie, Herz-Rhythmus-Störungen, rezidivierende und/oder frühe Schlaganfälle, brennende Schmerzen an Händen und Füßen, Angiokeratome und Hornhautablagerungen, eine sogenannte Cornea verticillata.

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Pre-existing anti-drug antibodies in Fabry disease show less affinity for pegunigalsidase alfa

Cited by 15 publications

References 18 publications

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease

Morbus Fabry

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