Enzyme replacement therapies (ERTs) approved for Fabry disease require infusions every 2 weeks (E2W). Pegunigalsidase alfa, a PEGylated ERT with a prolonged half-life vs. other ERTs, may allow extension of the dosing interval to every 4 weeks (E4W). BRIGHT F51 (NCT03614234) is an ongoing phase III, open-label extension study evaluating long-term efficacy and safety of pegunigalsidase alfa 2 mg/kg E4W in adults with Fabry disease previously treated with agalsidase alfa or beta E2W for ≥ 3 years who completed one year of pegunigalsidase alfa treatment in the BRIGHT study. This interim analysis reports results following 3–5 years of treatment (cutoff date December 31, 2022). Twenty-nine patients were enrolled. Median (interquartile range [IQR]) annualized eGFR slope during treatment was ‒2.2 (‒2.9; ‒1.1) mL/min/1.73 m2/year (males: ‒2.4 [‒2.9; ‒1.0, n = 23]; females: ‒1.8 [‒2.4; ‒1.3, n = 6]; anti-drug antibody [ADA]-positive: ‒2.6 [‒4.0; ‒1.7, n = 9 all male]; ADA-negative: ‒1.8 [‒2.7; ‒0.6, n = 20]). Median (IQR) change in plasma lyso-Gb3 from baseline to Week 208 was 3.2 (‒3.9; 8.5, n = 17) nM in males; concentrations remained low and stable in females. Overall, 51/477 treatment-emergent adverse events in 13 patients (45

Introduction Le pegunigalsidase alfa (PA) est un traitement enzymatique substitutif (TES) à base d’α-galactosidase-A PEGylée approuvé pour les adultes atteints de la maladie de Fabry (MF) aux États-Unis et en Europe. Les TES peuvent provoquer des réactions liées à la perfusion (RLP) qui se produisent plus fréquemment à des doses plus élevées. Les TES peuvent provoquer des RLPs qui se produisent plus fréquemment à des doses plus élevées. Nous présentons des analyses intégrées de 7 essais cliniques/extensions de l’incidence des réactions liées à la perfusion survenant entre le début de la perfusion et 2heures (RLP-2H) et 24heures après la perfusion (RLP-24H ; inclut RLP-2H) avec 2 doses de PA (1mg/kg toutes les deux semaines ; 2mg/kg toutes les 4 semaines). Résultats Sur 141 adultes (94M :47F), 111 ont reçu 1mg/kg de PA toutes les deux semaines et 30 ont reçu 2mg/kg de PA toutes les 4 semaines. Parmi les patients recevant 1mg/kg, 26/111 (23,4 %, 52 événements) et 32/111 (28,8 %, 71 événements) ont présenté des RLP-2H et des RLP-24H, respectivement ; parmi ceux recevant 2mg/kg, 6/30 (20,0 %, 38 événements) ont présenté des RLP-2H et des RLP-24H. Quelle que soit la dose, 90/109 (82,6 %) des RLP sont survenus jusqu’à 2heures après la perfusion et étaient plus fréquents chez les hommes (27/94 [28,7 %] RLP-2H et 31/94 [33,0 %] RLP-24H) que chez les femmes (5/47 [10,6 %] RLP-2H et 7/47 [14,9 %] RLP-24H).Les patients initialement positifs aux anticorps anti-médicaments (AAM+) (36M :1F ; 15/37 [40,5 %] RLP-2H et 18/37 [48,6 %] RLP-24H) présentaient une fréquence d’RLP plus élevée que les patients AAM- (58M :46F ; 9/83 [10,8 %] RLP- 2H et 12/83 [14,5 %] RLP-24H). Les RLP se sont surtout produits au cours de la première année de traitement. L’utilisation de la prémédication de base, telle que prescrite pour une TES antérieure, a diminué au fil du temps (base : 26/94 [27,7 %] 1mg/kg et 8/30 [26,7 %] 2mg/kg ;>24 à ≤30 mois : 6/59 [10,2 %] 1mg/kg et 4/29 [13,8 %] 2mg/kg). Quatre RLP sévères et graves conduisant à l’arrêt du traitement sont survenus chez 4 patients (hypersensibilité de type I [n=2 ; IgG- au départ], hypersensibilité [n=1 ; IgG+ au départ] et bronchospasme [n=1 ; IgG- au départ]), aucun n’ayant conduit au décès. Conclusion Moins d’un tiers des patients recevant de le PA ont présenté des RLP, sans que l’incidence des RLP n’augmente avec la dose. Les RLP étaient plus fréquents chez les hommes et les patients AAM+ au départ, quelle que soit la dose.

Introduction Le pegunigalsidase alfa (PA) est un traitement enzymatique substitutif (TES) à base d’α-galactosidase-A PEGylée approuvé pour les adultes atteints de la maladie de Fabry (MF) aux États-Unis et en Europe. Le PA a été étudié dans 7 essais cliniques/extensions incluant des patients atteints de la maladie de Fabry n’ayant jamais reçu de traitement enzymatique substitutif ou ayant déjà reçu un traitement enzymatique substitutif (TES-switch). La PEGylation de le PA pourrait masquer des épitopes, ce qui pourrait réduire l’incidence des réactions liées à la perfusion en modulant l’immunogénicité de le PA. Cette analyse des données regroupées des essais fournit des détails sur la survenue de réactions liées à la perfusion (RLP) chez les patients ayant subi un changement de TES et chez les patients naïfs de TES à qui l’on a administré 1mg/kg de AP toutes les deux semaines. Les effets indésirables survenus entre le moment de la perfusion et 2heures après la perfusion (RLP-2H) et jusqu’à 24heures après la perfusion (RLP-24H ; RLP-24H inclut RLP-2H) sont décrits. Résultats Cette analyse a porté sur 111 adultes (70M :41F ; âge moyen : 43,4ans) ; parmi eux, 94 sont passés de l’agalsidase alfa (n=22, 19,8 %) ou de l’agalsidase bêta (n=72, 64,9 %) et 17 (15,3 %) n’avaient jamais reçu de TES. Chez les patients ayant changé de traitement, des cas de RLP-2H et de RLP-24H sont survenus chez 22/94 (23,4 % [35 événements ; taux (pour 100 perfusions)=0,6]) et 28/94 (29,8 % [51 événements ; taux=0,8]) patients, respectivement ; chez les patients naïfs de traitement, des cas de RLP-2H et de RLP-24H sont survenus chez 4/17 (23,5 % [17 événements ; taux=1,5]) et 4/17 (23,5 % [20 événements ; taux=1,8]) patients, respectivement. La plupart des événements étaient de gravité légère/modérée, quelle que soit l’expérience antérieure de le TES (changement de TES : 47/51 [92,2 %] ; naïfs de TES : 19/20 [95,0 %]). Quatre effets indésirables graves ayant entraîné l’arrêt du traitement ont été signalés chez quatre patients (hypersensibilité de type I [n=2], hypersensibilité [n=1] et bronchospasme [n=1]), qui ont tous été résolus. La plupart des effets indésirables sont survenus au cours de la première année de traitement (changement de traitement : 40/51 [78,4 %] ; patients naïfs de traitement : 19/20 [95,0 %]). Conclusion Cette analyse a montré des RLP chez moins d’un tiers des patients atteints de MF naïfs de TES ou ayant changé de TES et traités par PA 1mg/kg. La plupart des RLP étaient de sévérité légère/modérée et se sont produites dans les 2heures suivant l’administration de le PA. Comme avec d’autres TES, les RLP ont été observées principalement au cours de la première année suivant l’instauration de le PA.

Background Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than −2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. Methods Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. Results Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18–60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was −7.3 (−30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was −0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. Conclusions Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. Trial registration number NCT02795676.

Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.

The specific features of the microstructure of multicomponent solid solutions, based on relaxor ferroelectrics both unmodified and modified by barium, were observed. A reduction of tetragonal distortion in the unit cell in ceramics containing Ba, as well as an increase in the size of its crystallites (which is a consequence of this reduction), facilitates domain reorientation owing to an increase in their mobility. This is the main reason for the sharp increase in the relative permittivity εT33/ε0 of the poled samples of modified ceramics, and the variations of some parameters that characterize the piezoelectric response.

PURPOSE:Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. METHODS:In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. RESULTS:Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. CONCLUSION:In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD.

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 m 2 and plasma lyso-Gb 3 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 m 2 /year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m 2 /year; and mean plasma lyso-Gb 3 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 m 2 /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.

Chimeric antigen receptor T (CAR-T)-cell, an adaptive immune therapy is approved for patients with acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Its use and subsequent toxicities are expected to rise in the coming years. The main toxicities are cytokine release syndrome, hemophagocytic lymphohistiocytosis and immune effector cell associated neurotoxicity syndrome. Cytokine release syndrome is observed in up to 40% of patients. Almost 20% of patient suffer from acute kidney injury after CAR-T cell infusion. Associated factors are high-grade cytokine release syndrome, a prior autologous or allogeneic stem cell transplantation andrequirement of intensive care unit. Several mechanisms may contribute to the occurrence of acute kidney injury after CAR-T infusion: hypoperfusion during cytokine release syndrome, cytokine injury, T cell infiltration, tumor lysis syndrome and sepsis-induced injury. Kidney injury is associated with substantial increase in morbi-mortality.