EP149: Safety and efficacy of pegunigalsidase alfa, every 4 weeks, in Fabry disease: Results from the phase 3, open-label, BRIGHT study

Abstract

Fabry disease is a rare genetic disorder caused by reduced or absent activity of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to the accumulation of potentially harmful sphingolipids, including globotriaosylceramide (Gb3 and globotriaosylsphingosine [lyso-Gb3]). This glycosphingolipid accumulation leads to organ dysfunction that primarily affects the kidneys, heart, and nervous system. Pegunigalsidase alfa is a novel, PEGylated, α-Gal A enzyme in development for the treatment of Fabry disease, which offers an increased half-life compared with current enzyme replacement therapies (ERTs). The increased stability of pegunigalsidase alfa and its prolonged half-life may allow the interval between infusions to be extended from 2 to 4 weeks, decreasing the treatment burden for patients with Fabry disease. The BRIGHT study (NCT03180840) evaluated the safety, efficacy, and pharmacokinetics of 2 mg/kg pegunigalsidase alfa administered once every 4 weeks to patients with Fabry disease who were being treated with one of the commercially available ERTs every other week. Here, we report the final BRIGHT study safety outcomes, as well as exploratory and efficacy outcomes after 1 year of treatment. The BRIGHT study was a Phase 3, open-label, switchover study of adults (age 18–60 years old) with Fabry disease. Patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 who had received previous ERT (agalsidase alfa or agalsidase beta >80% labelled dose/kg) for ≥3 years were switched to pegunigalsidase alfa (2.0 mg/kg), administered every 4 weeks for 1 year. The safety endpoint included treatment-emergent adverse events (TEAEs), which included treatment-related AEs. Efficacy endpoints such as changes in eGFR and plasma lyso-Gb3 concentration are also reported. This study enrolled 30 adults with a mean age of 40.5 years old, including 24 male and 6 female participants. The safety and pharmacokinetic analyses included all 30 enrolled patients, while the efficacy analysis included 29 patients. One patient withdrew from the study owing to a major traffic accident that was considered unrelated to treatment. Overall, 7 (23.3%) participants received agalsidase alfa and 23 (76.7%) participants received agalsidase beta before switching to pegunigalsidase alfa during the BRIGHT study. No patients developed de-novo antidrug antibodies during the study and there were no new safety signals that emerged from laboratory tests. A total of 183 TEAEs were reported by 27 (90%) patients. Of these TEAEs, 3 were severe and 2 were serious. No severe or serious TEAEs were related to study treatment. A total of 22 infusions caused 27 mild to moderate infusion-related reactions (IRRs), and there were no serious or severe IRRs. According to scheduled reductions, the mean (standard error [SE]) infusion duration decreased from 4.79 (0.11) hours at baseline to 2.27 (0.13) hours at 1 year. In the efficacy analyses (n=29), eGFR values were stable with a mean (SE) change from baseline of −1.27 (1.39) mL/min/1.73m2 at 1 year. Mean (SE) plasma lyso-Gb3 concentrations were stable throughout the study. Patients who completed the study could enroll in an open-label extension study (PB-102-F51 [NCT03614234]). Results from the BRIGHT study show that patients with Fabry disease receiving ERT every other week can be successfully transitioned to pegunigalsidase alfa 2 mg/kg every 4 weeks as an effective maintenance therapy schedule with a positive safety profile.