A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies

Abstract

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.

Keywords: Fabry disease; eGFR; enzyme replacement therapy; lysosomal storage disorders; lyso‐Gb3; pegunigalsidase alfa.

FIGURE 1

Patient disposition. *One male patient who received the first infusion of pegunigalsidase alfa 2 mg/kg at baseline withdrew consent after this visit. Another male patient who completed the trial showed deterioration of kidney function, and after receiving a total of 10 infusions of pegunigalsidase alfa 2 mg/kg E4W, the patient's treatment regimen was modified to pegunigalsidase alfa 1 mg/kg E2W at Week 40, with 7 subsequent administrations. E2W, every 2 weeks; E4W, every 4 weeks.

FIGURE 2

Anti‐drug antibody status in individual patients and overall safety population over 52 weeks. *One patient who was ADA‐positive at baseline withdrew consent after the first infusion, therefore no ADA data were available for this patient post pegunigalsidase alfa treatment. ^†The sampling at Week 4 was added as a protocol amendment and therefore was not taken from all patients. ADA, anti‐drug antibody.

FIGURE 3

eGFR profiles over 52 weeks (A) in male and female patients (median [IQR]), (B) stratified by baseline kidney function (eGFR >120 mL/min/1.73 m² vs. ≤120 mL/min/1.73 m²; median [IQR]), and (C) in individual patients according to ADA status at baseline (efficacy population). ADA, anti‐drug antibody; eGFR, estimated glomerular filtration rate; IQR, interquartile range.

FIGURE 4

Plasma lyso‐Gb3 concentrations over 52 weeks (A) stratified by sex (median [IQR]) and (B) in individual male patients according to ADA status at baseline (efficacy population). ADA, anti‐drug antibody; lyso‐Gb3, globotriaosylsphingosine; IQR, interquartile range.

FIGURE 5

Mean plasma concentration–time profiles of pegunigalsidase alfa (2 mg/kg) administered E4W: Semi‐log scale (PK population*). *The number of patients with available data varied at each time point (minimum n = 9). ^†Prior to dosing of the first infusion, all but one patient had pegunigalsidase alfa concentration values lower than the LLoQ (set as “0” for the analysis). Due to unknown reasons, one patient had a detectable value of 191 ng/mL. Therefore, the calculated mean concentration value of the pre‐dose time point at baseline was below the LLoQ (0.02 μg/mL). ^‡Pre‐dose sampling. At Weeks 24, 40, and 52, most patients had residual measurable plasma levels of pegunigalsidase alfa at the time of pre‐dose sampling due to the long half‐life of the drug (Table S8). E4W, every 4 weeks; LLoQ, lower limit of quantification; PK, pharmacokinetics; SE, standard error.