Introduction:
Enzyme replacement therapy (ERT) infusions for Fabry disease (FD) given every-2-weeks (E2W) can improve disease course. Pegunigalsidase alfa is a PEGylated ERT with increased half-life compared with other ERTs, potentially allowing dosing flexibility (1 mg/kg E2W or 2 mg/kg every-4-weeks [E4W]). The 1-year BRIGHT trial showed that adults with clinically stable FD (eGFR slope less negative than −2 mL/min/1.73m^2/year) switching from another ERT E2W to pegunigalsidase alfa 2 mg/kg E4W tolerated extended dosing intervals well.

Methods:
This 5-year interim analysis from the ongoing BRIGHT51 (NCT03614234) extension evaluates long-term safety and efficacy of 2 mg/kg pegunigalsidase alfa E4W. Outcomes are reported from baseline in BRIGHT to ≥3 years of treatment. Three patients changed to 1 mg/kg E2W (n=1 deteriorating kidney function, n=2 pain crises); efficacy analyses only included 2 mg/kg E4W data.

Results:
Of 29 adults (23M:6F; mean age 40.9 years), 13 (44.8%) reported 51 pegunigalsidase alfa-related treatment emergent adverse events (TEAEs; 10.7% of 477 total TEAEs); none were severe/serious. Nine patients (31.0%; 8M:1F) experienced 43 infusion-related reactions (IRRs; 2.4 events/100 infusions; 5/9 patients with IRRs had baseline antidrug antibodies [ADAs]); most IRRs occurred within year 1 (62.8%). Of nine patients with baseline ADAs, all were male, five seroreverted, three titer-boosted, and one not boosted. Median eGFR slopes (mL/min/1.73m^2/year) varied between −1.8 and −2.6 amongst subpopulations (males, −2.4 vs females, −1.8; ADA−, −1.8 vs ADA+, −2.6). Plasma lyso-Gb3 remained stable in females and showed non-clinically significant increase in males. Other stable parameters included pain and quality-of-life. Analysis of genetic data revealed out of the 24 pathogenic GLA variants observed in the study, c.679C>T (n = 4) was the most common, with c.427G>A and c.801+48T>G each observed in 2 patients. All other variants only occurred in 1 patient.

Conclusion:
These outcomes highlight continued tolerability of pegunigalsidase alfa 2 mg/kg E4W in stable adult patients switching from other ERTs. Further investigation is needed to determine the effect of pegunigalsidase alfa E4W dosing on kidney function, however these studies suggest that in ADA− females and males, kidney function is stable.