Abstract

Background: 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). Results: 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%) were considered treatment-related (all mild/moderate). Nine patients (31%) experienced mild/moderate infusion-related reactions. One patient developed transient de novo ADAs. Conclusions: Long-term treatment with pegunigalsidase alfa 2 mg/kg E4W was well-tolerated and maintained disease stability, especially in females and ADA-negative males; more data are needed to better understand outcomes in ADA-positive males. Clinical outcomes should be closely monitored during E4W treatment. The final results of this extension study will further assess the feasibility of this dosing regimen. Trial registration details: ClinicalTrials.gov, NCT03614234. Registered July 30, 2018; https://clinicaltrials.gov/study/NCT03614234. Graphical Abstract: