Fabry disease (FD) is an inherited disorder caused by alpha-galactosidase-A deficiency leading to accumulation of globotriaosylceramide (Gb3), its metabolite lyso-Gb3, and other sphingolipids, resulting in impaired organ function. Current treatments include enzyme replacement therapies (ERTs) requiring infusions every 2 weeks (Q2W). Pegunigalsidase alfa (PA) is a PEGylated alpha-galactosidase-A enzyme with increased half-life compared with current ERTs, potentially allowing for dosing flexibility (1.0 mg/kg Q2W or 2.0 mg/kg every 4 weeks [Q4W]). BRIGHT51 (PB-102-F51, NCT03614234), an ongoing phase 3, open-label extension, evaluates the safety and efficacy of 2.0 mg/kg PA Q4W in adults with FD up to 4 years. Patients were eligible if they had completed BRIGHT, a 1-year switchover clinical trial for patients who previously received agalsidase alfa or agalsidase beta Q2W. For this interim analysis, safety and efficacy are reported from baseline in BRIGHT to ≥2 years of treatment. 29 adults (23 M:6F; mean age 40.9 years) were enrolled in BRIGHT51, with mean (range) PA exposure of 38.3 (25.3–44.8) person-months. 27/29 patients (93.1%) reported 339 treatment-emergent adverse events (TEAEs); 11/29 patients (37.9%) reported 46 PA-related TEAEs, of which none were serious/severe. 6/29 patients (20.7%, all males) experienced a total of 38 infusion-related reactions, all mild/moderate in intensity. Nine patients had antidrug antibodies (ADAs) at baseline; no de novo ADAs developed following the switch to PA for ≥2 years. At week 108, mean (SE) change from baseline of eGFR was −5.10 (1.96) mL/min/1.73m2; overall, the mean (SE) eGFR slope was −2.77 (0.54) mL/min/1.73m2/year (male: −3.03 [0.61] mL/min/1.73m2/year; female: -1.74 [1.21] mL/min/1.73m2/year). Mean (SE) plasma lyso-Gb3 was stable through week 108 (baseline: 19.36 [3.35] nmol/L; week 108: 22.98 [3.72] nmol/L). PA 2.0 mg/kg Q4W showed no new safety concerns during ≥2 years; additional analyses are needed to further evaluate the long-term safety and efficacy of Q4W dosing in adults with FD.