Increased intervals in enzyme replacement therapy for stable type 1 Gaucher disease: A non-inferiority sequential trial emulation.

Abstract

To compare the efficacy and safety of extended interval (Q3-4W) enzyme replacement therapy (ERT) versus standard biweekly (Q2W) ERT in clinically stable type 1 Gaucher disease (GD) patients. We emulated a target trial with a sequential trial design, using data from the French Gaucher Disease Registry. Eligible patients were treated for ≥2 years biweekly without clinical events. Every 3 months, switchers to Q3-4W were matched to Q2W patients by age, sex, referral center follow-up, disease history (bone events, anemia, thrombocytopenia, splenectomy, and hepatosplenomegaly), and dose of ERT. The primary outcome was a composite of GD-related events (bone events, anemia, and thrombocytopenia). A 10% non-inferiority margin was prespecified. Secondary outcomes were biomarker changes and economic analyses. Among 280 eligible GD patients, 63 switched to Q3-4W and were matched to a total of 215 Q2W patients, followed for an average of 6.3 years. No significant difference in the risk of clinical events was observed between groups (hazard ratio: 0.98 [95% confidence intervals (CI): 0.54-1.51]). During follow-up, absolute risk difference remained below the 10% non-inferiority threshold at all timepoints. Biomarkers remained stable or slightly decreased in the Q3-4W group. The dosing interval extension led to an average reduction of 55 infusions per patient, corresponding to approximately €450,000 saved per patient over 6 years. In stable GD1 patients, extending ERT administration to every 3-4 weeks was non-inferior to the standard biweekly regimen, supporting personalized spacing strategies that may improve quality of life and reduce healthcare costs.