Antibody formation and efficacy of enzyme replacement therapy in adults with Pompe disease: Unlocking long-term insights

PURPOSE: Anti-recombinant human acid α-glucosidase (rhGAA) antibodies can develop in adult Pompe patients receiving enzyme replacement therapy (ERT), but their long-term impact on clinical treatment outcomes is currently unclear. METHODS: Pompe patients starting ERT ≥18 years of age were monitored for anti-rhGAA antibody titres (at start of ERT and designated time-points thereafter) and its neutralising activity. Six-minute Walk test (6MWT) and forced vital capacity (FVC) were assessed to evaluate clinical outcomes. RESULTS: We studied the antibody titre course (n=930) of 111 patients. High peak titres (≥31,250) were found in 34/111 patients, with high sustained antibody titres (HSAT) in 21/34. High titres were linked to more infusion associated reactions (IARs; p=0.008). Patients with high peak antibody titres had more stable supine lung function and 6MWT distance compared to those with respectively HSAT (p=0.02) or low/intermediate titres (p=0.03). No other group-level differences in outcomes were found. Neutralising activity was detected in nine patients without group-level impact; however, this activity or high antibody levels negatively affected disease course in some. CONCLUSION: High (sustained) antidrug antibody titres are associated with an increased risk of IARs. While they do not appear to significantly impact clinical outcomes at the group level, their (neutralising) effect can negatively impact disease course in individual patients.