Insights into immunogenicity and therapeutic strategies to mitigate the immune response in infantile-onset Pompe disease: A comprehensive systematic literature review

Priya Kishnani^1*JMP Van Den Hout²Andreas Hahn³David Kronn⁴Yin-Hsiu Chien⁵Mei Han⁶Jennifer Heuterman⁷Susan Sparks⁶Colin Glen⁸Nadia Daba⁶

• ¹Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, United States
• ²Centre for Lysosomal and Metabolic Diseases, Erasmus Universiteit Rotterdam, Rotterdam, Netherlands
• ³Department of Child Neurology and Center of Rare Diseases Giessen, Justus-Liebig-Universitat Giessen, Giessen, Germany
• ⁴Departments of Pathology and Pediatrics, New York Medical College, Valhalla, United States
• ⁵Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei City, Taiwan
• ⁶Sanofi, Cambridge, United States
• ⁷Sanofi, Amsterdam, Netherlands
• ⁸Lucid Group London, London, United Kingdom

Pompe disease, a rare autosomal recessive metabolic myopathy, is primarily treated with enzyme replacement therapy (ERT); however, ERT response depends on several factors, including ERT initiation age, dose, and cross-reactive immunological material (CRIM) status, especially in infantile-onset Pompe disease (IOPD). This systematic literature review (SLR) focused on three research questions: (1) how CRIM status is determined in IOPD patients in clinical practice, and how CRIM-negative status impacts outcomes; (2) how health professionals use CRIM status to inform their decisions on immune tolerance induction (ITI) regimens; and (3) which regimens are used in real-world clinical practice. The SLR was conducted using Embase and PubMed databases covering the literature from January 1, 2003, to August 4, 2022. The search terms used were "Pompe or IOPD" and "cross-reactive immunological material or CRIM." Data extraction was performed using pre-designed tables in Microsoft Excel. Among those identified, 54, 51, and 69 studies provided meaningful data for the respective research questions. The key theme was the importance of early diagnosis/treatment. Recently, there has been a major shift from direct CRIM testing using western blotting and mutation analysis to CRIM status prediction based on genetic variant analysis. The ITI regimen was mostly prescribed for CRIM-negative patients and some CRIM-positive cases in a prophylactic/naïve setting at ERT initiation to prevent the development of high antibodies and for IOPD patients irrespective of CRIM status in the ERT-experienced setting due to the presence of high and sustained anti-drug antibody levels. Frequently reported ITI regimen includes short rituximab and methotrexate course in an ERT naïve setting, with/without intravenous immunoglobulin. CRIM-negative patients receiving ITI with ERT have better clinical outcomes than those not receiving the ITI regimen. Presently, the ITI regimen used in CRIM-positive patients is variable and based on physician preference, family history, or specific variants. The study concluded that CRIM status determination is important in patients with IOPD and impacts management approaches. ITI use has been predominantly reported in CRIM-negative patients to improve the clinical outcomes, with other important factors being early initiation of ERT and treatment with 40 mg/kg/2 weeks alglucosidase alpha, which is higher than the label dose.