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. 2021 May;23(5):845-855.
doi: 10.1038/s41436-020-01080-y. Epub 2021 Jan 25.

Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction

Cindy Li  1 , Ankit K Desai  1 , Punita Gupta  2 , Katherine Dempsey  3 , Vikas Bhambhani  4 , Robert J Hopkin  5 , Can Ficicioglu  6 , Pranoot Tanpaiboon  7 , William J Craigen  8 , Amy S Rosenberg  9 , Priya S Kishnani  10
Affiliations

Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction

Cindy Li et al. Genet Med. 2021 May.

Abstract

Purpose: To assess the magnitude of benefit to early treatment initiation, enabled by newborn screening or prenatal diagnosis, in patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD), treated with enzyme replacement therapy (ERT) and prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and intravenous immunoglobulin (IVIG).

Methods: A total of 41 CRIM-negative IPD patients were evaluated. Among patients who were treated with ERT + ITI (n = 30), those who were invasive ventilator-free at baseline and had ≥6 months of follow-up were stratified based on age at treatment initiation: (1) early (≤4 weeks), (2) intermediate (>4 and ≤15 weeks), and (3) late (>15 weeks). A historical cohort of 11 CRIM-negative patients with IPD treated with ERT monotherapy served as an additional comparator group.

Results: Twenty patients were included; five, seven, and eight in early, intermediate, and late treatment groups, respectively. Genotypes were similar across the three groups. Early-treated patients showed significant improvements in left ventricular mass index, motor and pulmonary outcomes, as well as biomarkers creatine kinase and urinary glucose tetrasaccharide, compared with those treated later.

Conclusion: Our preliminary data suggest that early treatment with ERT + ITI can transform the long-term CRIM-negative IPD phenotype, which represents the most severe end of the Pompe disease spectrum.

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Conflict of interest statement

CONFLICT OF INTEREST

Cindy Li, Katherine Dempsey, Vikas Bhambhani, and William J. Craigen have no conflicts of interest to declare.

Ankit K. Desai has received research support from Sanofi Genzyme and Lysosomal Disease Network (LDN).

Punita Gupta has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics and Takeda Shire.

Robert J. Hopkin consults with Amicus Therapeutics, AVROBIO, Chiesi, Protalix BioTherapeutics, Sangamo, Sanofi-Genzyme and Takeda-Shire, and has been an investigator in clinical trials sponsored by Amicus Therapeutics, Protalix BioTherapeutics, Sanofi-Genzyme, and Takeda-Shire. He is on the speakers bureau for Alexion, Amicus Therapeutics, Sanofi-Genzyme. These activities have been monitored and found to be in compliance with the conflict of interest policies at Cincinnati Children’s Hospital Medical Center.

Pranoot Tanpaiboon is employed by Quest Diagnostics.

Can Ficicioglu has served as an advisor or consultant for Biomarin Pharmaceutical, Sanofi Genzyme, Swedish Orphan Biovitrum, Recordati, Orphan Technologies, Takeda Shire, Cycle Pharmaceuticals, Horizon Therapeutics, Alexion Pharmaceuticals, and Synlogic Therapeutics. Can Ficicioglu has received research grants for clinical research from Vtesse, Takeda Shire, Sangamo Therapeutics, Orphan Technologies, and Sanofi Genzyme.

Priya S. Kishnani has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics. Priya S. Kishnani has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Vertex Pharmaceuticals and Asklepios Biopharmaceutical, Inc. (AskBio). PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. Priya S. Kishnani has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease.

Figures

Figure 1.
Figure 1.. Kaplan-Meier survival analysis of CRIM-negative IPD patients treated with ERT monotherapy compared to those treated ERT+ITI (combined and by individual groups)
A & B) Comparison of overall and invasive ventilator-free survival in all patients treated with ERT+ITI (n=20) versus those treated with ERT monotherapy (n=11). Both overall and invasive ventilator-free survival were significantly prolonged in patients treated with ERT+ITI (p<0.0001). C & D) Comparison of overall and invasive ventilator-free survival in early (n=5), intermediate (n=7), and late (n=8) treatment groups, and the ERT monotherapy group (n=11).
Figure 2.
Figure 2.. LVMI in CRIM-negative IPD patients treated with ERT+ITI at baseline and final assessment
A) Comparison of LVMI (g/m2) in ETG (n=4), ITG (n=7), and LTG (n=7) at baseline; B) Comparison of LVMI (g/m2) in ETG (n=5), ITG (n=7), LTG (n=7) at final assessment. Upper limit of normal range is 64.0 g/m2.
Figure 3.
Figure 3.. Longitudinal CK and Urinary Glc4 in CRIM-negative IPD patients treated with ERT+ITI
A-C: CK in early, intermediate, and late treatment groups, respectively. D-F: urinary Glc4 in early, intermediate, and late treatment groups, respectively. The early treatment group exhibited continued stable trends in both CK and urinary Glc4 at or near normal range (CK upper limit of normal: 320 U/L, age 0–9 years; Glc4 upper limit of normal: 20 mmol/mol creatinine, age 0–6 months; 14 mmol/mol creatinine, age 6–12 months; 8.3 mmol/mol creatinine, age 1–3 years; 3.0 mmol/mol creatinine, age >3 years). Persistent elevation of biomarkers was seen in both intermediate and late treatment groups with a number of patients exhibiting worsening trends over time. This pattern is consistent with previously reported findings in long-term survivors of IPD.
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