An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease

Zoheb B Kazi, Ankit K Desai, R Bradley Troxler, David Kronn, Seymour Packman, Marta Sabbadini, William B Rizzo, Katalin Scherer, Omar Abdul-Rahman, Pranoot Tanpaiboon, Sheela Nampoothiri, Neerja Gupta, Annette Feigenbaum, Dmitriy M Niyazov, Langston Sherry, Reeval Segel, Alison McVie-Wylie, Crystal Sung, Alexandra M Joseph, Susan Richards, Priya S Kishnani, Zoheb B Kazi, Ankit K Desai, R Bradley Troxler, David Kronn, Seymour Packman, Marta Sabbadini, William B Rizzo, Katalin Scherer, Omar Abdul-Rahman, Pranoot Tanpaiboon, Sheela Nampoothiri, Neerja Gupta, Annette Feigenbaum, Dmitriy M Niyazov, Langston Sherry, Reeval Segel, Alison McVie-Wylie, Crystal Sung, Alexandra M Joseph, Susan Richards, Priya S Kishnani

Abstract

Purpose: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients.

Methods: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone.

Results: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators.

Conclusion: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.

Keywords: Pompe disease; alglucosidase alfa; antidrug antibodies; methotrexate; prophylactic immune tolerance induction.

Conflict of interest statement

Conflicts of Interest

Zoheb B. Kazi: Grant support: Lysosomal Disease Network; Sanofi Genzyme Ankit K. Desai: Grant support: Sanofi Genzyme

Bradley Troxler: None

David Kronn: Research funding: Sanofi Genzyme and New York Medical College

Seymour Packman: Recipient of a research grant from Sanofi Genzyme, Member of Sanofi Genzyme speakers’ bureau, Clinical trial of an unrelated product of Sanofi Genzyme

Marta Sabbadini: None

William Rizzo: None

Katalyn Scherer: None

Omar Abdul-Rahman: None

Pranoot Tanpaiboon: None

Sheela Nampoothiri: None

Neerja Gupta: None

Annette Feigenbaum: None

Dmitriy Niyazov: Speaker Bureau of Sanofi Genzyme

Sherry Langston: None

Reeval Seegal: None

Alison McVie-Wylie: Employment: Sanofi Genzyme

Crystal Sung: Employment: Sanofi Genzyme

Alexandra M. Joseph: Employment: Sanofi Genzyme

Susan Richards: Employment: Sanofi Genzyme

Priya S. Kishnani: Research support, honoraria, and Pompe and Gaucher Disease Registries’ advisory board membership: Sanofi Genzyme; grants: Shire Pharmaceuticals, Valerion; Amicus; personal fees: Alexion Pharmaceuticals, Inc., Amicus Therapeutics, Shire Pharmaceuticals; advisory board membership: Baebies, Inc.

Figures

Figure 1.
Figure 1.
Study timeline for infantile Pompe disease patients receiving ERT infusions every other week.D, day, Wk, week, mg, milligram, kg, kilogram, CBC with diff., complete blood count with differential, CK, creatinine kinase, Hex4/Glc4, glucose tetrasaccharide, rhGAA, recombinant human acid-alpha glucosidase, IgG, immunoglobulin G.
Figure 2.
Figure 2.
Immune response over time in the current TLD-MTX-treated CRIM-positive IOPD patients. Each patient’s trajectory is graphed individually as a curve. Positive titers

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