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 RichardsPriya S. Kishnani

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)887-895
Number of pages9
JournalGenetics in Medicine
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2019

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Glycogen Storage Disease Type II
Immune Tolerance
Methotrexate
Proteins
Therapeutics
Glucosidases
Longitudinal Studies
human GAA protein
Acids

Keywords

  • Pompe disease
  • alglucosidase alfa
  • antidrug antibodies
  • methotrexate
  • prophylactic immune tolerance induction

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

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

In: Genetics in Medicine, Vol. 21, No. 4, 01.04.2019, p. 887-895.

Research output: Contribution to journalArticle

Kazi, ZB, Desai, AK, Troxler, RB, Kronn, D, Packman, S, Sabbadini, M, Rizzo, WB, Scherer, K, Abdul-Rahman, O, Tanpaiboon, P, Nampoothiri, S, Gupta, N, Feigenbaum, A, Niyazov, DM, Sherry, L, Segel, R, McVie-Wylie, A, Sung, C, Joseph, AM, Richards, S & Kishnani, PS 2019, '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', Genetics in Medicine, vol. 21, no. 4, pp. 887-895. https://doi.org/10.1038/s41436-018-0270-7
Kazi, Zoheb B. ; Desai, Ankit K. ; Troxler, R. Bradley ; Kronn, David ; Packman, Seymour ; Sabbadini, Marta ; Rizzo, William B ; Scherer, Katalin ; Abdul-Rahman, Omar ; Tanpaiboon, Pranoot ; Nampoothiri, Sheela ; Gupta, Neerja ; Feigenbaum, Annette ; Niyazov, Dmitriy M. ; Sherry, Langston ; Segel, Reeval ; McVie-Wylie, Alison ; Sung, Crystal ; Joseph, Alexandra M. ; Richards, Susan ; Kishnani, Priya S. / 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. In: Genetics in Medicine. 2019 ; Vol. 21, No. 4. pp. 887-895.
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abstract = "Purpose: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-na{\"i}ve 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.",
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T1 - An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein

T2 - experience in infantile-onset Pompe disease

AU - Kazi, Zoheb B.

AU - Desai, Ankit K.

AU - Troxler, R. Bradley

AU - Kronn, David

AU - Packman, Seymour

AU - Sabbadini, Marta

AU - Rizzo, William B

AU - Scherer, Katalin

AU - Abdul-Rahman, Omar

AU - Tanpaiboon, Pranoot

AU - Nampoothiri, Sheela

AU - Gupta, Neerja

AU - Feigenbaum, Annette

AU - Niyazov, Dmitriy M.

AU - Sherry, Langston

AU - Segel, Reeval

AU - McVie-Wylie, Alison

AU - Sung, Crystal

AU - Joseph, Alexandra M.

AU - Richards, Susan

AU - Kishnani, Priya S.

PY - 2019/4/1

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N2 - 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.

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KW - methotrexate

KW - prophylactic immune tolerance induction

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