Low-dose treatment with methotrexate can reduce the immune reaction that often accompanies enzyme replacement therapies in infants with Pompe disease, researchers report.
Their study, “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” was published in the journal Genetics in Medicine.
Pompe disease is caused by mutations in the enzyme acid α-glucosidase (GAA) that results in the accumulation of the energy-storing molecule glycogen in cardiac, skeletal, and smooth muscles. Classic infantile-onset Pompe disease (IOPD) is often fatal within the first two years of life.
Recombinant (lab-made) human GAA (rhGAA) was approved as enzyme replacement therapy for Pompe patients in 2006. However, patients often develop immune tolerance to this therapy, in the form anti-rhGAA antibodies that make the therapy less effective.
To lessen this unwanted effect, researchers have started using immune tolerance induction (ITI) protocols that involve different treatments that suppress the immune system.
A previous study in a mouse model of Pompe disease showed that low-dose methotrexate, when given at the time of the enzyme replacement therapy, could reduce anti-rhGAA antibodies in a sustainable manner.
Methotrexate is a common chemotherapy used with cancer patients, and an immune suppressant used to treat autoimmune conditions.
This first-in-human study included 14 newly diagnosed infantile-onset Pompe disease patients, who were treated with low-dose methotrexate for their first three enzyme-replacement therapy infusions (TLD-MTX). Their median age at first treatment was 3.8 months.
Retrospectively, 37 patients treated with enzyme replacement therapy alone were assessed for levels of antibodies against the therapy. In this control group, the median age at first treatment was 6.9 months, and antibody levels were assessed about once a month for a year.
In the control group, 32.4% of patients developed intermediate or high sustained antibody levels. In the TLD-MTX group, only two patients — 14.2% — developed either intermediate or high sustained antibodies levels. The majority of IOPD patients maintained low levels of antibodies throughout the course of this study.
No significant adverse events were reported.
Overall, the study shows that low-dose methotrexate delivered at the same time as enzyme-replacement therapy can blunt the immune response seen by treatment with enzyme-replacement therapy alone.
The researchers conclude that these results “are encouraging and merit a larger longitudinal study.”