Antibodies to ERT Use Common in Children, Not Likely to Limit Efficacy
Most children with Pompe disease in a small study developed antibodies against the enzyme replacement therapy Myozyme (alglucosidase alfa) — marketed in the U.S. as Lumizyme — but their presence did not limit treatment efficacy, its researchers reported.
Children with the highest levels of antibodies also experienced most of all reported infusion-associated reactions.
“Antibody [levels] should be determined in case of (unexpected) clinical deterioration, especially when this decline is accompanied by IARs [infusion-associated reactions],” the researchers wrote.
The study, “Antibodies against recombinant human alpha-glucosidase do not seem to affect clinical outcome in childhood onset Pompe disease,” was published in the journal Orphanet Journal of Rare Diseases.
Myozyme, marketed by Sanofi Genzyme, is an enzyme replacement therapy (ERT) that provides a source of alpha-glucosidase (GAA), the enzyme that is missing or deficient in people with Pompe disease.
A lack of GAA leads to the buildup of the complex sugar molecule glycogen, primarily in muscle tissues, disrupting cells and resulting in muscle weakness and respiratory system decline. In classical infant-onset Pompe, respiratory and/or heart failure are common without treatment.
Enzyme replacement therapy, administered directly into the bloodstream by infusion, can clear excess glycogen from muscle tissues and lessen the severity of symptoms, improving survival, motor outcomes, and quality of life.
However, this treatment often induces an immune response that generates antibodies against the enzyme, potentially diminishing its effectiveness and increasing the likelihood of side effects.
Studies indicate that antibody formation in adults generally does not seem to interfere with the efficacy of replacement therapy. However, few studies have investigated the occurrence and impact of anti-GAA antibodies in Pompe patients who begin ERT as children.
Researchers at University Medical Center Rotterdam, in the Netherlands, examined 22 children and adolescents who began using ERT at ages ranging from about 1 to 16 years old. They had been treated for two to 19 years, with most receiving a standard 20 mg/kg dose every two weeks. Individuals with classic infantile-onset Pompe disease were excluded from this analysis.
Blood tests revealed that 20 of the 22 patients (91%) had developed anti-GAA antibodies above the normal range. Five had high antibody levels, or titers, 15 developed intermediate titers, and two had low titers.
Most (82%) developed their peak antibody titer within the first year of ERT use, after which the antibody titer declined and stabilized. There was no relationship between age at the start of ERT and peak antibody titer.
Among the five patients with high antibody titers, clinical assessments showed three of them to be in stable condition throughout the study. Another, severely affected by disease before ERT, showed improvements but deteriorated further after two years of treatment.
The fifth patient, known as patient 1, showed delayed motor development at the start of ERT as a 1 year old. The child’s development returned to normal levels during the first two years of treatment. Even when antibody titers again reached high levels after five years of treatment, no declines were seen in age-appropriate developmental test outcomes.
“In conclusion, none of the patients showed clear evidence of interference of anti-[GAA] antibodies with ERT efficacy,” the researchers wrote.
Antibodies isolated from the blood of these five patients were also generally unable to block the activity of GAA in cell-based tests, the researchers noted, including patient 1’s sample containing the highest antibody titer. These findings suggest the antibodies that bind to GAA do not interfere with the enzyme’s activity.
The impact of infusion-associated reactions (IARs) was examined — a type of hypersensitivity reaction that develops during or shortly after the infusion — because they have been linked with high titers of anti-GAA antibodies in adult Pompe patients.
Such reactions were experienced by four patients (18%), mostly within the first year of treatment. Out of about 6,200 infusions administered, there were 59 reported IARs, most of which were mild (98%) and resulted in nausea, dizziness, or rash.
Although no significant correlation was seen between the number of IARs and peak antibody titer across all participants, patient 1 with the highest peak titer had the largest number of infusion reactions at 28. Most IARs (86%) were seen in the five patients with the highest titers.
“Thus, there may be an association between high antibody titers and the occurrence of IARs in children as well,” the researchers wrote.
Genetic analysis also showed that the distribution of antibody titer peaks did not differ between patients with or without the IVS1 GAA gene variant — a common Pompe mutation. Patients with this variant can still produce small amounts of functional GAA enzyme, but there was no association between this residual GAA activity and peak antibody titer.
“The majority of patients with childhood onset Pompe disease do not develop high antibody titers,” the researchers concluded, and for those that do, “high antibody titers do not seem to affect clinical outcome.”
Future studies should include larger groups of these patients to draw more robust conclusions, the team said.
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