Pompe study ties high antibodies to infusion reaction risk
Findings could help doctors predict which patients may have reactions to therapy
Written by |
While most adults on Myozyme (alglucosidase alfa) for late-onset Pompe disease develop antibodies to the replacement enzyme, these usually do not limit efficacy; however, high and sustained levels of neutralizing antibodies are linked to more infusion-associated reactions and may lead some patients to stop therapy, a study found.
The findings could help doctors predict which patients are more likely to be affected by these antibodies, as “a potential impact was noted in individual cases,” the researchers wrote.
The study, “Antibody formation and efficacy of enzyme replacement therapy in adults with Pompe disease: Unlocking long-term insights,” published in Genetics in Medicine.
Pompe disease is caused by the lack of a working version of the acid alpha-glucosidase (GAA) enzyme. This enzyme normally helps break down glycogen, a stored form of sugar, in cells. When it is missing or dysfunctional, glycogen builds up to toxic levels — especially in muscle cells — and damages them.
Enzyme replacement therapy (ERT) provides the body with a functional version of the GAA enzyme to slow disease progression. However, the immune system can see this enzyme as foreign and produce neutralizing antibodies against it. High and sustained levels of these antibodies may render ERT ineffective, but “it remains a challenge to predict which patients will be impacted,” the researchers wrote.
Exploring antibodies
The researchers followed 111 adults with late-onset Pompe disease, a form that typically begins after age 1 and persists into adulthood. Patients started Myozyme, an ERT approved for all types of Pompe disease and sold as Lumizyme in the U.S., at a median age of 52. The team measured antibodies in blood samples over time and checked whether they could block the enzyme’s activity.
Most patients (81.1%) developed antibodies above a minimal level. The researchers divided them into three groups based on antibody levels: low, intermediate, and high. Nearly one-third of the 111 patients (30.6%) developed high levels. Among these, 32 had data available beyond six months. About two-thirds (65.6%) of them had high levels that lasted for years.
Antibodies usually rose soon after starting ERT, reaching a peak within the first year. After that, levels tended to go down. However, a second peak occurred in five patients with previous high, sustained levels of antibodies two to five years after the first peak. One patient experienced three peaks during the study.
Of the 111 patients, 32 (28.8%) had infusion-associated reactions. These side effects were more common in patients with high antibody levels than in those with low or intermediate levels. Some patients experienced repeated or very frequent reactions. In a few cases, ERT had to be stopped because of these reactions.
The researchers also looked at whether antibodies could block the enzyme’s activity. In nine patients, antibodies were neutralizing, meaning the GAA enzyme worked at less than half of its normal activity in lab tests. While this neutralizing effect “appeared to diminish over time without intervention,” in some patients, it lasted longer, the scientists said.
The researchers also tracked physical ability using the six-minute walk test (6MWT), which measures how far a person can walk in six minutes, and lung function using forced vital capacity, which measures how much air a patient can exhale after taking the deepest breath possible.
Patients across the groups were similar at the start of the study. The only difference was in the 6MWT, where patients with high and sustained antibody levels performed worse than those with high but non-sustained levels. Overall, changes in physical ability and lung function over time were similar across groups.
Patients with high but non-sustained levels tended to walk farther and showed more stable results over time. They also had more stable breathing function than patients with high, sustained antibodies. While antibodies did not affect outcomes overall, they “did seem to impact one or more clinical outcome measures in some individual patients,” the researchers wrote.
