Twins do well on high-dose ERT plus immune tolerance induction
Early treatment may have prevented antibody development
Early immune tolerance induction with rituximab, methotrexate, and intravenous (into-the-vein) immunoglobulin may have prevented twin babies with infantile-onset Pompe disease (IOPD) from developing antibodies against enzyme replacement therapy (ERT), according to a case report from the U.S.
The report, “Optimizing clinical outcomes: The journey of twins with CRIM-negative infantile-onset Pompe disease on high-dose enzyme replacement therapy and immunomodulation,” was published in Molecular Genetics and Metabolism Reports.
Pompe disease is caused by a lack of alpha-glucosidase, an enzyme that helps break down a sugar molecule called glycogen. Without the enzyme, glycogen accumulates in the body’s tissues, especially in muscles, causing them to weaken over time.
IOPD symptoms begin to manifest early in infancy, usually at around four months. Patients often develop hypertrophic cardiomyopathy, a condition in which the heart muscle thickens and the heart fails to pump enough blood. If untreated, they often don’t survive past age 2.
The main treatment for Pompe disease is ERT with a version of the missing enzyme. This reduces accumulation of glycogen in the body’s tissues, easing symptoms. How well ERT works can depend on the amount of enzyme that’s naturally produced by the body.
Antibodies and ERT
CRIM-negative patients, who can’t produce alpha-glucosidase themselves, are more likely to develop inhibitor antibodies against the replacement enzyme. These antibodies can make ERT less effective. To tone down the immune response, these patients often undergo immune tolerance induction.
The boy-and-girl twins, both with CRIM-negative IOPD, received high-dose Lumizyme (alglucosidase alfa), an ERT from Sanofi approved to treat all types of Pompe disease, in combination with rituximab, methotrexate, and intravenous immunoglobulin for immune tolerance induction.
The boy had difficulty with feeding and poor muscle tone shortly after birth. Four days after birth, an echocardiogram showed thickening of the heart’s walls. He was diagnosed with IOPD at 3 weeks, after genetic and enzyme activity testing. His sister, diagnosed a few days later, also had enlargement of the heart’s left ventricle, one of its pumping chambers.
The boy started on Lumizyme at 28 days, and his twin sister at 44 days. Heart function improved and biomarkers of glycogen clearance and of cardiac health normalized within a few months. The girl improved more slowly, likely due to “the later initiation of ERT,” the team wrote.
Both twins did well with the immune tolerance induction and developed low levels of inhibitor antibodies. At 28 months, they switched to Nexviazyme (avalglucosidase alfa), a next-generation ERT, also from Sanofi. The switch was well tolerated, and inhibitor antibodies didn’t rise.
By 39 months, the twins had normal heart function. They were making progress with their motor skills, although some difficulties remained. The case suggests that starting ERT early in combination with immune tolerance induction can be effective for treating CRIM-negative IOPD, the researchers wrote.
“Further studies assessing long-term outcomes in a larger cohort [group] of IOPD patients who are treated right after birth on [a] higher dose of ERT are needed to understand the degree of improvement,” the researchers wrote.
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