Lumizyme-Myozyme Given Early and at Higher Dose May Be Best for Infantile-onset Pompe

When administered early and above its recommended dose, Myozyme (alglucosidase alfa, known as Lumizyme in the U.S.) may improve the clinical outcomes and prognosis of people with infantile-onset Pompe disease (IOPD), a study reports.

Safety with a higher dose did not seem to be a concern, the investigators noted, although “close monitoring of biomarkers and antibody titers” was advised.

The study, “Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences,” was published in the journal Molecular Genetics and Metabolism Reports.

Pompe disease is caused by mutations in the GAA gene, which provides instructions to make an enzyme known as acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down a complex sugar molecule called glycogen.

Infantile-onset Pompe is the most severe form of this disease, with first symptoms appearing at birth or a few months later.

Myozyme/Lumizyme, an enzyme replacement therapy (ERT) developed and marketed by Sanofi Genzyme, is the only approved treatment currently available for these patients.

Although previous studies have shown that an ERT can work to reverse heart disease, improve patients’ motor skills, and extend overall survival, the timing and dosage at which the therapy is administered are critical to its success.

“Several studies suggested that patients may benefit from an ERT dosage higher than the labeled doses,” the researchers wrote, “but the dosage, frequency, timing, and indication for using a higher dosage were variable in these studies.”

Inconsistencies in study findings, along with the high variability in the severity and ages at which infantile-onset Pompe patients start on an ERT, have made it difficult for researchers and physicians to draw definitive conclusions on optimal use.

To investigate the long-term clinical benefits of Myozyme at high dose, investigators in Taiwan reviewed the medical records of 28 children and teenagers treated at high dose either initially or at a later time. (Taiwan has had a newborn screening program for Pompe disease since 2005.)

These 28 infantile-onset patients, with a median age of 8.3 years, were divided into three groups depending on their motor abilities: 15 were walkers, eight were weak walkers, and five were non-walkers.

Twenty-three of them were first treated with Myozyme at its recommended label dose of 20 mg/kg every other week. They then were moved to a higher dosage — either 30 or 40 mg/kg every other week, or 20 mg/kg every week  — at  a median age of almost 3 (35 months old). The five remaining patients started on Myozyme at 40 mg/kg every other week dose (double the recommended dose), with two of them further increasing their dose — one at 8 months old and the other at 18 months.

Results found a significant difference in the age at which gross motor skills declined among the three groups, with patients in the “walker” group declining at a slower pace than those in the other two groups.

Blood levels of creatine kinase (CK; a marker of muscle damage) and urinary levels of glucose tetrasaccharide (uGlc4; a marker of glycogen buildup) were also lower in patients in the “walker” group at their follow-up visit.

While both biomarkers tended to decrease in response to ERT use in patients who started treatment at the labeled dose during the first 6–12 months, they started to rise thereafter in all cases.

“In contrast, patients who received 40 mg/kg eow [every other week] beginning from ERT initiation retained normal uGlc4 and CK levels, and their motor function was also normal at their latest follow-up,” the researchers wrote.

Higher doses also seemed to be safe, the researchers wrote. “We observed no apparent differences in safety parameters among different ERT dosages,” but they added, “all patients … should have regular antibody monitoring.”

Among patients with classic infantile-onset Pompe diagnosed through newborn screening, researchers found motor function decline to be most likely among those who initiated ERT later, or were given the high dosage of the therapy at later stages of the disease.

“We suggest that a high dosage of ERT such as 40 mg/kg eow as the starting dosage, may be more effective than the labeled dose in stabilizing and improving the clinical prognosis of patients with IOPD [infantile-onset Pompe disease] even if they were identified through newborn screening,” the investigators concluded.