Early ERT Key in Severe Classic Infantile Pompe

Early treatment with enzyme replacement therapy (ERT) and immune tolerance induction (ITI) greatly improved clinical outcomes for infants with the severe, frequently ERT-nonresponsive, CRIM-negative infantile Pompe disease (IPD), a study has found.

“Our data suggest that the first few weeks after birth may be a critical period in newborns with CRIM-negative IPD, during which clinical symptoms may not yet be fully apparent, but timely treatment initiation can result in drastically improved clinical outcomes,” the investigators wrote.

The study, “Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction,” was published in the journal Genetics in Medicine. 

Pompe disease results from mutations in the GAA gene that lead to a deficiency of the enzyme GAA and an accumulation of toxic glycogen in muscle tissue. Classic IPD is characterized by early and progressive muscle weakness and dysfunction of heart muscles. Treatment with Lumizyme (alglucosidase alfa), the available ERT in Pompe, provides a form of the GAA enzyme to improve cardiac and muscle function.

Some children do not respond to ERT for a variety of factors, including their cross-reactive immunological material (CRIM) status. IPD patients who are CRIM-negative have inherited two defective copies of the GAA gene, one from each parent, resulting in a complete absence of the GAA protein. CRIM-negative IPD children typically have more severe symptoms with earlier onset and lower survival compared to CRIM-positive patients.

ITI is an approach used to ease or prevent the effects of anti-ERT antibodies, seen in CRIM-negative patients and responsible for treatment ineffectiveness. An ITI regimen with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) has shown good results in IPD patients.

Early initiation of ERT was shown to boost clinical outcomes in newborns with CRIM-positive IPD. For the current study, researchers in the U.S. sought to determine if early initiation of ERT and ITI would similarly improve outcomes and survival in CRIM-negative children.

Of the 41 CRIM-negative IPD children assessed, 20 who received ERT and ITI did not require invasive respiratory support and had at least six months of follow-up, were included in the analysis. Also included was an additional group of 11 CRIM-negative IPD patients who were treated with ERT alone.

Participants treated with ERT and ITI were grouped by age when treatment began, with five patients in the early (0 to 4 weeks) group, seven in intermediate (4 to 15 weeks), and eight in later start (after 15 weeks). In the ERT monotherapy group, the median age at treatment start was 13 weeks. Eighteen children began treatment with a standard ERT dose of 20 mg/kg every other week, while two received 40 mg/kg with the same frequency.

All children in the early and intermediate group were alive at the final assessment with median ages of nearly 2.3 years (early start) and almost 7 years (intermediate start). In turn, six of the eight patients in the late group were alive at the final assessment with a median age slightly older than 4. No statistical difference in survival was observed between the groups. However, patients treated with ERT and ITI had significantly longer survival than those on ERT alone, all of whom had died by a median age of 2.4 years.

No children in the early group required invasive breathing support during ERT treatment, compared to one intermediate group child, and two late group patients. Likewise, no early group patients required noninvasive ventilation, while three intermediate group patients and two late group children did. Notably, those in the early group were significantly less likely to require ventilation than either the intermediate or late group.

Chilren on ERT only were significantly more likely than those on both ERT and ITI to be ventilator-dependent, with all surviving patients requiring the use of a ventilator at a median age of 13.8 months.

The left ventricular mass index (LVMI) measures heart function with a reading above 64.0 grams per square meter (g/m²) being abnormal. Early, intermediate, and late group patients showed lower LVMI at follow-up compared to treatment start, with children in the early and intermediate start groups showing values within the normal range.

LVMI in the late group was significantly higher at final assessment than in patients on early start, with three children remaining above the normal range, compared to none in the early group. 

All five early patients continued feeding orally throughout treatment compared to four intermediate (57.1%) and two late group children (25.0%) At follow-up, two more children on intermediate start of treatment and another in the late group were able to feed orally.

All four of the early group patients evaluated were able to walk or meet developmental milestones, compared to five of seven intermediate group patients (71.4%) and three of the seven late group patients (42.9%) who could walk independently at the final assessment. The early group was significantly more likely than the late group to walk independently. 

With respect to disease markers, all three groups had elevated median creatine kinase levels (indicative of mucle damage), with no significant difference between groups. Six months into ERT,  all early group patients achieved normal biomarker levels in contrast to the other two groups. 

The early group also showed significantly decreased levels of the disease marker glucose tetrasaccharide compared to the late group.

All early and late group children maintained immune tolerance to ERT throughout treatment, along with five intermediate group patients.

“This study … illustrates significant improvements in overall clinical outcomes in those who were treated with ERT + ITI within the first month of life, compared with those treated at a later age,” the scientists wrote. “Every effort should be made to shorten the delay between diagnosis and treatment initiation … to ensure that these particularly vulnerable infants are offered the best opportunity for an optimal clinical course,” they added.

The study was limited by the small size and relatively young age of the early treatment group. Further research in a larger study population likely will be required, the scientists wrote.