Early ERT Is Key to Better Outcomes in Infantile-onset Pompe Study

Newborn screening enables treatment before damage becomes irreversible

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Enzyme replacement therapy (ERT) given as early as possible may lead to better outcomes in children with classic infantile-onset Pompe disease (IOPD), according to a long-term study conducted in Taiwan.

“Our study demonstrates that administering ERT as soon as feasible and employing short-term hydrocortisone premedication leads to better long-term outcomes,” researchers say.

The study, “Long-term outcomes of very early treated infantile-onset Pompe disease with short-term steroid premedication: experiences from a nationwide newborn screening programme,” was published in the Journal of Medical Genetics.

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Pompe disease is caused by mutations in the GAA gene that lead to a deficiency of the acid alpha-glucosidase (GAA) enzyme. This enzyme is responsible for breaking down a complex sugar molecule called glycogen. As a result, glycogen builds up to toxic levels in cells, especially those in the cardiac and skeletal muscles.

IOPD is the most severe form of this disease. In classic IOPD, symptoms appear within the first few months of life.

Myozyme, developed by Sanofi Genzyme (marketed in the U.S. as Lumizyme), was the first ERT approved for Pompe disease, and is designed to administer a working version of the GAA enzyme.

Previous studies have shown that ERT can improve the motor skills, heart function, and survival of patients. However, the outcomes in IOPD are dependent on when the therapy is administered, with poorer responses possibly occurring when muscle damage is already severe and irreversible.

In this long-term follow-up study, a team led by researchers at Taipei Veterans General Hospital, in Taiwan, analyzed the outcomes of IOPD patients who received ERT early and compared them with patients from other medical centers. The steroid hydrocortisone, given as a premedication, was used to reduce muscle inflammation and to prevent immune responses against the ERT.

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The center had established a newborn screening program for Pompe disease in 2008, with rapid diagnostic criteria for IOPD established two years later. Newborn screening uses a small blood sample collected shortly after birth to look for GAA enzyme activity. Upon confirmation of reduced GAA activity, another blood sample is analyzed to confirm the initial diagnosis.

Over a 11-year period (January 2010 to February 2021), 1,228,539 newborns were screened for Pompe disease, which led to 33 with confirmed IOPD. A total of 26 newborns received ERT within six hours of their first admission and were followed over an average of six years.

The treatment protocol first included hydrocortisone, given into the vein, at a 2 mg/kg dose. This was then followed by Myozyme. Hydrocortisone was tapered three months after the first ERT infusion. ERT was administered every other week but was given more often or at higher dosages if the patient’s clinical symptoms deteriorated.

During follow-up, comprehensive blood work was conducted every three to six months. Lung function was evaluated starting at age 3, and hearing and vision were evaluated at least once a year. Also, the patients’ developmental outcomes were assessed once or twice a year using the Bayley Scale of Infant and Toddler Development, second edition.

Patients with classic IOPD began ERT at a mean age of 9.75 days. When including those with non-classic IOPD, the therapy was started at an average of 11.18 days.

All patients survived without the need for assisted ventilation and with close-to-normal respiratory function, according to the researchers. All the children also had normal heart sizes and cognitive function, and they reached motor milestones within the expected time. Body weight and height were also normal for their age.

The team then compared the outcomes of their patients to those described in nine studies. Two studies were conducted in Taiwan, while the remaining seven were conducted in the U.S. or Europe. The researchers noted that most patients in the U.S. and European studies were diagnosed based on clinical signs and symptoms, rather than by newborn screening programs. When compared to the Taiwanese studies, clinical outcomes were worse and ERT was started at a later age in the other studies.

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When comparing outcomes of patients at the Taipei Veterans General Hospital with a group from a different center in Taiwan, “our patients had better clinical outcomes,” the researchers wrote. They attributed this to the early administration of ERT alongside hydrocortisone premedication.

Overall, patients following this early regimen reached independent walking at a younger age (11.9 months vs 15.15 months) and better (higher) cognitive scores on the Bayley scale, with a mean score of 105.0 vs. 82. Within two years of ERT, the children also had lower levels of creatine kinase, a muscle damage marker, and lower levels of antibodies against the ERT.

“Very early ERT using our rapid diagnostic and treatment strategy enabled our patients with IOPD to have better outcomes than patients in other medical centres,” the researchers concluded.