Myozyme at Higher Dose More Effective for Classic Infantile Pompe, Study Says
Children with classic infantile Pompe disease on higher and more frequent doses of Myozyme (alglucosidase alfa) live longer without needing respiratory support, and have better motor outcomes, than those who start treatment at the recommended dose, a real-world study reports.
Its researchers began treating all infants diagnosed at its Rotterdam center with Myozyme at 40 mg/kg each week in 2009.
The study, "Effects of higher and more frequent dosing of alglucosidase alfa and immunomodulation on long‐term clinical outcome of classic infantile Pompe patients," was published in the Journal of Inherited Metabolic Disease.
Pompe disease is characterized by excessive accumulation of glycogen (a sugar molecule) inside cells caused by the lack of an enzyme called acid alpha-glucosidase (GAA).
Classic infantile Pompe disease is the most severe form of the disease. In these infants, GAA levels are usually lower than 1%, reflected in an inability to achieve important motor developmental milestones, such as walking. Without prompt treatment, infants with classic infantile Pompe do not live past their first year.
Enzyme replacement therapy (ERT) is currently considered the gold standard treatment for Pompe disease. The approach works by providing the enzyme patients are missing.
Myozyme, sold under the brand name Lumizyme in the U.S., is an ERT marketed by Sanofi Genzyme that has been approved to treat patients of all ages and types of Pompe disease. It was approved in the EU in 2006.
In general, Myozyme is recommended to be given by an intravenous infusion (directly into the bloodstream) at a dose of 20 mg/kg every other week. However, in infants who are cross-reactive immunologic material (CRIM)-negative and tend to produce neutralizing antibodies against the therapy, this dosing schedule is less effective.
CRIM measures the amount of GAA that patients are able to produce. In general, those who are CRIM-positive respond better to ERT than patients who are CRIM-negative.
Researchers at Erasmus MC University Medical Center in the Netherlands presented the latest findings of a study aimed to determine if a more frequent and higher Myozyme dosing schedule would be more beneficial to infants with classic infantile Pompe, particularly those who were CRIM-negative.
Their analyses were based on data (collected through Dec. 31, 2016) from 18 children, including five who were CRIM-negative. Six had been treated at the recommended 20 mg/kg dosing schedule, and 12 received the medication at a weekly dose of 40 mg/kg.
All classic infantile Pompe patients newly diagnosed at this center have been treated at the higher dosing schedule since 2009, the researchers wrote. Those who started earlier on the lesser dosing schedule were moved to the 40 mg/kg schedule between 2009 and 2014 "due to clinical deterioration."
The study's main goal was to compare the effects of these two dosing schedules on a series of long-term outcomes, including the time children lived without requiring respiratory support and their ability to achieve key motor milestones.
Levels of neutralizing antibodies produced against the therapy were also measured in both groups.
Infants age 2 months or older who enrolled in the study after 2012 were treated with Myozyme at 40 mg/kg weekly and also received immunomodulation treatment with rituximab, methotrexate, and intravenous immunoglobulins (IVIG). The aim was to see if this immunomodulation provided extra benefits.
Study findings showed that nearly all (92%) children in the higher and more frequent dosing schedule lived without requiring respiratory support over the course of the study, as did half of those on the recommended dosing schedule.
Likewise, nearly all (92%) infants on the highest and more frequent doses of Myozyme learned to walk, while the corresponding percentage in those receiving standard treatment was lower (67%).
The two CRIM-negative infants treated with the recommended dosage of Myozyme died during the study. All three CRIM-negative children who given Myozyme weekly at 40 mg/kg were alive at the study's end.
Neutralizing antibodies against the therapy were detected in both groups, but their levels at age 3 tended to be lower in the group on the highest and more frequent doses of Myozyme.
Immunomodulation therapies failed to prevent the formation of neutralizing antibodies, the researchers reported.
"In conclusion, the current study shows that our classic infantile patients receiving 40 mg/kg/week from start have a better survival, ventilator-free survival and motor outcome than patients receiving 20 mg/kg eow [every other week]," the scientists wrote.
"Most notable, all three CRIM-negative patients in the 40mg group were alive and able to walk at study end irrespective of whether they received immunomodulation," they added.
Jose Marques Lopes, PhD
José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer's disease.
Tagged classic infantile-onset Pompe disease, CRIM status, Lumizyme, Myozyme, Sanofi Genzyme.
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