ERT: The sooner the better
Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.
The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”
But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.
“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.
Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,2 Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study3 by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.
While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”
Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
Neurological manifestations
With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.
“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”
Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”
In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.
“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,4 in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”
Dr. Toscano and his colleagues also reported cerebral aneurysms5 in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.
Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.