ERT prolongs survival in classic IOPD, study finds
But mortality rates remain high, so new therapeutic approaches are needed
Among children with classic infantile-onset Pompe disease (IOPD), enzyme replacement therapy (ERT) was associated with prolonged survival, but mortality rates remained high, according to a recent French study.
In general, while mortality rates were high in the first three years of life, patients then stabilized on ERT for several years, which was followed by  declines later in respiratory and muscle function.
“Classical IOPD remains a severe disease despite the substantial therapeutic progresses made within the last 16 years,” the researchers wrote. “This highlights the importance of developing new therapeutic approaches … to improve long-term outcomes.”
The study, “Long-term follow-up of 64 children with classical infantile- onset Pompe disease since 2004: A French real-life observational study,” was published in the European Journal of Neurology.
All types of Pompe disease are caused by mutations in the GAA gene, leading to a deficiency in functional GAA enzyme. Its severity is determined by how much residual GAA activity is left in a person’s cells.
Typically considered the most severe form of Pompe disease, classic IOPD is marked by very low or absent GAA activity, resulting in the onset of low muscle tone (hypotonia) and heart disease in the first months of life, with death from cardiorespiratory failure occurring at a median age of 6-9 months.
ERT, including Myozyme (alglucosidase alfa, which is sold as Lumizyme in the U.S.) and Nexviazyme (avalglucosidase alfa), aims to provide Pompe patients with a working GAA enzyme. For IOPD patients, it can prolong survival substantially, particularly when begun very early after birth.
More enzyme replacement therapy data needed
However, long-term data on the efficacy of ERT in larger groups of IOPD patients are lacking, according to the authors.
To address that knowledge gap, the researchers retrospectively analyzed outcomes from 64 classic IOPD patients diagnosed in France from 2004 — the year ERT became available in the country — to 2021. The data were provided by French expert centers for rare diseases.
At diagnosis, which occurred at a median age of 4 months, all patients had cardiomyopathy — a disease of the heart’s muscle — and cardiac failure was evident in 41%. Nearly all participants (92%) had severe hypotonia.
Most patients — 50 of 64 — initiated ERT at a median age of 4 months. For the remaining 14 patients, it was not begun due to the severity of their disease at diagnosis. Those patients were older and had higher rates of heart failure than those who did start ERT.
Ultimately, 10 children who were started on ERT eventually stopped due to ineffectiveness and disease progression.
Over the course of follow-up, 58% of patients died at a median age of 13 months. This included all who were never treated with or stopped using ERT, as well as 13 people who had used the therapy continuously.
Patients with a history of ERT survived significantly longer than those who never used it.
“The evolution of mortality seems to be in three phases,” the researchers wrote. Specifically, mortality rates were high in the first three years of life, relatively stable until about age 12, after which mortality rates rose again.
Overall, while ERT was associated with a lower risk of death, persistent cardiomyopathy throughout follow-up and/or heart failure were linked to a higher mortality risk. Failure to acquire walking ability, and an early need for ventilation or nutritional support also were associated with a worse prognosis.
CRIM status assessed
Cross-reactive immunologic material (CRIM) status — how much GAA activity a person has — was not associated with survival. Among the 16 patients who were CRIM-negative, meaning they had no GAA activity, use of immunomodulators to prevent an immune response against ERT appeared to improve survival.
In general, CRIM-negative patients had a more severe disease course than patients with some residual GAA activity, but their overall survival rates were not different.
Among surviving patients, ERT appeared to exhibit a loss of effectiveness after about age 6, when surviving patients saw declines in motor and lung function. In the long-term, the need for ventilation and nutritional support or wheelchair use increased, whereas cardiomyopathy decreased.
“Over the past decade, it has become increasingly evident that classical IOPD patients who initially respond well to ERT continue to have sustained cardiac benefits, but have a residual myopathy [disease that affects muscles that control voluntary movement] and respiratory decline that progresses despite therapy,” the researchers noted.
According to the scientists, this decline “seems to be multifactorial,” and involves both known and unknown factors that require further investigation.
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