Enzyme Replacement Therapy Loses Effectiveness in Pompe Patients with Long-term Use, Study Suggests 

Long-term enzyme replacement therapy (ERT) to treat people with Pompe disease loses effectiveness in maintaining walking ability, muscle strength, and lung function, a new study shows.

Despite these results, ERT improved lung function when compared to the predicted outcome without ERT, and some patients responded well to the long-term therapy while others did not.  

The study, “Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease,” was published in the journal Neurology. 

Pompe disease is a rare, inherited disorder caused by mutations in a gene that make an enzyme called acid alpha-glucosidase (GAA). A lack of GAA activity suppresses the body’s ability to convert glycogen — an energy storage molecule — into sugar that provides fuel to cells. This leads to the abnormal buildup of glycogen inside cells, which impairs tissues and organs. 

Enzyme replacement therapy with recombinant human GAA has become standard care in the treatment of patients with Pompe disease. ERT has been shown to improve walking ability and muscle strength, stabilize lung (pulmonary) function, and increase a patient’s chance of survival. 

However, short-term studies have found that the benefits of ERT peak after two to three years of treatment, followed by a plateau or a decline in effectiveness. Beyond five years, it is not known if the plateau continues or leads to a more rapid decline. Moreover, several studies have reported “substantial individual differences in treatment benefit,” the authors wrote.

To understand the long-term outcome of ERT, researchers at the Erasmus MC University Medical Center in the Netherlands and the Pitié-Salpêtrière University Hospital in Paris, France, collaborated in following 30 patients who continued ERT for 10 years after their participation in two clinical trials: Late-Onset Treatment Study [LOTS] (NCT00158600) and its extension study (NCT00455195). 

These trials tested the effectiveness of ERT in patients with late-onset Pompe disease — a form of Pompe that appears in late childhood to adulthood. 

The team investigated the effects of ERT on walking ability, muscle strength, and pulmonary function, and additionally looked at each individual’s response to treatment.

Walking ability was determined using the 6-minute walking test (6MWT) — the distance an individual is able to walk in six minutes. Muscle strength around the neck, shoulders, elbows, hips, and knees was measured using the Medical Research Council muscle strength grading scale.

Lung function was assessed by measuring the forced vital capacity (FVC), or the total volume of air that can be blown forcefully following a full inhalation. 

Of the 30 Pompe patients (14 men and 16 women) evaluated, 20 were from the Netherlands, and 10 were from France. The median age of the group was 49 years, and they were followed for a median length of 9.8 years. 

The analysis of the group as a whole showed that, at the beginning of ERT, the average 6MWT was 49% predicted (compared to similar healthy people). During ERT, the walking distance increased over the first three years, then significantly declined until the average 6MWT was lower than it was at the start of treatment. These findings were independent of the sex of the patient, or disease duration and severity. 

By the end of the follow-up period, 13 patients (43%) had become partially or fully wheelchair-dependent compared to seven patients (23%) before the start of ERT.

The muscle strength scores reflected this trend, as they were lower after ERT than they were before the treatment. Muscle strength scores were found to be dependent on the sex and walking ability of the patient. Men that had better walking abilities before treatment showed less decline in muscle strength compared to women. 

The analysis of lung function showed an initial percent-predicted FVC of 54% when patients were sitting upright, and 33% when lying down (supine). 

Overall, the FVC in the upright position remained stable for the first five years, and significantly declined over the next five years. The supine FVC was found to decline from the start of ERT. These results were independent of sex, or disease duration and severity. 

However, relative to the predicted FVC decline without ERT, patients had significantly better pulmonary function after 10 years of ERT. 

A high degree of variability was observed between the patients in their responses to treatment. For example, five patients continued to respond positively over the 10 years, whereas two patients did not respond to treatment at all. 

While most patients responded well at the beginning of ERT (93%), predicting their change in responsiveness was difficult. Some patients respond well for up to eight years while others declined after one or two years. 

Outcomes differed among the individuals as well. Some patients had improved walking abilities but reduced lost lung function, and others experienced the opposite. At the end of 10 years on ERT, half of the patients had improved walking abilities or lung function, or both. 

A safety assessment of ERT for 10 years found that it was well-tolerated with two patients stopping the treatment due to injection-related issues or high levels of anti-GAA antibodies. 

“Although >90% of patients benefit from ERT for the first 3 to 5 years, the observed secondary decline, suggesting diminished therapeutic efficacy over time, raises concerns and stresses the need for next-generation therapies,” the authors said.