Increased Myozyme Dosing May Help With Classic Infantile Pompe

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

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Patients with classic infantile-onset Pompe disease could benefit from increased dosing of Myozyme (alglucosidase alfa), an enzyme replacement therapy (ERT) marketed as Lumizyme in the U.S., according to a real-world European study.

Benefits were seen in improved survival and ability to walk. “On the basis of our results, we suggest that the current standard recommended dosage of alglucosidase alfa in patients with classic infantile Pompe disease should be reconsidered,” the scientists wrote.

The study, “Effect of alglucosidase alfa dosage on survival and walking ability in patients with classic infantile Pompe disease: a multicentre observational cohort study from the European Pompe Consortium,” was published in the journal The Lancet Child and Adolescent Health.

Pompe disease is characterized by deficient production or function of acid alpha-glucosidase — the enzyme that breaks down glycogen into glucose (sugar) in cells.

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The classic infantile form of Pompe is characterized by progressive generalized muscle weakness and progressive hypertrophic cardiomyopathy — a condition in which the heart muscle becomes abnormally thick and enlarged. These characteristics prevent affected children from achieving developmental milestones, like rolling over or walking, and typically lead to death within the first year of life without early treatment.

Yet the availability of ERT has led to improved survival, motor outcomes, and cardiac function in infants with classic infantile Pompe disease.

This study, in collaboration with the European Pompe Consortium, worked to evaluate the effects of Sanofi Genzyme‘s Myozyme regimens on overall survival and walking ability. A total of 124 patients diagnosed in France, Germany, Italy, and the Netherlands between Oct. 26, 1998, and March 8, 2019, were followed.

Most participants, 116, were treated with Myozyme, while eight were not. ERT was started at a median age of 3.3 months.

Mean follow-up was 60.1 months (five years) for those who received ERT and were included in the analysis and 2.1 months for those who did not. The median age for symptom onset was 1.2 months, with median age of diagnosis being 3 months.

Most patients had disease-causing mutations in both copies of their GAA gene — the gene coding for acid alpha-glucosidase. Eight of the mutations had not been reported before this study.

A majority of the participants, 55%, received the same dosage throughout the observation period. Thirty-one patients received the standard dosage of 20 milligrams per kilogram (mg/kg) every other week, 15 received an intermediate dosage of 20 mg/kg per week or 40 mg/kg every other week, and 18 patients received a high dosage of 40 mg/kg per week.

Of the patients, 42% had their dosing changed during follow-up. Dosage was increased in 28 patients, decreased in five patients, and variable (increased and decreased) in 15 patients. One patient’s starting dosage was 20 mg/kg every other week, which was changed to 30 mg/kg with unknown frequency. The exact dosage regimen was unknown in four patients.

The reasons for prescribing doses of Myozyme higher than the standard included severe disease state, the clinician’s personal experience, insufficient response, and respiratory insufficiency.

“The majority of physicians treating patients with classic infantile Pompe disease are not satisfied with the outcome of their patients on the standard recommended dosage,” based on the way dosing was adjusted, the researchers suggested.

Myozyme dosage was decreased in five patients during follow-up due to either good response to treatment, insufficient treatment response, or the parents’ decision.

The eight untreated patients all died within 11 months of birth due to cardiac arrest, progressive heart failure, or respiratory insufficiency.

During follow-up, 36 of the 116 treated patients died, with a median age at death of 22.3 months.

Among those patients who received a constant dosage of ERT, 16 (52%) on the standard dosage, 12 (80%) on an intermediate dosage, and 16 (89%) on the high dosage were alive at the last follow-up.

Results showed a significant difference in the five-year survival rate between the standard and high dosages. Overall survival was significantly longer in those given the high dosage as compared with patients given the standard dosage. No such difference was found with the intermediate dosage.

With regards to the group on variable dosage regimens, 20 of 28 patients (71%) treated with the increased dosage, 12 of 15 patients (80%) treated with variable dosages, and three of five patients (60%) treated with decreased dosage were alive at last follow-up.

Survival was highest for patients started on the high dosage and lowest for participants started on the standard dosage, with a similar pattern observed when comparing survival for final dosages.

Without treatment, children with classic infantile Pompe disease are usually never able to walk. As such, treated patients who survived past 18 months were evaluated for this milestone.

Of the 86 children fulfilling this criterion, 44 (51%) learned to walk at a median age of 16 months. The proportion of patients who learned to walk was higher in the high dosage group (93%) than in the standard (53%) or intermediate dosage groups (67%). However, there were no significant differences between the groups.

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Among these 44 patients, five of 10 patients treated with the standard dosage, four of six patients treated with intermediate dosage, and 12 of 14 patients treated with a high dosage maintained the ability to walk throughout follow-up.

In the group with less than 18 months of follow-up, two out of 30 participants learned to walk. One of them received variable dosage and one received an increased dosage.

Overall, “our results, which are consistent with literature, suggest that high dosage ERT given with a high frequency would optimise glycogen clearance from the cells and clinical outcome in patients with classic infantile Pompe disease,” the researchers wrote.

“From our real-world data, we conclude that survival in patients with classic infantile Pompe disease is significantly improved and that a higher proportion of patients learn to walk when treated with a dosage of 40 mg/kg per week, compared with the current standard dosage of 20 mg/kg every other week,” they added. “Based on these results, we suggest that the currently registered dosage should be reconsidered.”