Data Proves Inability of Available ERTs to Reverse or Stabilize Pompe

Data published in The Orphanet Journal of Rare Diseases confirmed that currently-available enzyme replacement therapies are unable to reverse or stabilize the progression of Pompe disease.

Data published in The Orphanet Journal of Rare Diseases last week confirmed that, while currently-available enzyme replacement therapies (ERTs) do provide better outcomes for cross-reactive immunological (CRIM)-positive patients with Pompe disease than alternative methods, the current therapeutic approaches are unable to reverse or stabilize the progression of the disease.

The study, “Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy,” was led by Rossella Parini, M.D. of the Pediatric Rare Diseases Unit in the Department of Pediatrics at Università degli Studi di Milano-Bicocca. It was a multicenter observational study taking place at 13 clinics throughout Italy, intended to evaluate and analyze the long-term effectiveness of ERTs in infantile onset Pompe disease (IOPD). A cohort of 28 patients (15 females, 13 males) were enrolled, each of whom was born between February 2002 and January 2013. All patients had IOPD diagnosed based on clinical symptoms, enzymatic and molecular analysis, and each received ERT within the first year of life.

Clinical, laboratory and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 5 years, 11 months.

In patients with Pompe disease, a deficiency of the lysosomal acid α-glucosidase (rhGAA) enzyme causes an accumulation of glycogen in the lysosome. ERT with recombinant human rhGAA became commercially available or IOPD patients in 2006 after positive data was reported from 2 pivotal studies, exhibiting the therapy’s ability to progress motor function, and improve cardiomyopathy and prolonged survival.

“Our study presents the results of a retrospective analysis of the clinical outcome of 28 Italian IOPD patients receiving ERT,” it was noted in the study. “To our knowledge this is the longest independent follow-up study in a heterogeneous group of IOPD patients.”

All patients received alglucosidase-alfa treatment within the first 12 months of age, and baseline ERT dosage was 20 mg/Kg/every other week in 26 patients, while the other 2 patients, who had participated in a clinical trial were administered 40 mg/Kg every other week. Because of poor clinical outcome or to infusion associated reactions (IAR), ERT dosage was adjusted in course of follow-up in 7 patients.

Both at the time of diagnosis and the start of treatment, all patients showed muscle weakness and hyptonia, increased serum CK and severe hypertrophic cardiomyopathy, with increased thickness of septum and left ventricular wall. Eight of the 28 patients had respiratory distress and one needed respiratory support.

The study concluded that the survival data analysis confirmed the poorest prognosis of CRIM-negative patients of any retrospective analysis of IOPD patients receiving ERT. The poor prognosis, it appears, is directly associated with the presence of elevated anti-rhGAA antibodies titers.

“In conclusion, after 10 years of ERT we are aware of the long-term poor outcome of CRIM-negative patients but at the same time it has emerged that many CRIM-positive patients, in spite of an initial ERT positive response fail to improve or stabilize their clinical conditions,” the study concluded. “The development of neonatal screening programs, allowing a very early pre-symptomatic beginning of ERT could lead to a significant improvement of the clinical outcome.”

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  1. Parini R, De Lorenzo P, Dardis A, et al. Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy. Orphanet Journal of Rare Diseases, 2018; DOI: 10.1186/s13023-018-0771-0.