Effects of a higher dose of alglucosidase alfa on ventilator‐free survival and motor outcome in classic infantile Pompe disease: an open‐label single‐center study

Abstract

BackgroundThough enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome.MethodsEight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated.ResultsAll eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3–5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation.ConclusionsOur data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease

“…Early initiation of rhGAA infusion after diagnosis through NBS improves the outcomes of IOPD, but muscle weakness, ptosis, and speech disorders still occurred [7], [17]. An increase in the dosage or frequency of rhGAA infusion appears to provide some benefits to these patients but is not sufficient to prevent residual symptoms [7], [22], [23]. In the current study, we demonstrated that albuterol speeded the climb of patients and selectively improved muscle function and movement quality, but we could not prove its benefit in the 6MWT consistently nor its significant benefit in other measurements.…”

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

“…However, recent advances in immune modulation with ERT have enhanced survival in CRIM‐negative patients and these patients have a new and emerging phenotype but data on pulmonary function tests has yet to be collected 54 . We will need to evaluate more of the patients with IPD over time to assess the impact of genotype, ACE genotype, CRIM status, and dose escalation on the rate of decline of FVC 19,22,41 . Finally, because these children had variable efforts with their maximal inspiratory and expiratory strengths measurements, these data were difficult to interpret.…”

Improvement in Cardiac Function With Enzyme Replacement Therapy in a Patient With Infantile-Onset Pompe Disease

“…Recent studies have demonstrated the increased effectiveness of higher doses of enzyme replacement therapy in infantileonset Pompe disease. 5,6,11 Case et al (2015) demonstrated the efficacy of alternative enzyme replacement therapy regimens (high frequency at 20 mg/kg weekly or high dose at 40 mg/kg every 2 weeks) in initially responsive patients who had experienced declining function on standard enzyme replacement therapy (20 mg/kg every 2 weeks). 5 Their patients demonstrated an overall trend for motor improvement from baseline after 52 weeks of the more intensive enzyme replacement therapy.…”

“…van Gelder et al (2016) reported that their data may suggest that a dose of 40 mg/kg weekly vs the currently recommended dose of 20 mg/kg every 2 weeks improves outcomes for CRIM-positive patients. 6 New trials in Pompe disease based on gene therapy are currently ongoing. 12 However, treatment of severe cardiac disease remains quite challenging.…”

“…However, given the severity of her symptoms and systolic dysfunction, the frequency was increased to weekly starting with the third dose based on evidence from studies that had demonstrated increased efficacy at higher doses. 5,6 Testing for crossreactive immunological material (CRIM) status was positive, requiring immune modulation (immune tolerance induction) with a low-dose immunosuppressant (methotrexate) and leucovorin rescue. The patient's immunoglobulin G (IgG) antibody titers were low after initiation of enzyme replacement therapy at the standard dose and did not increase as a result of the increased dosage.…”