Avalglucosidase alfa in infantile-onset Pompe disease: A snapshot of real-world experience in Italy

Abstract

Introduction: Infantile-onset Pompe disease (IOPD) is due to mutations in the GAA gene leading to profound deficiency of the lysosomal enzyme α-1,4-glucosidase. The disease is characterized by severe hypotonia, hypertrophic cardiomyopathy, macroglossia, and liver enlargement with onset in the first months of life. In the late-onset form (LOPD), muscle signs predominate with a clinical picture resembling muscle dystrophies. Enzyme replacement therapy with alglucosidase alfa (rhGAA) has been available since 2006 and patients treated with the enzyme show improved outcomes. Nevertheless, there is evidence that some patients have a suboptimal response or, after an initial improvement, reach a plateau with stabilization of the clinical picture. Thus, a new enzyme formulation, avalglucosidase alfa (neoGAA), with a higher degree of mannosylation, was developed.

Methods: We conducted a multicenter survey that collected data on four patients with IOPD, aged 6 to 16 years, who were switched to neoGAA thanks to a compassionate use program, after being treated for an average of 11.5 years with rhGAA. Follow-up data, including biochemical parameters and clinical features, were analyzed to determine clinical outcomes and the safety profile after a mean of 9 months.

Results: Patients with IOPD who were treated with neoGAA showed a positive change in biomarker levels. Moreover, the clinical picture revealed improved motor performance and cardiac parameters in patients who previously responded poorly.

Conclusion: This study highlights the improved efficacy of neoGAA, as a next generation enzyme replacement therapy, in 4 Italian patients with IOPD. Several clinical parameters showed a positive response to the new formulation suggesting that, if used at diagnosis, neoGAA may result in better outcomes for patients with IOPD.

Fig. 1

Patient #1. Color Doppler echocardiogram at baseline before the switch to neoGAA (a-b) showing marked myocardial hypertrophy (white and yellow lines), reduced in T3, after 9 months of ERT with neoGAA (c-d). Electrocardiogram at baseline (e) showing biventricular overload with high narrow QRS, Q waves, ST-segment elevation, and negative T in all leads; at T3 (f), the biventricular overload is markedly reduced (reduced QRS height RV > Vsn), the ST segment is no longer elevated, and negative T waves in the left leads disappeared.

Fig. 2

ALT, AST, CK, and LDH after initiation of neoGAA therapy in the four patients. Data on uGLC4 pre- and post-neoGAA were available for 3 of 4 patients. In Case #2, uGLC4 before neoGAA was 77 mmol/mol Creatinine (Cr) (range 49–122; nv 0.08–1.37 mmol/mol Cr); after 3 months of treatment uGLC4 excretion was 2.78 mmol/mol Cr. Case #3 had an uGlc4 of 9.51 mmol/mol Cr after 15 months of neoGAA, passing to 7.56 mmol/mol Cr after 18 months. In case #4, uGLC4 decreased by 10% after 9 months of therapy (from 28.9 mmol/mol Cr to 25.5 mmol/mol Cr.

Fig. 3

Changes in anti-rhGAA and anti-neoGAA antibodies after starting treatment with neoGAA in cases #1 (a) and #2, (b).