Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years

Abstract

The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.

Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years

“…While a study by van der Ploeg (2010) included walking and nonventilated patients [6], the patients included in this retrospective observational study had a wide spread of disease spectrum including severely affected patients that required NIV (9/22) or were confined to wheelchairs (3/22) [17,19]. This more severely afflicted cohort necessitated careful clinical assessment measures and it was not always possible to get all the relevant tests performed.…”

“…ERT maintained efficacy for 2 years [5] that resulted in stabilization of VCmax following ERT for 3 years and longer in LOPD patients [16,17,18]. There are additional reports showing significant improvement in pulmonary function, preventing or delaying ventilator dependency and prolonging survival [6,18,[19][20][21][22][23][24]25] and led to fewer hospital admissions [24]. ERT also demonstrated improvements in muscle strength, pulmonary function and survival [15].They reported less fatigue and improvement in motor function and quality of life to a variable extent [6,19,24].…”

“…There are additional reports showing significant improvement in pulmonary function, preventing or delaying ventilator dependency and prolonging survival [6,18,[19][20][21][22][23][24]25] and led to fewer hospital admissions [24]. ERT also demonstrated improvements in muscle strength, pulmonary function and survival [15].They reported less fatigue and improvement in motor function and quality of life to a variable extent [6,19,24]. However, there seemed to be up to a third of patients still declining in their motor performance and lung function [6,18,19,24].…”

“…ERT also demonstrated improvements in muscle strength, pulmonary function and survival [15].They reported less fatigue and improvement in motor function and quality of life to a variable extent [6,19,24]. However, there seemed to be up to a third of patients still declining in their motor performance and lung function [6,18,19,24]. The long-term effects of ERT on pulmonary function remain unclear.…”

Autophagy in Natural History and After ERT in Glycogenosis Type II

“…A limited number of ERT trials and observational studies have been published on late-onset patients (van der Ploeg 2010; Strothotte et al 2010;Angelini et al 2012;Regnery et al 2012). An observational study (Deroma et al 2014) in eight juvenile GSDII cases reported marked decrease of CK after ERT and stabilisation of disease course.…”