The only effective treatment for Pompe disease (PD) is enzyme replacement therapy (ERT), which requires regular injections of acid alpha-glucosidase (GAA), the enzyme that is deficient in PD patients. Since the first approval of ERT in 2006, significant improvements have been noted in the outcomes of PD patients with infantile-onset (IOPD) and late-onset (LOPD) forms of the disease.
However, follow-up studies of LOPD patients pointed to a secondary stabilization or decline in outcomes after an initial improvement. These studies were mostly limited to less than 5 years follow-up. Hence, long-term outcomes remain largely unknown.
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Several reasons contribute to the difficulty in establishing the general long-term effects of ERT on LOPD progression. These include the wide range of phenotypic presentations observed in individual studies, the very low prevalence of the disease in the general population, and the small sample sizes enrolled in published studies.
Nonetheless, efforts have been made to gather information on this important topic. For instance, Dornelles et al conducted a systematic search and meta-analysis to review the impact of ERT on key outcomes of LOPD patients. The study was recently published in the Journal of Clinical Medicine.
Also, a multicenter team of researchers determined the real-world long-term efficacy and safety of alglucosidase alfa in LOPD patients from 4 countries (Spain, Taiwan, Italy, Germany (STIG)).
“The aim of the STIG study was to evaluate the efficacy of alglucosidase alfa [Myozyme®] in a long-term period, as to date there is only limited knowledge on long-term courses over more than 5 years,” the authors said. The results from the STIG study (NCT02824068) were recently published n the Journal of Neurology.
Some Improvements in Functional Capacity
The outcomes evaluated by Dornelles et al included functional capacity parameters, upper-limb strength, quality of life (QoL), and time on ventilation (TOV). On the other hand, they did not analyze sleep quality or swallowing disorder due to the lack of studies matching the inclusion criteria.
Regarding patients’ functional capacity, conclusions were as follows:
- Forced vital capacity (FVC): no evidence of improvement during the performance of spirometry in the sitting, supine, or orthostatic positions (within-group mean change, 0.41%, 95% confidence interval [CI], -0.3%-1.12%). The conclusion was based on data from 15 studies (participants = 348, mean follow-up = 36.8 months) with low heterogeneity between studies and very low certainty of evidence.
- Six-minute walking test (6MWT): evidence of clinically significant improvement after ERT (within-group mean change, 35.7 months, 95% CI, 7.78-63.75). The conclusion was based on 14 studies (participants = 348, mean follow-up = 36.8 months) with considerable heterogeneity between studies and very low certainty of evidence.
- Walton and Gardner-Medwin Scale (WGMS): no effect observed in any of the included studies. The conclusion was based on 6 studies with very low certainty of evidence due to imprecision in the results of the studies.
No significant difference was observed in upper-limb strength, overall QoL, or mental component of the 36-item short form survey (SF-36). However, researchers did find a difference in the physical component (mean change, 1.96, 95% CI, 0.33-3.59).
Moreover, they found a weak evidence of a positive effect of ERT on TOV (mean change, -2.64 hours, 95% CI, -5.28-0.00).
“In conclusion, alglucosidase alfa effectively increases the distance achieved in 6MWT, improves the physical component of QOL, and may decrease TOV in treated patients. Stabilization of functional capacity, measured through FVC, was not confirmed,” the authors wrote.
Safety analysis included data on adverse events, mortality, and anti-alglucosidase alfa antibody (Ab) titers. Survival was not evaluated due to the lack of studies matching the inclusion criteria.
“Although most patients presented with elevated Ab titers, few showed a reduction in response to treatment or higher incidence of AEs,” they concluded.
Reported adverse events were mild and included tachycardia, desaturation, malaise, chills, facial erythema, erythema at the enzyme infusion site, urticarial reactions, hyperhidrosis, chest discomfort, vomiting, systemic arterial hypertension, flu-like symptoms, pruritus, bronchospasm, and hyperthermia.
According to mortality data retrieved from 9 studies, Dornelles et al calculated an incidence rate of death (events per person-year) of 4.4 events per 1000 person-years (95% CI, 1.5-12.8).
The STIG study
According to the STIG study, which enrolled 68 patients with LOPD, there is an initial positive effect of ERT on the most important outcome measures. However, the long-term benefit is more limited.
The 6MWT showed the most sustained positive effect after 10-year follow-up (P =.304). The Medical Research Council (MRC) grading scale remained stable, with a mild decline (P =.131). However, lung capacity declined over 10 years of ERT, with patients showing an FVC decline of almost 15%. This was associated with an increased necessity of ventilation in patients over time.
To conclude, the research team highlights the need for standardizing the clinical follow-up in LOPD patients.
“In addition to the frequently and regularly performed outcome measures like MRC, FVC sitting and 6MWT, especially FVC in the supine position, [maximum inspiratory pressure] and [maximum expiratory pressure] as well as disease-specific [patient-reported outcomes], eg, [Rasch-built Pompe-specific activity], and timed functional outcome measures should be part of each routine follow-up visit, at least once a year,” they recommended.
Dornelles AD, Junges APP, Pereira TV, et al. A systematic review and meta-analysis of enzyme replacement therapy in late-onset Pompe disease. J Clin Med. 2021;10(21):4828. doi:10.3390/jcm10214828
Gutschmidt K, Musumeci O, Díaz-Manera J, et al. STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa. J Neurol. 2021;268(7):2482-2492. doi:10.1007/s00415-021-10409-9