Search results
After screening 4286 titles and abstracts, 237 full-texts were retrieved and screened. Thirty-eight studies (encompassing 106 unique records) were included in the review: three RCTs (LOTS [3], PROPEL [24] and COMET [25]), three RCT extension studies [26, 27, 28], seven Pompe disease registry studies [29, 30, 31, 32], and 25 observational studies.
Enzyme Replacement Therapy in Late-Onset Pompe Disease: A Review of current evidence
Late-onset Pompe disease (LOPD), a rare inherited metabolic disorder, results from a deficiency in acid alpha-glucosidase (GAA) enzyme activity, leading to glycogen accumulation primarily in skeletal muscle. This deficiency causes progressive muscle weakness, impacting mobility, respiratory function, and ultimately, quality of life.Enzyme replacement therapy (ERT) with alglucosidase alfa has become the standard of care for LOPD, aiming to reduce glycogen buildup and improve clinical outcomes. This review summarizes the current evidence regarding the efficacy and safety of ERT in adult patients with LOPD.
Clinical Efficacy of ERT
Several studies have investigated the long-term effects of alglucosidase alfa in LOPD patients. Initial studies demonstrated improvements in muscle strength and respiratory function following ERT initiation [41, 42]. However, the response to treatment is highly variable [46].
The six-minute walk distance (6MWD) has emerged as a valuable outcome measure for assessing motor decline and treatment response in LOPD [40]. Studies have shown that ERT can stabilize or even improve 6MWD in some patients, indicating a positive impact on functional capacity.
Long-term observational studies, such as the prospective international study by Gungor et al., have reported a correlation between ERT and improved survival rates in adults with LOPD [44]. however, these benefits are often observed in patients who initiate treatment early in the disease course.
Furthermore, advancements in manufacturing have led to the production of alglucosidase alfa at a larger scale (4,000 liters), demonstrating efficacy, a favorable safety profile, and manageable immunogenicity in pediatric and adolescent patients [45].While this study focused on younger patients,it reinforces the potential benefits of optimized ERT formulations.
Safety and Administration of ERT
Alglucosidase alfa is generally well-tolerated, but infusion-related reactions (IRRs) are common, notably during initial infusions. These reactions typically manifest as mild to moderate symptoms like fever, chills, and rash. Pre-medication with corticosteroids and antihistamines can effectively mitigate IRRs [43].
The implementation of home-based infusions has proven to be a safe and convenient option for many adult LOPD patients, with lessons learned from extensive experience (over 18,380 infusions) demonstrating its feasibility and safety [43]. This approach enhances patient autonomy and reduces the burden of frequent hospital visits.challenges and Future Directions
Despite the benefits of ERT, meaningful challenges remain. The variability in treatment response highlights the need for personalized approaches and the identification of biomarkers to predict treatment outcomes. Further research is needed to understand the factors influencing treatment response, including genetic modifiers, disease severity at diagnosis, and individual patient characteristics.
The development of novel therapies, such as gene therapy and chaperone therapies, holds promise for addressing the underlying genetic defect in LOPD and perhaps offering more durable and effective treatment options.
Study details and baseline characteristics
The LOTS RCT evaluated the safety and efficacy of alglucosidase alfa compared to placebo (plus BSC). The COMET and PROPEL RCTs assessed the safety and efficacy of avalglucosidase alfa and cipaglucosidase alfa plus miglustat,respectively,compared to alglucosidase alfa. Mean ages across the three trials ranged from 44 to 48 years (Table 2,Additional file 2). The proportion of participants using a walking aid at baseline was 43% in LOTS and 23% in PROPEL (data were not reported for COMET). LOTS and COMET recruited only ERT-naïve patients, whereas PROPEL recruited mostly ERT-experienced patients.
Of the seven registry studies, there were three studies from### IPD from eligible trials
IPD was sought from the three identified RCTs: PROPEL, LOTS and COMET. Though, no IPD was provided by any of the sponsors. Amicus Therapeutics was contacted regarding sharing data from the PROPEL trial. in email correspondence,Amicus Therapeutics representatives indicated they were working on a process and platform to make these data available but failed to respond to further email contacts. Access to data from the LOTS and COMET trials was sought from the sponsor Sanofi via the data-sharing platform Vivli. sanofi declined the request stating that they considered the proposed research not to be in the interest of patients or the patient community.
in the absence of IPD from the sponsors of the RCTs, we digitised the mean difference plots of the outcomes (FVC % predicted and 6MWD) using the PlotDigitzer website (
### Risk of bias assessment
Risk of bias assessment results are presented in Additional file 2, Table 1. The COMET trial results were judged to have a low overall risk of bias but the LOTS and PROPEL trial results were judged to be at high risk of bias. Both LOTS and PROPEL had high risk judgements for the ‘bias in the selection of the reported result’ domain, since both trials failed to report results for all pre-specified analyses, as noted in the respective EMA reports [60, 61].
Another study quality issue identified was the reporting of results using only means in the published reports. Results data from regulatory documents showed skewing of the 6MWD data by outliers, with the means and medians differing substantially. The reporting of only means in the presence of outliers in a sample is not an accurate portrayal of the efficacy data. For example, the FDA reported that in COMET the mean change in 6MWD from baseline to week 49 for the alglucosidase arm was −1.7 m, whereas the median was 16.0 m; [20] the EMA reported that in LOTS the mean change in 6MWD from baseline to week 78 for the alglucosidase arm was 26.1 m, whereas the median was 15.0 m [62].
### NMAs of RCT evidence
Results from the primary analysis are reported on Table 1 and results of the sensitivity analyses and additional analyses are presented in Additional file 2.
In the primary analysis of FVC % predicted at 49/52 weeks, the results indicate that all three ERTs exhibit numerical superiority over placebo (which includes BSC). Though, the estimated mean differences did not reach statistical significance for any of the ERTs (Table 2). In contrast, for 6MWD there were statistically significant improvements compared to placebo for both alglucosidase alfa (by around 25 m) and avalglucosidase alfa (by around 54 m). Cipaglucosidase alfa with miglustat, while numerically superior to placebo, did not show statistically significant differences. Credible intervals for this comparison were wide, reflecting the small number of ERT-naïve patients in the PROPEL trial.
Analysis of additional time points revealed a consistent pattern (Additional File 2 – Tables 8 and 9), with no statistically significant differences.### Registry studies
Semplicini et al. [32] followed 158 patients for a median of around five years,finding a 1.4% annual increase in % predicted 6MWD up to 2.2 years, followed by a 2.3% decline (Table 2, Additional file 3).For muscle function outcomes,the Motor Function Measurement D2 sub-score showed a progressive 1.0% decline per year, and the D3 sub-score had a slower progressive decline (0.2% per year).
Tard et al. reported on the effect of switching from alglucosidase alfa to avalglucosidase alfa in 29 patients, reporting stabilization of 6MWD results after one year of avalglucosidase alfa (when compared to pre-switch one year data, which showed declines) [34].the reporting of 6MWD results data in Lefeuvre et al.’s study was somewhat unclear,even though the treated population experienced a decline in 6MWD. Martinez-marin et al.’s Spanish registry study reported yearly 6MWD declines of between 5 and 9 m in subgroups treated for < 5 years, 5-10 years and > 10 years [35].
All studies reported FVC % predicted, mostly as a long-term outcome. Annual declines in %FVC after up to five years of ERT ranged between 0.17% and 0.9%. Declines at time points between 5 and 13 years were similar across two studies ranging between 1.0 and 1.2% [29, 35]. Tard et al.found no statistically significant difference in %FVC in patients who switched ERT [34]. Three studies reported mortality, with mean or median ages at death ranging between 60 and 66 years [29, 32, 33].
### Other prospective studies
#### 6MWD results
The reporting of the 18 studies with 6MWD results varied (Table 5, Additional file 3). Only three studies reported results as medians [39, 48, 53] and only seven reported results as changes from baseline as absolute values [2, 36, 40, 47, 48, 51, 58]; five studies reported results as changes in % predicted 6MWD [41, 46, 55, 57, 58]. The remaining studies either reported results only graphically [49], or reported baseline and end of follow up data but with the difference represented only as a p-value[Angelini C, Semplicini C, ravaglia S, Bembi B, Servidei S, Pegoraro E, et al. Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy fo