Pompe disease (glycogen storage disease type II, acid maltase deficiency) is a rare metabolic myopathy caused by a deficiency of lysosomal acid α-glucosidase (GAA), resulting in the intralysosomal accumulation of glycogen. Pompe disease is characterized by a progressive loss of muscle strength and respiratory function and is inherited in an autosomal recessive manner [1]. Historically, supportive care has been the mainstay of treatment. Following decades of research, enzyme replacement therapy (ERT) for Pompe disease was approved in Europe and the United States in 2006, prompting a new era in the treatment of this disease. This was the first disease-specific treatment for an inherited muscular disorder, [2] consisting of the intravenous administration of recombinant human GAA (alglucosidase alfa) [3].

The therapeutic efficacy of alglucosidase alfa was first demonstrated in classic infantile Pompe disease [3, 4]. Patients with classic infantile Pompe disease present with symptoms shortly after birth and develop significant, progressive hypertrophic cardiomyopathy and loss of skeletal muscle function within months if they remain untreated [5]. Cardiorespiratory failure is the primary cause of mortality, typically occurring within the first year of life [5]. With the introduction of ERT, survival in patients with classic infantile Pompe disease has increased significantly; [5] the oldest infants treated with ERT are now 14 years of age [4, 6].

The rapid decline in classic infantile Pompe disease is explained by the complete lack of GAA activity [1]. However, the majority of patients with Pompe disease express some residual GAA activity, leading to a spectrum of disease presentations [7]. In adults, the disease progresses more slowly, with loss of ambulation and wheelchair and respirator dependency developing in later stages of the disease at varying ages [8]. Their primary cause of death is respiratory failure [1, 7].

Trials of ERT in adults were initiated much later than those in infants. The first and only placebo-controlled randomized trial started at the end of 2005 and included 90 patients. Over a period of 78 weeks, treatment with alglucosidase alfa resulted in an improved walking distance on the six-minute walk test and stabilization of pulmonary function, meeting both primary endpoints of the trial [9]. Since 2006, more adult patients are gradually being treated [10–15], but no studies to date have assessed the impact of ERT on survival in adults.

As an ultra-orphan drug, alglucosidase alfa is an expensive treatment; in several countries around the world, its high cost and lifelong administration have led to a debate on its reimbursement in adults. Survival is a key parameter in this discussion. Our centre has systematically collected data on patients with Pompe disease since 2002, before the approval of ERT. This activity has provided a unique set of long-term survey-based data allowing the evaluation of a large international patient population, both treated and untreated. To date, this database has the longest consistent follow-up providing information on patients with Pompe disease prior to and following ERT initiation. Findings from this survey recently revealed that untreated adults with Pompe disease have higher mortality than the general population [16]. Age, wheelchair and ventilator dependency, and level of handicap appeared to be the main indicators of lower life expectancy [16].

The aim of the current study was to use data collected from the same patient survey to explore the potential effect of ERT on survival in adults with Pompe disease. We report here the results of this prospective, international observational study.

This is the first study to show the beneficial effects of ERT on the survival of adult patients with Pompe disease, a clinically meaningful finding especially given the slowly progressive disease course and relatively short treatment period. ERT in Pompe disease was initially approved for all patients in the United States and Europe on the basis of the prolonged survival of severely affected infants with classic Pompe disease and later by the significant gain in walking distance and stabilized pulmonary function in adult patients [8, 9, 20].

We observed the significant effect of ERT on survival as part of an international observational study that provided access to data from 283 adult patients with Pompe disease. Because most adult patients with Pompe disease eventually die of respiratory failure [1, 7], the beneficial effect of ERT on survival is likely to be related to its positive effect on pulmonary function. The hazard ratio of 0.41 indicates that given a specific point in time a patient on ERT has a 59% smaller chance of dying than someone not on ERT. The interpretation of this effect over the entire follow-up period is, however, not intuitive. Because of the time-dependent nature of the analysis it was not possible to estimate the additional years of life gained under ERT. However, we have made ‘ad hoc’ calculations assuming the adjusted HR can be interpreted as a relative risk over approximately 4 years median and 8 years maximum follow-up (from start of treatment). Using the overall raw death rate as an estimate of the raw death rate of the treated population (16%, 46/283), eight years of ERT would result in 1 year of life gained.

Our estimate should be conservative as many patients in our cohort started treatment late in their disease course and ERT was not registered until 2006. It has been hypothesized that starting treatment early in the disease course results in a better clinical outcome [9–11, 13]. Indeed, all patients (with one exception) in the ERT group who subsequently died were dependent on a wheelchair and/or a ventilator and thus had a very advanced stage of disease when they first received ERT. The effect of ERT on survival may therefore be greater if treatment is initiated earlier. In addition, the positive effect of ERT observed in this analysis overall suggests that patients with advanced disease may also benefit from treatment. Further research is required to investigate the association between disease severity and treatment effect.

Collecting sufficient data to demonstrate treatment efficacy is a challenge in rare diseases. Demonstrating improved survival is particularly difficult in a slowly progressive disease such as adult Pompe disease. The opportunity to compare the natural course of Pompe disease with the disease course following ERT highlights the importance of our unique database. In this cohort, the majority of patients switched from being untreated to being treated with ERT during follow-up. Therefore, we conducted Cox regression analyses using ERT as a time-dependent variable, which was considered the most suitable method because it prevents “immortal time” bias. Immortal time bias refers to a period of follow-up or observation time during which death cannot occur, [21] which in our study would be the time until ERT became available for the patients who survived to that time point and received treatment afterward.

Our study was observational and did not have the scientific rigor of a randomized controlled trial, which is generally considered the most appropriate method for comparing the effects of (alternative) treatments. However, a placebo-controlled randomized clinical trial over as many years as in our observational study is not possible nor is it ethically acceptable to conduct; our prospective follow-up study provided a valid alternative [22]. In addition, a clinical trial requires very strict inclusion and exclusion criteria and may not be representative of the entire adult Pompe patient population. Recruitment through a patient organization could also result in more or less severely affected patients being excluded. However, demographic and clinical characteristics of our study population show that patients were included across the entire disease spectrum and were representative of the whole patient population. A number of confounders were adjusted for in the analysis, including age, gender and disease severity, as well as country of residence to capture country specific differences such as variation in approaches to care. Selection bias was further minimized through the time dependent nature of the analysis, as the same patient could contribute to both the untreated and treated period.

Our results were robust across the different models, strengthening our conclusion that ERT positively influences patient survival. We used the equivalent of an intent-to-treat approach, because this is the standard method of analysis used to assess treatment effects in clinical trials. This cohort included 19 patients who stopped treatment during follow-up, and it may be perceived as unfair to include their time after discontinuation of ERT as “time on treatment”. An additional analysis in which patients who discontinued treatment were followed only until the end of treatment provided similar results to the intent-to-treat analyses, but with greater statistical significance.

Enzyme replacement therapy with alglucosidase alfa is currently the only approved disease-specific therapy for Pompe disease. Although not curative, it has changed patients’ perspectives through demonstrated improvements in muscle strength, pulmonary function, and other clinical parameters. Our novel findings reported here show ERT to also have a positive impact on survival of adult patients with Pompe disease. This may be considered an important and clinically meaningful observation, which is particularly relevant with respect to the recent discussion concerning the reimbursement of ultra-orphan drugs.