Home-based enzyme replacement therapy in children and adults with Pompe disease; a prospective study

Pompe disease, or glycogen-storage disease type 2 (OMIM #232300), is a progressive lysosomal myopathy. The disease is caused by a deficiency of the enzyme acid α-glucosidase (GAA; EC number 3.2.1.20). A differentiation is made between the classic infantile form, in which patients develop a severe cardiomyopathy and respiratory insufficiency and die before the age of 1 year without treatment, and non-classic or late-onset Pompe disease, which can be divided into atypical, childhood onset and adult Pompe disease. In the late-onset forms, patients present with an axial and limb-girdle pattern of muscle weakness and weakness of the respiratory muscles at any age but do not have a hypertrophic cardiomyopathy. An exception to this are atypical infantile patients, which do have a hypertrophic cardiomyopathy but are more mildly affected than their classic infantile counterparts [1‐5]. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme) has been available [1]. In classic-infantile Pompe patients, ERT prolongs lifespan, enables patients to reach previously unmet motor milestones, improves motor outcomes and ventilator-free survival, and generally leads to normalisation of the left ventricular mass index (LMVI) in the majority of classic-infantile patients [6‐10]. Notably, classic infantile patients can nowadays reach adulthood due to treatment with ERT. In late-onset patients, ERT improves or stabilises skeletal muscle strength, muscle function, and respiratory function; in addition, survival is improved [11‐19].

Since 2008 home-based ERT has been provided for Pompe patients in the Netherlands, as this diminishes the burden of treatment, allows for more patient flexibility and autonomy [20] and is thus a more patient-centred approach to ERT. Over 80% of Dutch Pompe patients receive their infusions at home. However, in most countries, ERT is only provided in hospital due to the risk of severe infusion associated reactions (IARs) reported on the label, such as anaphylaxis, severe allergic and immune-mediated reactions and risk of cardiorespiratory failure [21, 22].

We recently demonstrated that home-based ERT can be safely provided in adults with Pompe disease [23] based on the analysis of 18,380 infusions. In the present study, we further investigated the safety of home-based therapy by conducting a prospective survey over one year in children and adults, covering the whole Pompe disease spectrum. We included patients with the classic infantile, atypical infantile, childhood onset and adult phenotypes. Patients were asked about complaints during infusion and the 24 to 48 h afterwards, as in the literature, IARs are also reported in the 48 h after alglucosidase alfa administration [24]. Additionally, we assessed the ability of our current protocol to capture minor health complaints, to further optimise care with home-based infusions for Pompe disease if needed.

The results of this prospective study demonstrate that home-based ERT in Pompe disease can be safely implemented in both classic infantile Pompe patients receiving high dosage ERT (40 mg/kg/week) and late-onset patients as few, mostly mild, symptoms were reported during or after infusion. Only a few IARs occurred during the study period, and none needed emergency clinical care. This is in line with a previous long-term follow-up study, which demonstrated that alglucosidase alfa can be safely administered at home in adult patients with Pompe disease [23]. Despite home-infusions not being included in the summary of product characteristics (SmPC) due to the risk of anaphylaxis, severe allergic and immune-mediated reactions, and risk of cardiorespiratory failure in response to alglucosidase alfa [21, 22], home-infusion with alglucosidase alfa should be considered. Patients’ quality of life is negatively impacted by time-consuming infusions [27]; home-based ERT can diminish the burden of treatment, increase patient flexibility and autonomy [20], and is, thus, a more patient-centred approach to ERT.

Most patients in this study indicated that they did not experience any health complaints before infusion. The reported health complaints were mostly mild. Fatigue, headaches and feeling generally unwell were most frequently reported during and within 24 h after infusion; symptoms subdued after that in most patients. Whether the fatigue or headaches were caused by the alglucosidase alfa infusion (i.e. IARs), Pompe disease itself or environmental factors (such as having a nurse by your side for several hours or being limited in your activities) remains unknown. Fatigue is a common symptom of Pompe disease and has been reported in 24% up to 85% of adult Pompe patients [28‐31]. Hence, unsurprisingly, fatigue was reported in 9.5% of patients during or after infusion in our study. Possible explanations for fatigue in Pompe disease include peripheral fatigue from both skeletal and respiratory muscle weakness [29], with respiratory muscle weakness potentially leading to daytime sleepiness and fatigue [29, 32, 33]. Central fatigue may also play a role, with a sense of cognitive, psychosocial or mental exhaustion leading to fatigue [28, 29]. We postulate that fatigue is multifactorial and that both peripheral fatigue as well as central fatigue may contribute to fatigue in Pompe disease [29, 34]. It has been reported that fatigue improves significantly during ERT in several patient subgroups [28]. To manage fatigue and treat Pompe disease in general, treatment options such as rehabilitation, exercise and nutritional interventions should be considered [28, 35], as these can be complementary to ERT [35‐37]. In addition to fatigue, headaches were reported relatively often during or after infusion (in 7.6% of patients). However, this may not be due to ERT per se. It should be noted that some Pompe patients experience headaches caused by nocturnal hypoventilation due to diaphragmatic weakness, though morning headaches upon waking up are more exemplary of this [33]. A prior study in a cohort of 73 patients demonstrated that 15% of patients with IARs experienced fatigue, and 23% of patients with IARs experienced headaches [24]. However, fatigue and headaches constituted a smaller fraction of IARs in this study [24] compared with the higher fraction of these health complaints in our study, possibly due to our study method; using a home infusion cohort and the primary outcome measure being symptoms reported by patients rather than IARs reported to the hospital.

Interestingly, gastrointestinal complaints such as abdominal pain, diarrhoea, heartburn and vomiting were only reported within 24–48 h after infusion but not during infusion. We could not find an explanation for the mere occurrence of gastrointestinal complaints after the administration of ERT. Still, temporary worsening of GI symptoms has been previously described within 48 h of ERT infusion [38]. We cannot rule out that these are side effects of ERT [39]. However, gastrointestinal complaints have also been reported to be part of the symptom complex in Pompe disease [40, 41], for glycogen accumulates in smooth muscle throughout the gastrointestinal tract [40, 42‐49]. Overall, ERT has been reported to lead to long-term improvements in GI symptoms [40, 41]. All symptoms that patients in this study reported are also included in the summary of product characteristics (SMPC) of alglucosidase alfa [22].

Of the health complaints reported in this study, only four (14.8%) were reported to the treating hospital as an IAR. Thus, there was underreporting of health complaints to the Erasmus MC University Medical Center. However, these health complaints were all either mild, pre-existing, had an unclear relation to ERT, or occurred after infusion. Though mild symptoms, such as fatigue or headache, do not pose an immediate health risk to patients, these complaints may be important to the patient. This highlights the importance of patient-reported outcomes in the evaluation of medical care, as these may help clinicians address reported symptoms better and generate data that are truly relevant to the patient and complementary to clinical data [31]. To improve individual patient care, it is thus essential to inquire whether the patient experiences minor health complaints around infusions during outpatient clinic visits. If any complaints are reported, then the burden of these complaints should be explored, and medical action should be taken if necessary.

Interestingly, of the patients who indicated feeling sick or ill before infusion, 38.5% experienced health complaints during infusion, versus 5.3% of patients who were not sick or ill before infusion. This may imply that patients who are sick or ill prior to administration of ERT may be at an increased risk to develop health complaints during infusion, possibly due to activation of the immune system. However, more research is needed in this regard.

Patients reported slightly more IARs on average than were reported to the treating hospital. However, some patients reported fewer IARs in the past three months than had been reported to the treating hospital. This difference could be explained by recall bias, as patients had to answer retrospectively how many IARs they had experienced in the past three months. All IARs could be managed at home and did not require immediate hospital evaluation. In the Netherlands, we have learned from experience that pausing the infusion causes symptoms to disappear in the majority of IARs. As such, this is the first step in the current SOP for IAR management. If needed, the next step is to administer antipyretics, antihistamines and/or corticosteroids, depending on the type of IAR. This is consistent with what has been described in literature on effective management of IARs in enzyme replacement therapies [24, 50‐53]. Interestingly, in the adult group, none of the patients reported that the infusion was paused due to IARs, which is the standard first response in our home infusion SOP. This could be explained by the fact that these IARs were very mild and were accepted as such (i.e. one adult patient with repetitive IARs experienced transient skin rashes at the highest infusion rate). Although most patients did not experience IARs, five out of 116 patients (3 classic infantile, and 2 adults; 17.6% and 2.4% of patient within these groups respectively) experienced multiple IARs. The higher prevalence of both health complaints, IARs and interventions in response to IARs within the classic infantile group could be explained by the fact that classic infantile patients have less than 1% residual activity of alpha-glucosidase [1], making them more likely to have an adverse response to ERT [54]. Another explanatory factor may be the higher dosage and frequency of ERT given to classic infantile patients (40 mg/kg/week versus 20 mg/kg/biweekly). However, a previous study reported that patients treated with a high dosage did not seem to have more IARs than those treated with the standard recommended dosage [55]. Additionally, the four patients in the childhood-onset group receiving a dosage higher than the standard recommended dosage of ERT did not report any IARs. Further investigation on the role of ERT dosage in the aetiology of IARs is needed [56].

Although our study had a high response rate of 88.1%, there was a relatively large difference in response rates between groups, with the childhood-onset patients having a substantially lower response rate of 68.8% than the other groups. This is likely explained by the fact that most patients in this group are adolescents or young adults, typically with a higher rate of non-response [57], limiting the interpretation of data in this group.

This study demonstrates that home-based ERT in Pompe disease is safe across the whole phenotypic spectrum. We did not encounter any new ERT-related health problems. Insights gained from this study can be used as a base for the implementation of home infusions in other countries and for further optimisation of patient care with home-based ERT in Pompe disease. Mild symptoms that occur during or after infusion may still be relevant to the patient, even if they do not pose a health risk.