Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients

Fabry disease (OMIM 301500) is a rare inherited X-linked lysosomal storage disease. Mutations in the GLA gene cause a deficiency of the lysosomal enzyme α-galactosidase A. As a result glycosphingolipids with a terminal α-galactosyl moiety, predominately globotriaosylceramide (Gb3), accumulate in lysosomes [1]. This accumulation is believed to result in the symptoms and complications of the disease. During childhood presenting symptoms consist of characteristic neuronopathic pains, gastro-intestinal complaints and hypohidrosis. Complications usually occur later in life and include progressive renal insufficiency, stroke, cardiac hypertrophy or infarction, and cardiac arrhythmia [2]. The phenotype of the disease is very variable, ranging from severe end-organ damage and early death in classically affected males to less pronounced disease manifestations in some male and the majority of female patients.

Enzyme replacement therapy (ERT) is currently the only approved therapy for Fabry disease and aims at restoring the defective degradation of accumulated substrates by infusion of recombinant α-galactosidase A. In 2001 the European Medicines Agency (EMA) approved two recombinant enzyme preparations in Europe: agalsidase alpha (Replagal™, Shire, at a registered dose of 0.2 mg/kg/eow) and agalsidase beta (Fabrazyme, Genzyme, at a registered dose of 1.0 mg/kg/eow). In the USA, only agalsidase beta is licensed. Treatment with both preparations is reported to diminish Gb3 in tissue biopsies, decrease left ventricular hypertrophy and stabilize renal function [3‐8]. These effects seem most prominent in patients with less severe organ involvement at start of therapy [9, 10]. Studies on the effect of ERT on the prevention of Fabry related complications are limited. One phase IV study was conducted showing limited efficacy of treatment with agalsidase beta showing a modest decrease in incidence of complications [9]. Such a study was never performed for agalsidase alpha. Although one study could not demonstrate differences between agalsidase alpha and agalsidase beta at and equal dose of 0.2 mg/kg/eow [11], the superiority of either one of the products at their registered dose has not been proven so far.

In June 2009 Genzyme identified a virus (vesivirus 2117) in one of the six bioreactors at their Allston manufacturing facility. Genzyme has reported that this virus is not known to cause disease in humans. Genzyme temporarily interrupted its production, which resulted in a worldwide shortage of agalsidase beta. Assuming a quick recovery of full production, the EMA advised in an online press release on 25 June 2009 [12] that: ' priority should be given to children, adolescent, and adult male patients. However, adult female patients in whom the disease is less severe may receive Fabrazyme at a reduced dose'. This decision was based upon the supposition that female patients with no clinically significant end organ damage could more easily tolerate a lower dose of therapy. In a subsequent online press release on 23 April 2010 [13] the EMA advised that: ' for patients on the reduced dose who demonstrate a deterioration of the disease, physicians should consider restarting the original treatment with the full dose of Fabrazyme or switching to an alternative treatment, such as Replagal'. Initially, in the Netherlands only less affected female patients received a reduced dose. However, from October 2009 persisting shortages forced dose reductions in all Dutch patients, including males. In the absence of sufficient agalsidase beta to restore full dose, Dutch Fabry patients could indicate their preference to stay at a reduced agalsidase beta dose or switch to agalsidase alpha.

On 19 October 2010 the EMA released an assessment report on the shortage of agalsidase beta noting an increase in reporting of adverse events since the start of the shortage, possibly due to the lowered dose [14]. More specifically, it was stated that: 'this pattern of adverse events resembles the natural, but accelerated, course of Fabry disease'. In addition, the post-marketing registry on outcomes of treatment with agalsidase beta (the Fabry Registry, sponsored by Genzyme) showed that a higher percentage of reports was received of patients suffering from neuronopathic pains, diarrhoea and abdominal pain, compared to the period before the shortage[14]. This suggested increase in adverse events and complaints is difficult to interpret. It is possible that indeed a lower dose of agalsidase beta leads to disease progression or to an accelerated disease course. However, it is also possible that the anxiety caused by the shortage and the recommendations by the EMA to treat patients at full dose of agalsidase beta in case of an adverse event, led to increased awareness and reporting of adverse events. Thus, there is a need for objective data to assess the impact of the agalsidase beta shortage. We studied the incidence of clinical events per person per year before and during the shortage in the adult Dutch Fabry cohort. In addition, we analyzed lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires.

The global enzyme shortage of agalsidase beta and the subsequent dose reductions caused distress and concern in both patients and physicians. This was further supported by an EMA report, describing an increase of reports of (serious) adverse events suggesting an accelerated course of Fabry disease [14]. We aimed to study the effects of the shortage by comparing clinical event incidence in the period before, to clinical event incidence during the shortage in the same patients. In summary, we did not find an increase in clinical event incidence during the agalsidase beta shortage or could establish that a reduced dose of agalsidase beta led to progression of disease during the shortage in an adult Fabry cohort. No definite conclusions can be drawn of the effect on left ventricular mass due to large variation of the (limited) data. During the shortage quality of life was significantly reduced in females on the vitality and general health subscales of the SF-36 questionnaire. The vitality subscale addresses energy level and tiredness and the general health perception subscale how patients experience their health (e.g. expectation of decreasing health). The SF-36 outcomes reported here are in accordance with earlier reports that demonstrated a decreased quality of life for male and female Fabry patients [26, 27]. Because of the small sample size and wide confidence intervals, caution should be taken in interpreting these results, as the SF-36 differences before and during the shortage were rather small. It is unclear whether these differences in subscales actually represent a clinical meaningful detoriation, especially for the individual patient. This issue, also referred to as 'minimal clinical important difference' (MCID) is determined in many other chronic diseases. Comparing our mean changes to the minimal clinical important difference in the literature [21‐23], it can be doubted whether the changes actually represent a clinical meaningful difference.

The difference in outcome of our study and the EMA report could be explained by several reasons. As mentioned by the EMA, reporting bias due to increased awareness for adverse events might have overestimated the number of adverse events reported. The advice of the EMA to reinstitute the recommended dose in patients with deterioration of the disease may have stimulated physicians to report adverse events, as this might have favoured allocation of agalsidase beta for their patients. In addition, some of the criteria used to suggest deterioration during the shortage were of rather subjective nature (e.g. fatigue, nausea, diarrhoea), but were nevertheless considered as an adverse event. It is questionable whether subjective criteria truly represent clinical detoriation. Finally, the EMA report used the Fabry registry to assess more objective criteria of clinical detoriation (occurrence of complications of the disease e.g. cardiovascular events). The incidence of these events was too low and the observational period too short to draw definite conclusions.

Importantly, we could establish an increase in plasma lysoGb3 in nearly all patients evaluated, following reduction of the therapeutic enzyme dose. Plasma lysoGb3 elevation is a hallmark of Fabry disease[28] and is associated with clinical manifestations[29]. Therefore, this observation leads to the conclusion that recurrence of storage material most likely has occurred in these patients. This is in line with observations made for lysoGb3 and Gb3 after induction of neutralizing antibodies [24, 30, 31]. We could not demonstrate a correlation between clinical event incidence and noted increases of lysoGb3. The lack of correlation with clinical outcome could be explained by the fact that enzyme replacement therapy has at best a modest effect on the course of the disease. In other words: complications will occur both in treated and untreated patients, ERT only results in a slightly different complication rate in patients with advanced disease [9, 10] and at most stabilization of disease parameters in less severely affected patients [5, 8]. Also, on the short term the expected number of clinical events of this slowly progressive disease would be rather low. Given the modest treatment effect, it is unlikely that on the short term a lower dose of enzyme therapy has a major impact on the incidence of complications in such a heterogeneous and small cohort. Therefore, on the short term the biochemical response is probably the most sensitive way to evaluate the effects of the shortage.

Interestingly, an increase in lysoGb3 occurred both in patients with an agalsidase beta reduction to 25% of the initial dose (1 mg/kg/eow) and those switched to agalsidase alpha (0.2 mg/kg/eow). We noted that the pre-shortage lysoGb3 values were higher in the reduced agalsidase beta group. One might argue that the expected increase of lysoGb3 in the reduced agalsidase beta group could be less pronounced than the switch group, because the pre-shortage values were already at their near maximum level (i.e. pre-treatment levels). However, as the pre-shortage samples in the reduced agalsidase beta group did nod reach pre-treatment values this is unlikely.

All patients with an available lysoGb3 value who switched to agalsidase alpha were previously dose reduced on agalsidase beta. Therefore, the increase in lysoGb3 could be attributed to the reduced agalsidase beta dose (and not to agalsidase alpha). However, these patients were approximately treated with agalsidase beta for six months, and subsequently with agalsidase alpha for about a year. It is therefore more likely that the increase is related to dose rather than preparation. This supports the earlier observations that not the enzyme preparation, but the doses are the most important determinants of biochemical response [24]. The importance of biochemical markers to assess the effects of dose changes is elegantly shown in Gaucher disease, where chitotriosidase reflects differences in doses [32] as well as impact of withdrawal of imiglucerase treatment, which coincides with clinically relevant deterioration of disease such as decreases in platelet counts [33‐35].

There are several limitations to this study. The period in which we examined the outcome of the agalsidase beta shortage was rather short. It is possible that the incidence of clinical events increases over a longer observation period. Therefore, studies in larger cohorts, with a longer follow-up are required. Lastly, it remains difficult to determine whether the clinical events that occurred during the shortage-period are caused by the shortage itself, or by the progressive nature of the disease despite therapy[9]. The two clinical events that occurred within a month after the agalsidase beta shortage (an implantation of a pacemaker and a cardiac defibrillator) serve as an example: it is questionable (if not unlikely) whether these events were caused by a reduced agalsidase beta dose.

In conclusion, we established no increase in the clinical event incidence during the shortage of agalsidase beta. We disagree with the conclusion from the EMA report of an accelerated course of disease as a result of a lower dose of Fabrazyme. The impact on the biochemical response, however, indicates the recurrence of storage material and supports the supposition that there is a biochemical dose effect of ERT.