Force Majeure: Therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease

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Abstract

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously — usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase — and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.

Introduction

Gaucher disease is one of the most frequent lysosomal storage disorders in man. The disorder is caused by deficient activity of the enzyme glucocerebrosidase (EC 321.45) [1], [2], for which therapeutic augmentation has proved to be highly effective. Gaucher disease is clinically heterogeneous [3], [4]. Often classified operationally into three principal subtypes, the condition mainly affects the macrophage system [5]. Visceromegaly and cytopenias as well as disabling bone disease characterize type I disease. In contrast, manifestations in the central nervous system define the neuronopathic forms of Gaucher disease: type II disease, the acute and rapidly fatal form and type III disease with a more attenuated neurological course [5].

Treatment with enzyme replacement therapy (ERT) was initially developed using placentas as a resource and later using recombinant technology [6], [7], [8]. This enzyme, imiglucerase, manufactured by Genzyme Corp, MA, USA, has become available in 1994 and currently more than 1700 patients are being treated in Europe, parts of the Middle East and North Africa. ERT requires an apparent lifelong treatment with regular infusions. This therapy has shown to be extremely beneficial, resulting in normalization of blood counts, reductions in spleen and liver sizes, and improvement in bone symptoms [6], [7], [8]. So far ERT with imiglucerase is the only registered enzyme. Two new enzyme preparations are at the final stages of development programs: velaglucerase (h-GCB, Shire Human genetic Therapies, MA, USA) and taliglucerase (pr-GCD, Protalix Biotherapeutics, Carmiel, Israel [9], [10]). Substrate reduction therapy (miglustat, Actelion therapeutics) is an oral treatment registered for Gaucher disease and indicated for mild to moderately affected adult patients for whom enzyme replacement therapy is not suitable (EMEA) or not a therapeutic option (FDA) [11].

In June 2009, Genzyme identified a virus (vesivirus 2117) in one of six bioreactors at the Allston manufacturing facility. The consequence of this infection is that it impairs the viability of the non-human Chinese Hamster Ovary (CHO) cells used to produce imiglucerase. Genzyme reported that this virus is not known to cause disease in humans. To clear the infection and restore full production rapidly, Genzyme temporarily suspended the manufacture of imiglucerase — a cessation that has caused a severe shortage of imiglucerase worldwide. At the end of June, the EMEA informed physicians in Europe of a temporary shortage of imiglucerase, which was expected to last for only a few weeks and with a reduction of supply to approximately 60% of normal [12]. This estimate was based on the assumption that most imiglucerase hypothecated to “work-in-process” (WIP) at the time of that their plant was shutdown would become available for distribution. However, by early August, it became clear that 80% of this WIP material would not to be released for further processing. Two lots were eventually found to be safe for further use, resulting in a worldwide availability of only 20% of the original amount of enzyme until the end of the year.

Given this force majeure, only a minority of patients with Gaucher disease can continue to receive treatment. The clinical implications of a temporary interruption of treatment are not easy to predict. Gaucher disease is heterogeneous; some patients have rapidly progressive disease, especially in childhood, while others may remain stable without treatment for decades. The consequences of treatment interruptions have only been documented in small groups of patients [13], [14], [15], [16], [17], [18]. In summary, some of these patients remained stable up to 47 months, but progression of the disease at variable rates has also been reported. In many adult patients, interruption of therapy did not cause immediate reversal of the achieved therapeutic effects (i.e., within weeks). Perhaps the most important overall conclusion is that clinical deterioration may or may not occur when enzyme therapy is interrupted but on the basis of current knowledge, which patient will suffer a deterioration, if any, and to what extent, cannot be predicted.

In the United States, a Cerezyme Stakeholders Working Group consisting of physicians, patients, and Genzyme representatives was installed in response to this emergency. The group set out guidelines for the protection of the most vulnerable patients [19]. In addition, it should be noted that in early July, the FDA has contacted both Shire and Protalix about the possibility of initiating a treatment protocol for use of their phase III drugs at the time of imiglucerase shortage, and accordingly, two new protocols have been approved (NCT00954460 and NCT00962260, respectively).

To protect the interests of Gaucher patients most at risk from complications, in Europe, the EMEA released guidelines at the end of June and revised these by mid-August. These guidelines are shown in Table 1 [20]. Although the distribution of vulnerable patients is not equal among the different European and affiliated countries, Genzyme initially had to decide to allocate 20% of previously ordered enzyme to each of these countries. The European and affiliated countries are summarized in Table 2. Following the EMEA guidance and management by Genzyme, concerns arose within the Gaucher community as to the equity of distribution, identification of patients at risk and their monitoring — as well as the potential access to alternative and emerging treatments. To address these concerns, a professional meeting of stakeholders in Europe was organized rapidly, the results of which are reported here.

Section snippets

Methods

Under the initiative of the European Gaucher Alliance (EGA), representing the interests of patients with Gaucher disease in Europe and several affiliated nations, including Israel, expert physicians, patient representatives, and laboratory experts met under the auspices of the European Working Group on Gaucher Disease (EWGGD, a daughter of the European Study Group on Lysosomal Diseases (ESGLD)). Pharmaceutical companies (Genzyme, Protalix, Shire, and Actelion) were invited during a separate

Imiglucerase supply

What is the current status of treatment continuation and interruption?

According to recent data from the Gaucher Registry, Europe and affiliated countries (see Table 2) represent more than 35% of all patients treated with imiglucerase worldwide. All participants were asked to collect and present data on the number of patients treated with imiglucerase before the shortage and the composition of this population with respect to number of children and type III patients. Also the number of patients

Conclusions

The force majeure leading to an acute lack of imiglucerase therapy for the chronic treatment of Gaucher disease patients is unprecedented and has shocked the entire Gaucher community. The possibility of such an event has hitherto not been imagined by either physicians or patients — but nonetheless, the episode vividly illustrates the vulnerability of sophisticated biotechnology as well as the need for safety measures (stocks of products and/or effective alternatives). In the early aftermath of

Disclosures

Carla E.M. Hollak received reimbursement of expenses and small honoraria for lectures from Genzyme Corporation, Shire HGT, and Actelion. All honoraria are donated to the Gaucher Stichting, a national foundation that supports research in the field of lysosomal storage disorders.

Stephan vom Dahl received research grants, reimbursement of expenses, consulting fees, and honoraria for lectures from Genzyme Corporation, Actelion Pharmaceuticals, and Shire Human Genetic Therapies.

Johannes M.F.G. Aerts

Acknowledgments

We appreciate the generous support by ASIM (Arbeitsgemeinschaft für angeborene Stoffwechselstörungen in der Inneren Medizin) to conduct the meeting.

The input from physicians and patients in Europe and affiliated countries who were not present at the meeting is highly valued. We are grateful for the data provided by Genzyme concerning the Eastern European countries. We acknowledge the help of P.J.T. Hollak, PH Translations, for editorial support.

References (23)

  • N.W. Barton et al.

    Replacement therapy for inherited enzyme deficiency — macrophage-targeted glucocerebrosidase for Gaucher's disease

    N. Engl. J. Med.

    (1991)
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