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					                                                                         Technology & Services Section

                                          Gaucher Disease and the Impact of Cerezyme ®

        a report by
        Hans Ebels, MD

        Genzyme Europe BV

Cascade of Reactions Leading to                             abdominal pain and diarrhoea/frequent stools, and
Dysfunction of Organs                                       experiencing ‘stitches’ or stinging pain in the side
                                                            when playing or exercising. It is likely that the
Gaucher disease patients have deficient activity of the     consulted physician will first suspect a common
enzyme glucocerebrosidase. Progressive macrophageal         harmless disorder such as a viral infection. Repeat
accumulation of glucocerebroside leads to the massive       checking, though, should show repeat abnormalities,
enlargement of macrophages, also known as ‘Gaucher          and may raise the index of suspicion of a more serious
cells’, initiating a cascade of reactions early in life.    disorder requiring further diagnostic work-up.
Gaucher cells can be found wherever macrophages
normally reside and their presence underlies the major      The Spectrum of Clinical
clinical manifestations. These enlarged cells               Manifestations
hypersecrete chemokines and (pro-) inflammatory
cytokines attracting alternatively activated macrophages    For many years, the main focus in clinical
inducing a low-grade chronic inflammatory                   management was on the visceral and haematological
response,1,2 eliciting secondary processes, leading to      Gaucher manifestations. It is in recent years that the
further pathology. A large mass of these metabolically      extent, progression and clinical consequences of
overactive Gaucher cells has significant indirect effects   skeletal involvement have become adequately
on weight gain, growth and caloric requirements3 and        appreciated. It is now acknowledged that the bone
may be responsible for a skinny appearance with             complications and the often irreversible consequences
muscle wasting and low weight-for-height. Gaucher           thereof are usually the most debilitating aspect of
disease, if untreated or managed sub-optimally, can         Gaucher disease. Bone abnormalities are seen in a
cause damage to cells, tissues and organs throughout        variety of presentations, both symptomatic and
the body and may lead to potentially irreversible,          asymptomatic, in the majority of patients.5
functional loss or even to early death.
                                                            Bone marrow infiltration with Gaucher cells (and
How Gaucher Patients Come to                                other activated macrophages) seems to be the first step
Medical Attention                                           with secondary processes presumably leading to
                                                            abnormalities in mineralisation and bone structure
It is unlikely that individuals with Gaucher disease will   (bone remodelling failure). The reduced fat content of
come to medical attention with full-blown classical         bone marrow is best visualised using magnetic
textbook Gaucher symptoms. The first medical                resonance imaging (MRI) in which the T1-weighted
consultation is likely to occur during childhood when       signal is decreased in affected areas. Bone crises,
symptoms such as bone pain, bruises, nose bleeds and        believed to be due to oedema and resembling crises in
fatigue are still more subtle and the spleen is mildly      sickle cell anaemia, are more prevalent in children
enlarged.4 Further seemingly innocuous symptoms             than in adults. Mostly, clinical proof of osteonecrosis is
may include gastrointestinal disturbances, e.g. upper       present. Otherwise, various types of bone pain may

1. Boven L A, van Meurs M, Boot R G et al., “Gaucher cells demonstrate a distinct macrophage phenotype and resemble
   alternatively activated macrophages”, Am. J. Clin. Pathol. (2004);122(3): pp. 359–369.
2. Deegan P B, Moran M T, McFarlane I et al., “Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher
   disease”, Blood Cells Mol. Dis. (2005); 35(2): pp. 259–267.
3. Hollak C, “Abnormal Energy Expenditure and Glucose Metabolism in Type 1 Gaucher Disease”, Gaucher Clin. Persp.
   (1999); 7(1): pp. 1–3.
4. Pastores G M, Weinreb N J, Aerts H et al., “Therapeutic goals in the treatment of Gaucher disease”, Semin. Hematol.
   (2004); 41(4 Suppl 5): pp. 4–14.
5. Pastores G M, Wallenstein S, Desnick R J, Luckey M M, “Bone density in Type 1 Gaucher disease”, J. Bone & Mineral
   Res. (1996); 11(11): pp. 1801–1807.                                                                                   1

    Technology & Services Section

    occur in Gaucher disease, including dull, achy, non-          initial clinical studies and independent published
    specific, or intense and localised pain. Skeletal growth      case series: clinically significant responses in systemic
    retardation is very common. Children may reach and            parameters can be expected to occur in type 1 and
    close-off puberty at a later age than normal youngsters.      type 3 Gaucher patients treated with the best
                                                                  standard of care – Cerezyme.4 Cerezyme is
    In the past, huge spleens up to 70 times normal size and      efficacious in completely or partially reversing or
    deformed by infarction, necrosis and fibrosis could be        preventing further deterioration of Gaucher disease
    encountered, but nowadays, with improved medical              manifestations in most disease domains, including
    care, splenomegaly is likely to be more subtle. Liver         the skeletal compartment. Its safety profile is well-
    enlargement – frequently less marked and occurring            defined and remarkably positive. Furthermore,
    later than splenomegaly – may add to abdominal                Cerezyme infusions are generally very well
    distension, discomfort and early satiety. Haematol-           tolerated; increasingly, such infusions are
    ogical abnormalities result from displacement of              administered in the patient’s home.
    haematopoietic elements and sequestration of blood
    products in the enlarged spleen. Chest radiography            International panels of physicians with expertise
    may detect the bilateral reticulonodular infiltrates.         in Gaucher disease have collaborated on
                                                                  developing therapeutic and outcome monitoring
    Impact on Quality of Life                                     recommendations, both for children 7,9,10 and
                                                                  adult 11,12 patients. In addition, based on the
    Gaucher disease can severely impair the quality of life       collective efficacy data, a disease management
    of patients and their families and significantly reduce       model for Gaucher disease was designed. This
    life expectancy.6 Whether on their own or in                  model, encompassing recommendations for initial
    combination, symptoms, particularly skeletal                  assessment and on-going monitoring and for setting
    complications, may diminish patients’ feelings of             individualised therapeutic goals, enables physicians
    well-being and functional health and prevent them             caring for Gaucher patients to optimise their
    from working or pursuing family or leisure activities.        clinical management.4
    Especially in the paediatric age group, this chronic
    disease can lead to limited attention span, learning          Genzyme, committed to the development of
    difficulties, low self-esteem, psychosexual problems          products and services to satisfy, currently, unmet
    and behavioural abnormalities.7                               medical needs, will contribute to furthering
                                                                  knowledge about Gaucher disease, and will gladly
    Cerezyme® (Imiglucerase) Enzyme                               assist researchers and healthcare professionals to
    Replacement Therapy                                           achieve this. Building on Genzyme’s experiences
                                                                  with Cerezyme, enzyme replacement therapies are
    To date, thousands of Gaucher disease patients have           currently also available for mucopolysaccharidosis I
    benefited from Cerezyme.8 The rationale for this              (Aldurazyme ®, laronidase) and Fabry disease
    therapy is very simple: replace the deficient enzyme.         (Fabrazyme ®, agalsidase beta). Should it be
    Clinical outcomes, collected over a period of                 approved by the European Medicines Agency
    approximately 15 years from the International                 (EMEA), Myozyme® – as enzyme replacement
    Collaborative Gaucher Group (ICGG) Registry                   therapy for Pompe disease – will become available
    cohort of some 4,000 patients, mirror the results of          in the near future. ■

    6. Damiano A M, Pastores G M, Ware J E, Jr, “The health-related quality of life of adults with Gaucher’s disease receiving
       enzyme replacement therapy: results from a retrospective study”, Quality of Life Res. (1998); 7(5): pp. 373–386.
    7. Grabowski G A, Andria G, Baldellou A et al., “Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and
       assessment. Consensus statements”, Eur. J. Pediatr. (2004); 163(2): pp. 58–66.
    8. Cerezyme (imiglucerase) Summary of Product Characteristics,
    9. Baldellou A, Andria G, Campbell P E, Charrow J, Cohen I J, Grabowski G A et al., “Paediatric non-neuronopathic
       Gaucher disease: recommendations for treatment and monitoring”, Eur. J. Pediatr. (2003); 163: pp. 67–75.
    10. Charrow J, Andersson H C, Kaplan P, Kolodny E H, Mistry P, Pastores G et al., “Enzyme replacement therapy and
        monitoring for children with type 1 Gaucher disease: Consensus recommendations”, J. Pediatr. (2004); 144(1): pp.
    11. Weinreb N J, Aggio M C, Andersson H C, Andria G, Charrow J, Clarke J T et al., “Gaucher disease type 1: Revised
        recommendations on evaluations and monitoring for adult patients”, Semin. Hematol. (2004); 41(4 Suppl 5): pp.
    12. Andersson H C, Charrow J, Kaplan P, Mistry P, Pastores G M, Prakesh-Cheng A et al., “Individualization of long-
        term enzyme replacement therapy for Gaucher disease”, Genet. Med. (2005); 7(2): pp. 105–110.

                                                           BUSINESS BRIEFING: EUROPEAN PHARMACOTHERAPY 2006

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