1. The ZAGAL Study: Long-term Management and Follow-up of use of Miglustat in type 1 Gaucher disease in Spain. Pilar Giraldo Haematology Department. Miguel Servet University Hospital FEETEG

2. Disclosures Received reimbursement of expenses and honoraria for lectures and occasional consultancies on the management of Gaucher disease, from Protalix, Genzyme, Actelion and Shire June 29th 2012

3. The ZAGAL Study Design Efficacy Safety Recommendations June 29th 2012

4. After approval miglustat in EU (2004) Objectives To establish a set of recommendations for collecting safety, efficacy and QoL data (12 months and longer follow-up) To guarantee the safe and proper use of miglustat in everyday clinical use Treatment Followed the recommendations of the European Working Group on Gaucher Disease Advisory Council ZAGAL study. (Zavesca en Gaucher Leve) June 29th 2012

5. ZAGAL study 350 92 Total 442 Age at diagnosis W&W28.7% RST 12.6% Mean: 3.1 y Type of therapy Giraldo P et al Orphanet J Rare Dis. 2012 June 29th 2012

6. ZAGAL study VariablesTolerantIntolerantTotal No(%) 28(53.8)24(46.1)52 Mean age(range) 51(18-85)48.9(22-71)49.9(18-85) M/F(F%) (53.6)(41.6)(48.0) Age at Dx 31(2-78)35(5-56)33(2-78) SSI at Dx 6.5(3-7)6.7(3-7.5)6.6(3-7.5) Genotype N370S/N370S(%) 6(21.4)2(8.3)8(15.3) N370S/L444P(%) 9(32.1)12(50.0)21(40.3) N370S/other(%) 10(35.7)8(33.3)18(34.6) Other/other 3(10.7)2(8.3)5(9.6) Splenectomy Naïve/switch 6(21.4) 8/20 2(8.3) 3/21 8(15.3) 11/41 Total 282452 General characteristics GD1 patients treated with miglustat according tolerance June 29th 2012

7. ZAGAL study Hb g/dL 9 Platelets x10 9 /L Spleen volume mL Liver volume mL 52 4115 3324203038 52 4115 3324203038 52 4115 3324203038 52 4115 3324203038 June 29th 2012 Years

8. ZAGAL study CCL18/PARC ng/mL QT nMol/mL.h 52 41 15 332420303852 41 15 3324203038 Years June 29th 2012

9. ZAGAL study S-MRI patternScore Non-homogeneous diffuse 3 Non-homogeneous mottled 2 Non-homogeneous reticular 1 Normal 0 Homogeneous 4 Complications: bone infarct, avascular necrosis, bone crisis and vertebral collapse 4 Roca M et al Eur J Radiol. 2007 June 29th 2012

10. ZAGAL study. Bone marrow changes after 2 years of miglustat A. Baseline B. 2 years SE T1 after 12 months on miglustat Non-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanters SE T1 at baseline Non-homogeneous diffuse pattern Involvement of left trochanter Roca et al., (unpublished observations) In Pastores GM et al 2008 REMARKS: Bone marrow-MRI improvement in naïve patients Roca M et al. Eur J Radiol. 2007;62:132-7. June 29th 2012

11. ZAGAL study. Bone marrow changes after 2 years of miglustat Baseline 2 years June 29th 2012

12. ZAGAL study June 29th 2012

13. Quality of life: SF-36 scales June 29th 2012

14. ZAGAL study Changes in the atherogenic profile of patients with type 1 Gaucher disease after miglustat therapy. In 26 GD1 patients treated with miglustat for up to 36 months: Group A: 10 patients therapy-naïve significantly: plasma HDL-c and apoA-I, and slightly increased TC; TG, CRP concentrations, and TC/HDL-c ratios decreased significantly Group B: 16 patients switched from enzyme replacement therapy (ERT); No changes in HDL-c and apoA-I, or in the TC/HDL-c ratio. CRP was observed after 12 months. LDL-c and apoB were not significantly altered in either patient group Miglustat appears to have beneficial effects on plasma lipid, lipoprotein, and CRP concentrations in therapy-naïve GD1 patients, resulting in an improved atherogenic lipid profile.. Puzo J et al Atherosclerosis. 2010 June 29th 2012

15. ZAGAL study In summary: 42 patients are on miglustat therapy and 15 patients have more than 7 years under therapy. The goals of therapy have been achieved. 3 patients died by non-related causes (2 neoplasia and 1 hearth attack), 1 patient have discontinued by planning to become pregnant 6 discontinuing by poor filling or intolerance. 8 patients had transitory diarrhea and flatulence. June 29th 2012

16. ZAGAL study. Adverse events and discontinuation June 29th 2012

17. ZAGAL study. Recommendations In order to avoid gastrointestinal disturbances during Miglustat therapy, we are recommending two strategies: To administrate therapy without meals for example 2 hours before breakfast, lunch and dinner To start therapy in scalating doses: during the first week only 100 mg /day during the second week only 200 mg/day during third week and later total therapy with 300 mg/day Simultaneously it is convennient consider the content of carbohidrates in the diet according the following suggestions: Giraldo P et al. Haematologica. 2009;94(12):1771-1775. June 29th 2012

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25. FEETEG

26. Pilar Giraldo Sº Hematología. HU Miguel Servet FEETEG