The ZAGAL Study: Long- term Management and Follow- up of use of Miglustat in type 1 Gaucher disease in Spain.

Transcription

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

2 Disclosures n Received reimbursement of expenses and honoraria for lectures and occasional consultancies on the management of Gaucher disease, from Protalix, Genzyme, Actelion and Shire

3 The ZAGAL Study n Design n Efficacy n Safety n Recommendations

4 ZAGAL study. (Zavesca en Gaucher Leve) 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

5 ZAGAL study Moderate: 25.5% Severe: 1.7% Mild: 72.7% 92 Age at diagnosis SSI in type 1 GD distribution W&W28.7% RST 12.6% Mean: 3.1 y Total 442 ERT 58.7% Mean: 10.2 y Type of therapy Giraldo P et al Orphanet J Rare Dis. 2012

6 ZAGAL study General characterispcs GD1 papents treated with miglustat according tolerance Variables Tolerant Intolerant Total 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

7 14, , , ,5 ZAGAL study Hb g/dl Platelets x10 9 /L Years Spleen volume ml 2000 Liver volume ml Years

8 ZAGAL study QT nmol/ml.h Years CCL18/PARC ng/ml

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

10 ZAGAL study. Bone marrow changes after 2 years of miglustat A. Baseline B. 2 years SE T1 at baseline Non-homogeneous diffuse pattern Involvement of left trochanter SE T1 after 12 months on miglustat Non-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanters of signal in both 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.

11 ZAGAL study. Bone marrow changes after 2 years of miglustat Score S-MRI U/L TRAP-5b ng/ml CCL18/PARC nm/ml.h Chitotriosidase Baseline 2 years

12 ZAGAL study BUA, Z-scores and T-scores for bone mineral density of calcaneous by ultrasound (CUBA CLINICAL BONE DENSITOMETER). In 24 patients on miglustat therapy. Bone BUABaselin Mean (range) Month24 Mean (range) p Score Baseline Mean (SD) Month24 Mean (SD) Change 95%CI p Rigth calcaneous 82.4 (47-101) 84.2 (66-100) 0.04 Z- score (0.9) -1.10(0.9) 0.09, T- score (0.9) -1.28(0.9) 0.09, Left calcaneous 74.2 (32-100) 75.6 (48-101) 0.06 Z- score (0.9) (0.5) 0.09, T- score (1.1) -1.07(0.4) 0.08,

13 Quality of life: SF-36 scales Spanish Population before therapy after 24 m ERT after 24 m SRT PF RP Pain GH Vit SF RE MH

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

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.

16 ZAGAL study. Adverse events and discontinuation

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):

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25 FEETEG

26 Pilar Giraldo Sº Hematología. HU Miguel Servet FEETEG