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
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
The ZAGAL Study n Design n Efficacy n Safety n Recommendations
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
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
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 28 24 52
14,5 14 13,5 13 12,5 12 11,5 ZAGAL study Hb g/dl Platelets x10 9 /L 160 140 120 100 80 60 40 52 41 38 33 30 24 20 15 20 52 41 38 33 30 24 20 15 0 Years 500 400 300 200 100 0 Spleen volume ml 2000 Liver volume ml 1500 1000 500 38 33 30 24 20 52 41 38 33 30 24 20 15 0 52 41 15 Years
ZAGAL study 3000 2500 2000 1500 1000 500 0 QT nmol/ml.h 600 500 400 300 200 100 0 Years CCL18/PARC ng/ml 52 41 38 33 30 24 20 15 52 41 38 33 30 24 20 15
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
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.
ZAGAL study. Bone marrow changes after 2 years of miglustat Score 15 10 5 0 S-MRI 1 2 3 4 5 6 7 U/L 25 20 15 10 5 0 TRAP-5b 1 2 3 4 5 6 7 ng/ml 1500 1000 500 0 CCL18/PARC nm/ml.h 12000 10000 8000 6000 4000 200 0 Chitotriosidase 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Baseline 2 years
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 - 1.30(0.9) -1.10(0.9) 0.09, 0.42 0.01 T- score - 1.33(0.9) -1.28(0.9) 0.09, 0.48 0.01 Left calcaneous 74.2 (32-100) 75.6 (48-101) 0.06 Z- score - 1.06(0.9) -0.92 (0.5) 0.09, 0.30 0.01 T- score - 1.46(1.1) -1.07(0.4) 0.08, 0.45 0.01
Quality of life: SF-36 scales 100 90 80 70 60 50 40 30 20 10 0 Spanish Population before therapy after 24 m ERT after 24 m SRT PF RP Pain GH Vit SF RE MH
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
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.
ZAGAL study. Adverse events and discontinuation
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.
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Pilar Giraldo Sº Hematología. HU Miguel Servet FEETEG