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

disease in Spain.

Pilar GiraldoHaematology Department. Miguel Servet University Hospital

FEETEG

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

The ZAGAL Study

Design Efficacy Safety Recommendations

June 29th 2012

• 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

ZAGAL study

35092

Total 442

Mild: 72.7%

Moderate: 25.5% Severe: 1.7%

SSI in type 1 GD distribution

Mild: 72.7%

Moderate: 25.5% Severe: 1.7%

SSI in type 1 GD distribution

Age at diagnosis

ERT 58.7%Mean: 10.2 yW&W28.7%

RST 12.6%Mean: 3.1 y

Type of therapy

Giraldo P et al Orphanet J Rare Dis. 2012 June 29th 2012

ZAGAL study

Variables Tolerant Intolerant Total       No(%) 28(53.8) 24(46.1) 52Mean 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)SplenectomyNaïve/switch

6(21.4)8/20

2(8.3)3/21

8(15.3)11/41

Total 28 24 52

General characteristics  GD1 patients treated with miglustat according tolerance

June 29th 2012

ZAGAL study

Baseline

0.5 1 2 3 4 5 6 711.5

12

12.5

13

13.5

14

14.5

Baseline

0.5 1 2 3 4 5 6 70

100

200

300

400

500

YearsBaseline

0.5 1 2 3 4 5 6 70

500

1000

1500

2000

Hb g/dLPlatelets x109/L

Spleen volume mL Liver volume mL

52 41 1533 24 203038 52 41 1533 24 203038

Base-line

1 2 3 4 5 6 70

20

40

60

80

100

120

140

160

52 41 1533 24 203038 52 41 1533 24 203038

June 29th 2012

Years

ZAGAL study

Baseline

0.5 1 2 3 4 5 6 70

500

1000

1500

2000

2500

3000

Baseline

0.5 1 2 3 4 5 6 70

100

200

300

400

500

600CCL18/PARC ng/mLQT nMol/mL.h

52 41 1533 24 203038 52 41 1533 24 203038

Years

June 29th 2012

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

ZAGAL study. Bone marrow changes after 2 years of miglustat

A. Baseline B. 2 years

SE T1 after 12 months on miglustatNon-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanters

SE T1 at baselineNon-homogeneous diffuse patternInvolvement of left trochanter

Roca et al., (unpublished observations) In Pastores GM et al 2008

Before miglustat After miglustatBefore miglustat After miglustat

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 trochanter

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 trochanter

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 trochanter

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 trochanter

REMARKS: Bone marrow-MRI improvement in naïve patients

Roca M et al. Eur J Radiol. 2007;62:132-7. June 29th 2012

ZAGAL study. Bone marrow changes after 2 years of miglustat

0

5

10

15

1 2 3 4 5 6 705

10152025

1 2 3 4 5 6 7

TRAP-5bS-MRI

1 2 3 4 5 6 7 1 2 3 4 5 6 7

0200

400060008000

1000012000

Chitotriosidase

nM/m

L.h

0

500

1000

1500

CCL18/PARC

ng/m

L

U/L

Sco

re

Baseline 2 years

June 29th 2012

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

June 29th 2012

Quality of life: SF-36 scales

0

10

20

30

40

50

60

70

80

90

100

PF RP Pain GH Vit SF RE MH

Spanish Population

before therapy

after 24 m ERT

after 24 m SRT

June 29th 2012

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 groupMiglustat 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

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

ZAGAL study. Adverse events and discontinuation

June 29th 2012

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/dayduring 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

Dietary Recommendations

June 29th 2012

Dietary Recommendations

June 29th 2012

Dietary Recommendations

June 29th 2012

Dietary Recommendations

June 29th 2012

Dietary Recommendations

June 29th 2012

Dietary Recommendations

June 29th 2012

Dietary Recommendations

June 29th 2012

FEETEG

Pilar GiraldoSº Hematología. HU Miguel Servet

FEETEG