Gaucher disease in Romania – Baseline

characteristics, specific diagnosis, treatment

and outcome

Cecilia Lazea1,2) , Simona Bucerzan1,2) , Camelia Alkhzouz1,2), Ioana Nascu1,3) , Anca Zimmermann4) , Radu Popp,5), Paula Grigorescu-Sido 1,2)

1) Centrul Regional de Genetica Medicala - Spitalul Clinic de Urgenta pentru Copii, Cluj; 2) Disciplina Pediatrie I - UMF “Iuliu Hatieganu” Cluj; 3) Unitatea de Primire a Urgentelor - Spitalul Clinic de Urgenta pentru Copii, Cluj 4)) Department of Endocrinology and Metabolic Diseases, 1st Clinic of Internal Medicine, Yohannes Gutenberg

University, Mainz, Germany 5) Catedra de Genetica, Departamentul de Stiinte Moleculare - UMF “Iuliu Hatieganu” Cluj

I. Lysosomal storage

disease

- Lysosomal storage disease ← Accumulation of

glucocerebrosides in the lysosomes of monocyte-derived

macrophages

- more than 70 diseases described

- incidence in the Caucasian population : 1/7500

Sphingolipidoses: Gaucher disease

Fabry disease etc.

Mucopolysaccharidosis

Glycoproteinosis

Mucolipidosis

Glycogen storage disease type II (Pompe disease)

Lysosomal disease

- enzima lizozomală

(hidrolaza acidă –pH optim =5)

gena - 1q

β

acida

Gaucher disease

Essential date

Glucocerebrosides accumulation Displaced nucleus

Gaucher cell

Hematologic manifestations : - anemia

- thrombocytopenia type 1

Hepatosplenomegaly

Bone involvement

Neurological involvement: - acute……………..type 2

- chronic…………...type 3

Gaucher disease

Clinical presentation (+/- severe)

Monogenic disease, AR

12-year-old male with

Gaucher disease type I

18-year-old female with Gaucher

disease type 1

3-year-old female with Gaucher disease type 3

Specific treatment in Gaucher

disease Therapy to reduce glycosylceramides accumulation

1. Enzyme replacement therapy

2. Substrate reduction therapy

3. Molecular chaperone therapy

4. Gene therapy

Specific treatment in Gaucher

disease

USA Europe Romania

• Imiglucerase - Cerezyme (Genzyme) 1994 1997 2002

• Velaglucerase - Vepriv (Shire)* 2010 2010 -

• Taliglucerase - Protalix (Pfizer) 2012

* - approved in 2010 at the time of temporary reduction of Cerezyme's production

capacity compared to world-wide requirement

1. Enzyme replacement therapy (ERT)

Obiectives: replacement of enzymes missing from lysosomes

12 Ver 1 Jan 2010

1880 1900 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

Gaucher and Cerezyme Time Line

1882 – Philippe

Gaucher describes

a 32-year-old with

enlarged spleen

1985 – Beutler & Ginns

identify acid

β-glucocerebrosidase

gene

1955 – Lysosome

discovered by de

Duve

1994 – Cerezyme® recombinant

glucocerebrosidase approved

in US; 1997 – Cerezyme

approved in EU

1965 – Roscoe Brady:

glucocerebrosidase

deficiency causes GD

1991 – Ceredase®

placental ERT

approved in US

and the EU

1932 – Aghion

identifies

glucocrebrosidase

accumulation as

cause of GD 1983 – First patient with

Gaucher treated with

enzyme purified from

human placentas

2002 – Cerezyme

real-world efficacy

(1028 pts, 2-5 yrs) Weinreb Am J Med 2002

2007/8 –

Cerezyme efficacy

in bone Charrow Clin Genet 2007;

Wenstrup J Bone Miner Res

2007;Sims Clin Genet 2008

2008 – Cerezyme

pediatric efficacy

(887 pts, 8 yrs) Andersson Pediatrics 2008

Treatment Basics

USA Europe Romania

● Miglustat (Zavesca)/Actelion Pharmaceuticals 2002 2003 -

- Imino-N-alkylate sugars :

- N-butyl-deoxynojirimycin – NB-DNJ

- 3x100 mg/day, p.o.

-results: - redused efficacy compared to ERT

- long-term safety needed to be carefully evaluated

- adverse effectes- diarrhea; tremor

● Eliglustat (Cerdelga)/Genzyme 08.2014 01.2015

- “EDGE” study: - 19 countries (Romania);

- 170 pacients (including 2 Romanian patients)

2. Substrate reduction therapy

The aim: reducing the biosynthesis of glycosphingolipids

Specific treatment in Gaucher

disease

Mechanism of Action = Substrate Reduction

Substrate Reduction Therapy (SRT) restores the imbalance between production and removal of glucosylceramide

Ceramide + Glucose

Glucosylceramide

Synthase

Acid β-glucosidase

deficient in

Gaucher disease

Eliglustat

Glucosylceramide

14

- Gene mutation → lysososmal enzyme configuration defects:

- active sites involvement → enzyme inactivation (a)

- respecting active sites → active enzyme (b)

● Chaperone: • pharmacological: - small molecule, ligand → protecting the

degradation of lysosomal enzymes that have undergone configuration defect, but

they are still active (b)

- allows - correct configuration of enzymes

- their traffic to lysosomes (where they dissociate from the enzyme:

reversible binding)

- cross the blood-brain barrier!

* Under investigation

• Chaperone therapy*

• Gene therapy*

- aim: introduction of the GBA gene into:

- hematopoietic stem cells

- muscle cells “secretant”

* Currently under investigation ≥ 1995

II. Gaucher disease in Romania.

Results of The National Health Expertise

Center for Lysosomal Diseases Cluj :

- patients data

- treatment

- therapy results

A. Clinical data of Romanian

patients with Gaucher disease

(evaluated in our centre)

In Romania

- specific diagnosis of lysosomal storage disease is

available since 1997:

- enzymatic diagnosis – for the most common 19

forms of lysosomal storage disease

- molecular diagnosis - Gaucher disease

- Genetic Pathology Center Cluj

(Prof. Dr. Paula Grigorescu-Sido)

- Biochemistry Department U.M.F. Cluj

(Conf.Dr.Cristina Drugan)

* These include the 5 most common types of lysosomal storage diseases with

specific treatment Fabry disease

MPS type I; MPS type II

Pompe disease

Gaucher disease

79p.

69,2%

Other

Sphingolipi

doses 20p.

17,5%

MPS 31p.

20,3%

MPS type

II/III 3p.

1,9%

Pacients diagnosed with lysosomal storage disease in

Center Cluj Napoca (n = 152) :

120 (78,9%) treatable!!!!

Type II - 16 p.

type III B - 6 p.

type I - 7 p. 31 p Type IVB - 1 p.

Type VII - 1 p.

Fabry disesae – 15 p.

GM1gangliozidosis – 12 p.

GM2 gangliozidosis – 2 p.

Niemann-Pick dis. – 5 p.

Metachromatic – 1 p.

leukodystrophy

Gaucher disease

type 1 – 76 p.

Type 3 – 3 p.

75% Sphingolipidosis

(114 p.)

1,9%

Gliogenosis type II

Pompe disease 3p.

79 p

35

0,6%

α Manozidosis 1 p.

Fabry

13,15%

79 pacients/62 families nonconsanguineous /30 counties+ Bucuresti

1-6 pacients/county

Type 1: 76 pacients

Type 3: 3 pacients

Reported

to International

Gaucher Registry

Epidemiologic data of Romanian patients/2017.

• Diagnosis

Gaucher disease

0

10

20

30

40

50

60

70

80

1998 2000 2002 2004 2006 2008 2010 2012 2013 2014 2015 2016

Number of patients diagnosed with

Gaucher disease

(1997-2016)

9

47 40

25

16

65 63

53

66

76 79

•Epidemiologic data of Romanian patients

Prevalence 1/250.000 vs. 1/300.000 (Germany; Spain)

79 diagnosed patients vs 200 probably ill - in Romania*

:

M: 41,8%

33 p

F: 58,2%

46p

F/M:1,37/1

* Grabowski: 1/100.000

Gaucher disease

Age: a). at onset: 2-64 years

b). actual

0

5

10

15

20

< 10 10-20 20-30 30-40 40-50 50-60 60-70 >70 ani

1

18

6

14

17

8

5

2

• Molecular data of patients with Gaucher disease

1 2

1 N370S/N370S 15% 30,1%

2 N370S/L444P 38% 15,3%

3 N370S/others 12,4% 39,3%

4 N370S/? 32% 9,6%

5 L444P/L444P 2,6% 5,6%

Genotype: Romanian patients (1) vs.

reported patients in Int. Gaucher Reg. (May 2014)

44,4% 48,4%

total splenectomy

• Clincal data of patients with Gaucher disease

Severity score for patients who had splenectomy

1 – no splenectomy

2 – patients with splenectomy

3- total patients

1 2 3

12 ± 3 16,8 ± 4,6 13,4 ± 4,2

p=0,01

30%

23 p

Patients 1 2

Type of

Gaucher disease

I 97,4% 91,4 %

III 2,6% 6,6 %

Gender F 58,7% 53,4 %

M 41,5 % 46,6 %

Age at diagnosis 1,6-70 (-0,9)-91

Splenectomy 31,1% 23,8 %

Patients under specific

treatment

98/100*% 79,8%

Age at therapy initiation 1,75-70,16 0-87,1

Anemia 52,9% 42,9 %

Thrombocytopenia 37,7% 25,1 %

Growth deficiency 50% 31 %

Chronic bones pain 91% 49,8 %

Bone crisis 7,8% 13,6 %

Fractures 18,1% 11 %

• Romanian patients (1) vs.

Reported patients in Int. Gaucher Reg. (May 2014)

B. Specific treatment of Romanian

patients with Gaucher disease

(evaluated in Cluj Napoca)

Cerezyme available in Romania since:

2001 - compensated 66%

2002 - compensated 100%

2006 - Comission for treatment of

Gaucher disease

Sources: - ECAP/ICAP

- CNAS

Specific Enzymatic Therapy

Gaucher Disease in Romania/2016

Treatment (present)

• 79 patients (confirmed diagnosis)

4 died

5 patients → abroad (3 patients under treatment; other 2?)

• 70 patients in Romania

• 69 patients under enzyme replacement therapy! - Cerezyme (CNAS): 68 patients*

- Vpriv (donation): 1 patient

Gaucher Disease

* 2 patients treated with Eliglustat (2013-2015) (EDGE study)

Year Number of patients treated with Cerezyme

CNAS ECAP/ICAP* Total

2002 2 - 2

2003 2 2 4

2004 3 12 15

2005 11 14 25

2006 11 14 25

2007 20 13 33

2008 23 13 26

2009 24 13 37

2010 24 14 38

2011 28 14 42

2012 33 14 47

2013 56 - 56

2014 63 - 63

2015 64 64

2016 68 - 68

* ~ 30.000.000 E

C. Evaluation of patients with

Gaucher disease under

enzyme replacement therapy

(monitorized in Cluj)

• Evolution under enzyme replacement therapy:

very good! Amelioration or resolution of anemia and thrombocytopenia:….0,5-1,5 ys

Reduced organomegaly……………….…………….........2 ys

Clinical evaluation of bone disease favorable……..3-4 ys

Normalization of chitotriosidase ………………………...3 ys

• Evolution of untreated patients

Clinical evolution progressively worsening

Triple value of chitotriosidase: 25.570 77.500! (3X)

4 of the patients died (cause):

- associated disease:

- cirrhosis of the liver hepatitis B and C virus (ERT initiated)

- haemolytic autoimmune anaemia (untreated)

- car accidents (ERT intermittent in SUA)

- Gaucher disease type 3 severe form (ERT with Ceredase/donation)

Objectives after 4 years of enzyme

replacement therapy

Absent anemia

97,2 91,8

75,6 79,5

Thrombocytopenia>

120.000/mmc

95,8 78,5

Splenomegaly ≤8xN Hepatomegaly ≤1,5xN

94,5 90,8

Romanian

patients

Int.Gaucher Registry

Absent bone crisis

99 99

Weinreb N.L. et al, A benchmark analysis of the achievment of

therapeutic goals for type 1 Gaucher disease patients treated

with imiglucerase. Am. J. Hematol. 2008

Conclusions

1. Gaucher disease is still undiagnosed in our country

2. Severe forms of disease are more prevalent

3. The patients have access to specific enzyme and molecular diagnosis

4. Evolution under enzyme replacement therapy is very good

Thanks:

- Foundation of patients with lysosomal

diseases in Romania

- CAS & DSP-Cluj

- CNAS Bucuresti

- Sanofi Genzyme

Gaucher patients’ Day

Thanks for your attention!