Suivi spectro des patients NPC traités par Miglustat · Suivi spectro des patients NPC traités par Miglustat Frédéric Sedel Neurometabolic Department, Pitié-Salpêtrière Hospital,

Suivi spectro des patients NPC traités par Miglustat

Frédéric Sedel Neurometabolic Department, Pitié-Salpêtrière Hospital, Paris, France

Glucosylceramide

GM3

Miglustat

Lactosyl ceramide

GM2

GM1

Miglustat in NP-C

•  Inhibits the synthesis of glycosphingolipids •  Small molecule, crosses the blood brain barrer

(20–30%)

•  29 juvenile/adult patients randomised 2:1 to miglustat versus standard care

•  12-month comparison period, then extensions •  HSEM as primary outcome measure •  Secondary measures:

–  Gait –  Swallowing –  MMSE –  Hearing

•  +10 children treated in an open trial for 12 months

Miglustat in NP-C: Human Trial

Patterson et al. Lancet Neurology. 2007;6:665-672. HSEM: horizontal saccadic eye movement; MMSE: Mini-mental state examination.

-0.463

0.055

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

Alp

ha c

hang

e vs

bas

elin

e (m

s/de

gree

)

Miglustat

Control

All patients p=0.09

-0.485

0.234

Excluding benzodiazepine users p=0.03

(n=18) (n=8) (n=13) (n=7)

Velocity of horizontal saccadic eye movements

Patterson et al, 2007

Retrospective Cohort Study Design •  International, multicentre, observational cohort study

–  66 patients treated in 25 expert centres from 12 countries

•  Inclusion –  All patients with NP-C at the expert centres who were

treated or had previously received treatment with miglustat (not in clinical trial)

•  Period of observation: January 2003 to July 2008 •  Secure web-based questionnaire

–  Patient demographics/characteristics, treatment history –  Disease progression: clinical functional composite score

Pineda et al. Mol Genet Metab 2009;98:243-249.

Natural history of neurological signs in NP-C

Wraith et al, 2010 Years since diagnosis

Dis

abili

ty s

cale

com

posi

te s

core

uni

ts

All 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 1 2 3 4 5 6 7

Improvement

Deterioration (N=57)

Retrospective study of 66 patients treated with off-label miglustat

*Total number of patients per age group Pineda et al, 2009

Treatment difference:

Mean (95%CI): -0.070 (-0.275, 0.136) N*=26 Missing values=4

<6 years (n=22)

Mean (95%CI): -0.157 (-0.394, 0.080) N*=17 Missing values=2

6–11 years (n=15)

Mean (95%CI): -0.162 (-0.329, 0.006) N*=22 Missing values=2

≥12 years (n=20)

Before treatment

After treatment

Improvement Deterioration

Annual composite score change (mean 95%CI) -0.4 -0.2 0 0.2 0.4

Modifying dysphagia in NP-C: retrospective survey

•  Parameter score for swallowing declined from 0.12 to 0.36 in pre-treatment phase

•  Remained stable at 0.37 post-treatment

Adapted from Wraith et al, 2009; Walterfang et al, 2012

Mea

n sc

ores

Ambulation Manipulation Language Swallowing

At last clinical contact

At initiation of miglustat therapy

At diagnosis 0

0.1

0.2

0.3

0.4

0.5

0.6

Case reports and small uncontrolled studies/personnal experience

Pineda M, Perez-Poyato MS, O'Callaghan M, Vilaseca MA, Pocovi M, Domingo R, Portal LR, Pérez AV, Temudo T, Gaspar A, Peñas JJ, Roldán S, Fumero LM, de la Barca OB, Silva MT, Macías-Vidal J, Coll MJ. Mol Genet Metab. 2010 Apr;99(4):358-6 (16 children)

Fecarotta S, Amitrano M, Romano A, Della Casa R, Bruschini D, Astarita L, Parenti G, Andria G. Am J Med Genet A. 2011 Feb 22 (4 children)

Kumar A, Chugani HT. Pediatr Neurol. 2011 Jan;44(1):57-60. (2 children)

Zarowski M, Steinborn B, Gurda B, Dvorakova L, Vlaskova H, Kothare SV. Eur J Paediatr Neurol. 2011 Jan;15(1):84-7. (1 child)

Scheel M, Abegg M, Lanyon LJ, Mattman A, Barton JJ. Mol Genet Metab. 2010 Mar;99(3):291-5. (1 adult)

Zaaraoui W, Crespy L, Rico A, Faivre A, Soulier E, Confort-Gouny S, Cozzone PJ, Pelletier J, Ranjeva JP, Kaphan E, Audoin B. Mol Genet Metab. 2011 Feb 23. (1 adult)

NP-­‐C  

Cho Cr

NAA

Cho Cr

NAA

Normal  

Magnetic resonance spectroscopy in NP-C

Cho, choline; Cr, creatine

Increased choline Low N-acetyl aspartate (NAA)?

Follow-up using brain spectroscopy after 24 month-treatment with miglustat of three patients with NP-C

M, month; Cho, choline; Cr, creatine; NAA, N acetylaspartate Galanaud et al, 2009

0.350

0.400

0.450

0.500

0.550

0.600

0.650

0.700

M0 M6 M12 M18 M24 M36 M48 M60

N=13 N=10

N=7 N=5

N=4

N=3

N=3

N=3

Normal range

Months of treatment

Cho

/NA

A va

lue

Follow-up of 13 NP-C patients using NMRS

•  Evolution of the Cho/NAA in non-treated patients: -1% per year; after treatment: -10% per year; p=0.001

•  Positive correlation between the Iturriaga score, time from disease onset and Cho/NAA (covariance=0.38)

NMRS, nuclear magnetic resonance spectroscopy

Myoinositol  

N  

Hyperammonemia  Lactate  Absent      

Energy  Cho/Cr  

Cerebral  folate  deficiency  

Intox  Lipids/oligos  

28  ms  

28  ms  

28  ms  

135  ms  

135  ms  

N  

Cho/NAA  

135  ms  

Intérêt  de  la  specto  IRM  pour  le  Dg  des  maladies  métaboliques  

mI  Cho  

NAA  

Cr  

Lac  

B  A  

C  

D  

E   F  

Lipids/oligos  

Sedel et al, en révision

Cerebrotendinous xanthomatosis: treatment monitoring using NMR spectroscopy

M0 M9 M25 M41 M57

M0 M16 M28 M42 M46

P1

P2

N=10; P<0.01

Conclusions

1)  MRS = biomarqueur fiable pour le suivi thérapeutiques dans les MMHs de l’adulte

2)  Evidence d’un effet thérapeutique du Miglustat dans NPC

3)  Moins d’intérêt chez l’enfant?

Thanks to…

CETNP: “comité d’évaluation du traitement des maladies de Niemann Pick”

-­‐ Bertrand  Audoin  -­‐ Elsa  Kalphan  -­‐ Chris@ne  Tranchant…  

Thierry Billette Brigitte Chabrol Benedicte Heron Hélène Ogier François Feillet Vassili Valayanopoulos

Nicole Baumann Philippe Latour Marie Vanier Frédéric Sedel Julien Baruteau Dries Dobbelaere