Post on 24-Jun-2020
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