V. Planté-Bordeneuve
Service de Neurologie – Réseau Amylose
CHU Henri Mondor – Créteil - France
Nouvelles perspectives thérapeutiques dans les
amyloses à transthyrétine
Académie nationale de Pharmacie
Séance du 4 novembre 2015
Déclarations / conflits d’intérêts
Investigateur principal des essais thérapeutiques de phase III Apollo
(Alnylam) et Isis CS2-CS3 (Isis pharmaceuticals)
Consultant– Isis pharmaceuticals (San diego USA – Mars 2015)
Consultant – Pfizer (Londres- 2013, Barcelone 2012), orateur invité au
symposium sur les « Amyloses à Transthyétine » Académie de
Neurologie, Cancun, Mexique, et congrés national de neurologie,
Antalya, Turquie Novembre 2014 – Pfizer
Invitation au congrès de la « Peripheral nerve Society » , Quebec,
Canada Juillet 2015 – Alnymlam pharmaceuticals
Description au Portugal (Andrade 1952)
Autosomique dominant
Dépôts amyloides de fibrilles de TTR
Tissus cibles: SN périphérique / cœur
Décès entre 8 et 15 ans
II: 4
I: 2I: 1
II: 2 II: 3II: 1
III: 2III: 1
IV: 1
III: 3 III: 5 III: 7
IV: 2
III: 6III: 4 III: 8
IV: 4 IV: 8 IV: 11IV: 12IV: 13IV: 15 IV: 21 IV: 27IV: 28IV: 29IV: 30IV: 31IV: 32IV: 19
IV: 14IV: 16
IV: 17IV: 18
IV: 25
IV: 20IV: 22 IV: 24IV: 26IV: 23
V: 1
IV: 6
IV: 3 IV: 5
IV: 10
IV: 7 IV: 9
Neuropathie Amyloide Familiale à Transthyrétine
(NAF-TTR)
Andrade C. Brain 1952, 75: 408-427
Transthyretine (TTR) – Géne ATTR
Tétramère (55 kDa), soluble
Transport de la thyroxine et du rétinol
Sites de synthèse
Foie (95%), plexus choroides, rétine
Gène ATTR (18q 11.2-12) – 7 kb
4 exons (200pb)
>120
Mutations TTR
(+ 1 microdeletion)
Amyloidogénique Non amyloidogénique
Neuropathie
>75 mutations
Val30Met
Cardiomyopathie
Val122Ile
Hyperthyroxinemie
Euthyroidienne
(position 109)
Polymorphismes
Neutres
(Gly6Ser, Val119Met)
Benson M. Muscle &Nerve 2007, 36: 411-23; Bulawa et al PNAS, 2012, 109:9629-9634
Neuropathie amyloide familiale à TTR
Atteinte sensitivo-motrice axonale longueur
dépendante et systémique
Cardiovasculaire
Gastro-
intestinale
Génito-
sphinctériens
Brésil
Val30Met
Début < 30 ans
Suède
Val30M / Début: 56 ans
Japon
Hétérogénéité /
Val30M
Début 60 / 30 ans
Portugal:
Val30Met / Début 33 ans
Holmgren et al. J Med Genet 1994
Bittencourt et al. Eur J Neurol 2005
Coelho et al. J Med Genet 1994
Sakoda et al. Clin Genet
1983
Koike et al. Arch Neurol
2002
Planté-Bordeneuve V. et al; Lancet Neurol 2011
Répartition et différences à travers le monde:
régions « endémiques » / autres (Europe, USA, Brésil, Asie…)
Peut on traiter une amylose à tranthyrétine en 2015 ?
Oui +++
Mais…
Les traitements actuels visent à empécher la formation de
nouveaux dépôts d’amylose, donc à stabiliser la symptomatologie
Dans tous les cas…
Il faut faire le diagnostic au plus tôt et traiter au plus vite
Mais encore….
Les traitements agissant sur les dépôts préexistants se
développent !
La transplantation hépatique (TH) dans les NAF-TTR
Première approche thérapeutique
1990 : première TH chez 2 patients ATTR-Val30Met suédois
Objectifs :
«Tarir» la source principale du variant pathogène
Arrêt de la progression des symptômes
0
0,5
1
1,5
2
2,5
3
Before LT
+ 5 days
+ 6 months
Survie à 10 ans
I groupe contrôle (no LT)= 56%
II: groupe TH = 100%
Yamashita T et al. Neurology 2012, 78:637-43
0
25
50
75
100
125
150
175
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
No information (n=66)Non-Val30Met (n=267)Val30Met (n=1711)
Transplantation hépatique dans les NAF-TTR - Survie
Données du registre international
Disparité des résultats selon les groupes :
Val30Met / non Val30Met
Selon l’âge des premiers symptomes
0
20
40
60
80
100
0 5 10 15
Patient
surv
ival(%
)
Years after transplantation
Val30Met - Early onset
Val30Met - Late onset
Non-Val30Met - Early onset
Non-Val30Met - Late onset
n=1342
n=170
n=109n=81
B G Ericzon et al., Transplantation 2015
NAF à TTR
Autres stratégies de traitement
Neurodegeneration
Stabilisateurs de
TTR :
- Tafamidis
- Diflunisal
Thérapie génique
Inhiber la transcription:
- Oligonucléotide antisens
- siARN
«Résorber» l’amylose:
déplétion du composant P
(CPHPC) + Anticorps
monoclonaux antiSAP
Stabilisateur de TTR : Tafamidis
Le Tafamidis stabilise la TTR
plasmatique de sujets sains WT et de
patients porteurs des variants V30M et
V122I en conditions dénaturantes / Urée
(0 à 72h)
Bulawa et al PNAS, 2012, 109:9629-9634
Fx005 : étude de phase III controlée / double aveugle tafamidis per os 20mg/jour versus placebo - durée 18 mois
128 patients ATTR-V30M stade précoce
Fx006 : Extension de Fx005 en « ouvert » - durée 12 mois
Fx1A-201: étude phase II en ouvert: 21 patients non Val30Met- 12 mois
Coelho et al. Neurol. 2012; 79:785-92; J Neurol 2013, 260: 2802-14;
Merlini G et al. J Cardiovasc Trans Res 2013, 6: 1011-1020
Tafamidis: essais pivôts
mBMI
P<0.0001
p=0.44
Tafamidis Placebo
Monthly Rate of Change and Mean Change from Baseline (ITT)
7
NI S- LL
p=0.02
p=0.04
NIS-LL
Tafamidis (Vyndaqel®)
Bonne tolérance
Interruption de traitement 4 tafamidis / 3 placebo
Incidence SAE similaire, infection urinaire (SAE) chez 2 patients traités
AMM Europe (Nov. 2011), Japon (2013) et non aux USA
«Patients avec neuropathie amyloide TTR de Stade 1 avec
variants pathogène (V30M / non V30M)»
L’effet sur l’atteinte cardiaque (cardiomyopathie) reste non élucidé
Etude ATTRACT(2015)
Etude Tafamidis /
phase IV
(CHU Henri
Mondor)
Population: 45 patients inclus• 41 traités > 6 mois
• 24 hommes, 18 V30M /23 avec 11 # variants TTR • Age: 63.6 ±11.5 ans, évolution 26.9 ±14.8 mois• Scores NIS= 34.7 ± 38.2, BMI=23.5 ±3.7
• Dernière évaluation à 26±15 mois• 8 décès / 33 pts traités• Score NIS = 50.0 ± 44.2 (p<0.001)• BMI =23.9±3.7 (p=NS)
• N= 28 patients traités > 18 mois (jusqu’à 75)• Score NIS=59.1± 48 (p<0.001) • Figure Vb:1 patient respondeur (ΔNIS ≤4), 8
patients ΔNIS ≤8 • 11 patients autres options de treatment / 6 décès
! At last evaluation, for the entire cohort 41 pts
" NIS score deteriorated and scored on averaged 50.0 [SD=44.2], range 6-157.7 (p<0.001)
" Mean BMI was stable at 23.9 [SD=3.7] (p=0.07)
" mPND stages are shown in Figure II. Only 15 patients are still in stage I and 4 are now in stage IV.
" KPS (Figure III) 7 patients have now a Karnofsky below 50%
" Neurophysiological scores correlated with clinical data
" Figure IV shows the progressive reduction of responders over time based on NIS (ΔNIS ≤4)
!
TREATING TRANSTHYRETIN FAMILIAL AMYLOID POLYNEUROPATHY: LONG TERM EXPERIENCE WITH TAFAMIDIS Violaine Planté-Bordeneuve 1, 2, Farida Gorram1, 2, 5, Hayet Salhi1, 2, Tarik Nordine1, 3, Samar Ayache1, 3, Thibaud Damy1, 4, Philippe Le Corvoisier1, 5, Daniel Azoulay1, 6,
Cyrille Feray1, 6, Jean-Pascal Lefaucheur1, 3.!!!!!!!!! !!!!!!!1. Amyloid network - Henri Mondor University Hospital- APHP – Créteil France 4. Heart failure unit - Cardiology Henri Mondor University Hospital- APHP – Créteil France
2. Department of Neurology - Henri Mondor University Hospital- APHP – Créteil France 5. Inserm - Clinical Investigation Center 1430 - Henri Mondor University Hospital- APHP – Créteil France
3. Clinical Neurophysiology Unit - Henri Mondor University Hospital- APHP – Créteil France 6. Liver Transplant Unit - Henri Mondor University Hospital- APHP – Créteil France
Introduction
! Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a relentless autosomal
dominant neuropathy with fatal outcome in about 10 years
! Up to 120 pathogenic missense mutations are known in the TTR gene. In Europe, the
TTR- Val30Met is the most frequent variant
! Liver transplantation which removes the main source of mutated TTR was the first
therapeutic approach, resulting in survival improvement and stabilization of the
neuropathy, mainly in Val30Met patients below 50 years of age
! Recently, an oral medication, the TTR stabilizer Tafamidis (Vyndaqel*) has been
approved in Europe (2011) for patients with symptomatic TTR-FAP at early stage i.e.
“walking unaided”. In France, the drug was available since 2010, through an early
access program at first only for Val30Met patients
! The goal of this study is to assess the long term efficacy of treatment with Tafamidis
(Vyndaqel*) in our population of TTR-FAP patients
Results - part I
! Study profile (Figure I) : 45 patients enrolled (26 males, 21 ATTR-V30M)
" Loss of follow up (2 patients) and treatment discontinuation for side effects (2
patients), 1 for abdominal pains and 1 for transient renal failure at 6 and 9 months
respectively
" Eight patients died after an average follow up of 26.2 months (4 from cardiac
failure / 4 from progression of the neuropathy). At last update, tafamidis
(Vyndaqel*) was ongoing in 33 patients.
! Baseline characteristics of the population (Table 1) in 41 patients
" 24 men, 18 were V30M and 23 had 11 different pathogenic TTR variants, mean
age: 63.6 y-o [SD= 11.5], average disease duration 26.9 months [SD= 14.8],
range 6-75; 9 patients of Portuguese origin
" Mean scores for NIS were 34.7 [SD= 38.2] and 23.5 [SD=3.7] for BMI; PND
staging was stage1: 22 pts, stage II: 11pts, stage IIIa: 3pts, stage IIIb: 5pts;
Karnofsky was estimated 80-100% in 22 pts, 60-70% in 18pts, 50% in 1pt
Discussion/Conclusion!
! Tafamidis (Vyndaqel*) failed to stop the progression of the neuropathy in patients with different pathogenic TTR variants and a wide range of age and
severity of the neuropathy
! Based on the NIS evaluation, the number of responders gradually decreased especially after 18 months of Tafamidis. Only one patient still responded to
treatment (ΔNIS ≤4) after 30 months
! However, 8 patients had a moderate deterioration (ΔNIS ≤8) of their neurological condition on long term follow up (18-75 months), suggesting a partial
control of the progression of the neuropathy
! The BMI remained stable in keeping with preserved general condition
! Tafamidis (Vyndaqel*) was well tolerated. No major safety concerns was observed
! Limits: this study was open labeled without control FAP patients as comparators. The natural history of the neuropathy is most likely variable following the
TTR variant, the age of the patients
! Our results provide a useful therapeutic strategy in this devastating condition. For patients initially treated by tafamidis, we recommend a careful monitoring
of the neuropathy and of cardiac parameters in order to switch to other therapeutic options within one year in case of disease progression
! Additional anti-amyloid therapeutics are needed in this context!
!
Patients Number
Follow up
N=41 6-75 months
N = 13 6-18 months
N = 28 ≥ 18 months
V30M 18 4 14
Non-V30M
A19A(1) - L68I(1) - I107V(6) - S77T(2) -
G89L (1) - I122V(3) -
S77P(3) -T49I/G6S(1) -
V28M(2) - Y116S (1) -
S77Y(2)
A19A(1) - L68I(1) - I107V(2) - S77T(1) -
G89L (1) - I122V(2) -
S77P(1)
T49I/G6S(1) - V28M (2)- I107V (4) - S77T (1) -
Y116S(1) - I122V(1) -
S77P(2) - S77Y(2)
Age, years Mean ± SD 63,6 ± 11,5
65,5 ± 7,8
62,7 ± 13,8
Male 24 7 17
NIS Mean ± SD
34,7 ± 38,2
23,8 ± 28,4 39,8 ± 41,5
PND
Stade I-II 33 11 22
Stade IIIa 3 2 1
Stade IIIb-IV 5 0 5
KPS
80-100 % 22 7 15
70-60 % 18 6 12
≤ 50 1 0 1
BMI Mean ± SD
23,5 ± 3,7 23,6 ± 3,11 23,5 ± 4,1
Results – part II
! Patients were then classified into 2 groups according the duration of treatment
" Group 1 (N1=13 patients): median term follow up from 6 to 18 months
" Group 2 (N2=28 patients): long term follow up from 18 up to 75 months
" Baseline characteristics of each group were similar (Table I)
! At last evaluation in Group 1 (Figure Va)
" Mean NIS: 30,4± 26,9 (p=0.07), 6 patients stable (ΔNIS ≤4)
! At last evaluation in Group 2 (Figure Vb)
" Mean NIS: 59,1± 48 (p<0.001). Only 1 patient stable (ΔNIS ≤4), 8 patients had a moderate progression on NIS (ΔNIS ≤8) (green arrow
" At last update in this subset, 6 patients had died, 11 patients turned to other therapeutic options including liver transplantation in 4.
!!!!
22
11
3
5
0
15 14
6
2
4
0
5
10
15
20
25
Number of
patients
PND BASELINE
LAST PND
Stage IIIb Stage IV Stage I Stage II Stage IIIa
6/12 12/18
0!
20!
40!
60!
80!
100!
120!NIS/2440
BASELINE NIS
LAST NIS
+13
+6
+21
+10
+10
+12
+14
66 y-o
A19Asn 71 y-o
V122I
53 y-o
V30M
59 y-o
107V
55 y-o
S77T 79 y-o
I122V
Time (months)
NIS = 13
Baseline
Last follow up P-Value
Mean ± SD
Median
[range]
39,9 ± 41,5
18
[0-134,5]
59,1± 48
20
[6-175,7]
NS
0!
20!
40!
60!
80!
100!
120!
140!
160!
180!Nis/2440
BASELINE NIS
LAST NIS
+5,25
+6 +5 +8
+15
+43 +37
+4
+23,25
+9 +6
+30,5
+46
+16
+18
+8
+15
+51,75
+5,25
+15
+15 +18
+19
+38
+41,25
+13 +21
+4,5
45 y-o
V30M
≥42 18/30 30/42
NIS = 28
Baseline
Last follow up P-Value
Mean ± SD
Median
[range]
39,9 ± 41,5
24,5
[0-134,5]
59,1± 48
43
[6-175,7]
0,001
6 M o n th s
!N IS "4
!N IS > 4
1 2 M o n th s
!N IS "4
!N IS > 4
2 4 M o n th s
!N IS "4
!N IS > 4
3 6 M o n th s
!N IS "4
!N IS > 4
Methods
Patients treated with Tafamidis (Vyndaqel*) orally 20mg /day enrolled prospectively
(2010 - 2014) ! Inclusion criteria:
" Age > 18 years-old
" TTR pathogenic mutation carrier
" Symptomatic TTR-FAP with NIS > 4 and no other cause of neuropathy
" At enrollment before November 2011, mPND was stage I to IIIb, and only stage I or II
afterwards
! Evaluation performed at 6 months, then at least annually
! End points:
" Total Neuropathy Impairment Score (NIS): composite clinical score of decreased
motor function (79% of total score), sensory loss (13% of total score), tendon reflexes
(8% of total score); scale 0 [Normal] to 244 [Total impairment]. Responders were
defined as patients with a ΔNIS ≤4 between baseline and last update
" Modified Polyneuropathy Disability Score (mPND): stage I= sensory disturbance
but no walking impairment; stage II= walking impaired but able to walk without aid;
stage IIIa= walking with I stick; stage IIIb= walking with 2 sticks; stage IV= wheelchair
or bedridden
" Karnofsky Performance Status (KPS): scale 100 [Normal – No evidence of disease]
to 0 [dead]
" Body Mass Index (BMI): kg/m2
" Neurophysiological studies: Large nerve fiber tests: motor (MNCS) and sensory (SNCS)
nerve conduction studies, vibration detection threshold (VDT) - method of limits. Score 0 (normal) to 3 (MNCS, SNCS, VDT abnormal). Small nerve fibers tests: laser evoked potentials
(LEP), sympathetic skin responses (SSR) or sudoscan since 2013, quantitative sensory testing
(QST) with cold and warm detection thresholds - method of limits and heart rate variability to
deep breathing (HRDB). Score 0 (normal) to 4 (all 4 tests abnormal)
A score of 0.5 assigned for each abnormal test at the lower and upper limbs respectively. A score of 1 assigned for abnormal HRDB
! All patients provide informed consent for the study
! Statistics
" Results summarized using descriptive statistics. Analysis were carried out using a
SPSS 17.0 software with Wilcoxon’s rank test used to compare end points
22
18
1
17 17
7
0
5
10
15
20
25
Number of
patients
BASELINE
KARNOFSKY LAST KARNOFSKY
80-100!%! 70-60 % ≤ 50 %
45 patients enrolled
(25 males, 21 ATTR-V30M
mean age 63,3 y-o, range [32-83])#
N=41 patients
treated
> 6 months
33 pts
Ongoing treatment
8 Deaths ● mean follow up 26,5 [±13,4], range 6-44 ● 4 from cardiac failure ● 4 following progression of the neuropathy
2 patients
Lost follow-up
2 Treatment discontinuation
●!1#Abdominal#pains##●#1#transient#renal#failure##
MEAN FOLLOW UP
26 MONTHS [SD 15,2]
Up to 75 months
BASELINE
Last update
Figure I: Study Profile
Table 1: Baseline Characteristics of the study population
Figure II : mPND at baseline and at last update (N=41) Figure III : KPS at base line and at last update (N=41)
Figure Va: NIS in Group 1: Patients treated 6-18 months (N=13)
Figure V b: Follow up NIS: Patients treated ≥ 18 months (N=28)
Figure IV: Number of responders over time based on NIS evaluation (ΔNIS ≤4) 0
References: - T Coelho, LF Maia, A Martins da Silva et al. Long term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 2013; 260: 2802-2814,
- G Merlini, V Planté-Bordeneuve, D Judge et al. J Cardiovasc. Trans. Res. 2013, 6(6): 1011–1020.
!
†79 y-o
V30M
72 y-o
V30M
† 76 y-o
S77P 40 y-o
V30M
58 y-o
I107V 64 y-o
T49I
46 y-o
V28M
52 y-o
V30M
53% 44%
15% 9%
V. Planté-Bordeneuve July 2015, PNS meeting
Autres stabilisateurs de TTR : Diflunisal (Dolobis®)
AINS ex Dolobis®
Etude de phase I: le Diflunisal 500mg/ jour oral Se fixe sur les sites T4 / TTR
Stabilisation des tétraméres circulants de TTR
Sekijima et al, Amyloid 2006, 13: 236-49
Etude de phase III en double aveugle
diflunisal 500mg/jour contre placebo
130 patients randomisés
Durée 24 mois
Etude de phase III Diflunisal (Dolobis®) / Placebo
Résultats
Taux de «répondeurs»(#NIS<2) à 24
mois
Diflunisal: 29.7% / Placebo: 9.4%
(p<0.007)
Evénements indésirables
Décès: 9 placebo / 4 diflunisal
Interruption lié au TTT:
4 diflunisal /2 placebo
(hémorragie digestive, insuffisance
cardiaque,glaucome, nausées,
céphalée, insuffisance rénale)
Disponible aux USA, Canada,
Turquie…
En France, disponible au CHU
Mondor en l’absence d’alternative
thérapeutique
ISIS-TTRRx binds at the 3’UTR and
therefore inhibits the translation
of all known TTR mutations as
well as wild-type TTR
5' UTR 3' UTR
V30M
F33L V122I T60A
T49A
L12P
I84S
I68L
F64L
E89Q
L111M
ISIS-TTRRx Inhibits the Translation of All
Known TTR Mutations and Normal TTR
Antisense Mechanism of Action
RNase H Oligonucleotides
3
Oligonucléotide antisens / ARNm
Thérapie génique dans les Amyloses TTR
Oligonucléotides antisens / ARNsi
Coelho T et al., NEJM 2013, 369, 9: 819-29
ISIS-TTRrx
Potent & Durable Reductions in Transthyretin Levels
in Healthy Volunteers Treated with ISIS-TTRRx Multiple Dose – CS01
• 300 mg will be used for the Phase 3 study
siRNA– ALN-TTR-01 (N=32 patients) et
ALN-TTR-02 (N=17 volontaires sains)
Activity of siRNA against WT and Mutant TTR In Vitro Dual-Luciferase Reporter Assay
*p<0.05, **p<0.01, one-way ANOVA with Bonferroni’s post-hoc test 22
** **
**
** **
*
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Empty
Vector
WT V30M T60A S77F S77Y V122I
No
rma
lize
d m
RN
A C
on
ce
ntr
ati
on
1x10-5
0.001 0.1 10
0
0.2
0.4
0.6
0.8
1
1.2
1.4
[siRNA] (nM)
TT
R/G
AP
DH
(re
lati
ve to
co
ntr
ol)
S77F
S77Y
T60A
V122I V30M
5’ UTR 3’ UTR
siRNA
target site
Coelho T et al., NEJM 2013, 369, 9: 819-29Ackermann E et al., Amyloid 2012, 19: 43-44
Essais de phase I : ASO / siRNARéduction de l’ARNm et du taux
plasmatique de TTR
Essais de phase III en
cours (2013)…
Y aura t-il un traitement curatif des dépôts amyloides ?
Bodin K et al. Nature 2010; 468: 93-97
Nature 2010,468: 93-97
Merci.…
www.reseau-amylose-chu-mondor.org…