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…