jfma, session 5 - 8e amylose

JFMA, Session 5

Stabilisateurs et amylose TTR cardiaque : enfin un traitement (?)

Pr Michel SLAMA

CHU X BICHAT - Université Paris Sud XI

Liens d’intérêt

-PFIZER -ALNYLAM -GSK/IONIS -Association Française contre l’Amylose

Transthyrétine •  Protéine de transport

•  127 acides aminés, 56 kDa •  Homotétramère soluble produit par le foie •  Transporte la thyroxine et le rétinol (sites de liaison largement inoccupés) •  Circulant dans le sang et le liquide cérébro-spinal

Cascade amyloidogénique

Supprimer la TTR amyloidogénique Stabiliser le tétramère Dégrader les fibrilles amyloïdes

Homo tétramère Mauvais repliement Fibrilles amyloïdes Dépôt tissulaire Synthèse hépatique Monomère

Castano et al., Am Coll Cardiol 2015 Oct

Transplantation hépatique 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

§  Améliore la survie chez les patients NAF-Val30Met §  Stabilise la neuropathie §  Mortalité à 1 an 7-25%

§  Données du registre international

0

20

40

60

80

100

0 5 10 15

Patie

nt s

urvi

val (

%)

Years after transplantation

Val30Met - Early onset

Val30Met - Late onset

n=1342

n=170

n=109 n=81

B G Ericzon et al., Transplantation 2015, 9: 1847-54

PROGRESSION OF CARDIOMYOPATHY AFTER LIVER TRANSPLANTATION IN PATIENTS WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY, PORTUGUESE TYPE1.

Olofsson, B-‐O et al, Transplanta1on. 73(5):745-‐751, March 15, 2002.

n = 10

Homo tétramère Mauvais repliement Fibrilles amyloïdes Dépôt tissulaire Synthèse hépatique Monomère

Supprimer la TTR amyloidogénique Stabiliser le tétramère Dégrader les fibrilles amyloïdes

Sites d’action

TTR stabilizers Diflunisal / Tafamidis

Berck J et al. JAMA 2013, 310 (24): 2658-67); Bulawa et al PNAS, 2012, 109:9629-9634; 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

disea

seco

urse,

loca

le,an

dcasesreported

bythese

commonTTR

variants

aredescribed

inTab

le1.

Sev

eral

structurally

distinct

classes

of

small

molecu

leTTR

amyloid

inhibitors

hav

ebee

ndis-

covered

through

screen

ing

orelab

orated

through

structure-based

design.23–26These

inhibitors

func-

tion

bybindingoneorboth

ofthetw

oeq

uivalen

tthyroxine(T

4)sitesat

theTTRquartern

arystructure

interfac

e.Binding

tothe

largely

unocc

upied

(495%

)T

4sitesstab

ilizes

thenativestateofTTR

toan

extentproportional

tothe

binding

affinity.

Native

state

stab

ilization

substan

tially

raises

the

barrier

fortheTTRdissociation,whichis

thetypical

rate-lim

iting

step

ofTTR

amyloidogenesis.23,24,26,27

The

structures

ofthe

inhibitors

utilized

inthis

study,

alongwith

theirco

rrespondingdissociation

constan

ts,max

imum

therap

euticserum

levels,

and

human

plasm

abindingstoichiometries

aresu

mmar-

ized

inTab

le2.23,28–30Diclofenac,diflunisal,an

dflufenam

icacid

areallnonsteroidal

antiinflam

ma-

tory

drugs

(NSAID

s).The

firsttw

oare

Food

and

DrugAdministration(FDA)ap

proved

.Diclofenac

isamodestfibrilform

ation

inhibitorin

vitroag

ainst

WTan

dV30M

TTR.25Moreover,itslow

max

imum

therap

eutic

level

and

low

binding

stoichiometry

with

TTR

inhuman

plasm

alimitsitsusefulness

clinically

(Tab

le2).

Diflunisal

isa

better

fibril

form

ation

inhibitor

relative

todiclofenac

against

WTTTR.23Diflunisal

has

also

bee

nsh

ownto

hav

ea

bindingstoichiometry

exceed

ing1.5

toserum

TTR

when

given

orallyto

human

subjectsat

itsreco

m-

men

ded

dosage

(Sek

ijim

aY.,

unpublish

eddata).

Flufenam

icacid

isslightlybetterat

inhibitingWT

TTR

fibrilform

ation

inco

mparison

todiflunisal.28

Table

1CommonTTRam

yloidosisch

aracteristics

TTR

Age

ofonset

Disea

seco

urse

Loca

tion

Cases

publish

ed

WT

80

Late-onsetcardiacinvolvem

ent

Worldwide

25%

ofpeo

ple

over

age80a

V30M

30–60

Presents

withpolyneu

ropathyan

dau

tonomic

dysfunction,then

system

icinvolemen

t(heart,

gastrointestinal

tractetc)

Worldwide

4400

V122I

60s

Late-onsetcardiacam

yloidosis

African

–American

Most

common

variantb

T60A

50s

Late-onsetcardiacam

yloidosiswithsome

neu

rologicinvolvem

ent

Appalachian,Irelan

d440

L58H

40s

Usu

ally

presents

withCTSan

dis

slowly

progressiveover

twodecad

esMaryland,German

450

I84S

20–30

CTSat

30,vitreousopacities40–50s,

then

heart

involvem

ent

Indiana,

Switzerlan

d430

CTS¼carpal

tunnel

syndrome.

aLeadsto

SSA.Consideringthepopulationover

80,25%

werefoundto

hav

ecardiacinvolvem

entonau

topsy.16Thenumber

ofpatients

with

cardiacam

yloid

dep

ositionthat

dev

elopclinically

sign

ifican

tdisease

(SSA)is

noten

tirely

clear.

bApproxim

ately3.9%

ofAfrican

American

s(1.3

million)areheterozy

gousforthis

variant.22

Table

2Structuresan

dproperties

ofselected

TTR

amyloidogenesis

inhibitors

WT

V30M

Maxim

um

therapeu

tic

concentration(mM)

Molareq

uivalent

boundto

human

plasm

aTTRat

10.8mM

a

Kd1(nM)

Kd2

Kd1(nM)

Kd2

Diclofenac

60

1.2mM

160

3.9mM

50.04

Diflunisal

75

1.1mM

——

400

0.13

Flufenam

icacid

30

225nM

41

320nM

54

0.20

Inhibitor1b

55nM

——

—1.38

aRan

geis

from

0to

2,representingtheex

tentofoccupan

cyofthetw

obindingsitesav

ailable

oneach

TTRtetram

er.

b2–[(3,5-dichlorophen

yl)

amino]ben

zoic

acid.

Nativestatestab

iliza

tionby

NSA

IDS

SRMiller

etal

546

Lab

oratory

Investigation(2004)84,545–552

•  Diflunisal (Dolobis) •  phase III / placebo study

•  TTR-FAP V30M /non V30M, stage I + II •  Available in US

•  Tafamidis (Vyndaqel@) •  phase III +extension

•  TTR-FAP V30M, stage I early •  AMM Europe (2011), Japan (2013), Israel, Russie, Mexique, Argentine,

Brésil (2017) / not in US / UK

•  Diflunisal •  Dolobis, Dolobid ® •  Commercialisé en 1971 •  Retiré du marché en 2004 •  Dérivé de l’acide salicylique, propriétés analgésiques et

anti inflammatoires •  Inhibe la production de prostaglandines •  Non disponible en France; disponible « off label » USA,

Italie, Suede

Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial

•  Investigator-initiated international, double-blind, RPC study (Sweden Italy Japan England US) 2006 - 2012

•  130 ATTRFAP patients with clinically detectable peripheral or autonomic neuropathy

randomly assigned to diflunisal 250 mg or placebo twice daily for 2 years

•  50% with cardiac involvement •  Neuropathy Impairment Score plus 7 nerve tests (NIS+7) from 0 (no neurologic

deficits) to 270 points (no detectable peripheral nerve function). •  Secondary outcomes: quality of life questionnaire (Short Form-36(SF-36)) and

modified body mass index (mBMI).

Berk JL et al, JAMA. 2013 December 25; 310(24): 2658–2667

•  Problem with the study = attrition: ttt stopped in 52% patients (42% diflunisal group, 61% placebo group) mostly because of disease progression

•  pts w. cardiac involvement: 24 months ’ diflunisal treatment •  did not significantly reduce LV wall thickness or LV longitudinal

strain compared with placebo. •  subgroup analysis of patients with abnormal BNP levels, the rate of

increase in LV wall thickness did appear to be slower with diflunisal treatment compared with placebo.

placebo diflusinal p

NIS+7 +25 +8,7 0,001

SF 36 physical-‐

-‐4,9 +1,5 0,003

SF 36-‐mental -‐1,1 +3,7 0,022

TT stopped 61% 42%

Castano A. et al, Congest Heart Fail. 2012 ; 18(6): 315–319

13 pa8ents with confirmed wild-‐type or mutant TTR cardiac amyloidosis. mean follow-‐up of 0.9±0.3 years BNP, Tn, IVS, LV EF, LV mass: NS

Tn BNP

LV mass EF mBMI MAP

GFR Hgb

Takahashi R et al, Journal of the Neurological Sciences 345 (2014) 231–235

•  Six consecutive Val30Met FAP patients (65.8 ±7.3 y)

•  Open label study with oral diflunisal (250 mg bid)

•  One patient ceased to take diflunisal because of hematuria •  Average EF 70%, IVS = 12.5 – 13.8 mm •  Follow up: a 4.4 ± 0.9 years •  No change in FAP stage, deterioration of motor

and sensory symptoms and of clinical scores •  Improvement of dysautonomic symptoms •  MIBG (H4): 1.7 ±0.9 à 1.9 ± 1 (N = 2.3-3.7)

Tafamidis Meglumine (Vyndaqel ®) •  2003

•  Approved by the European Medicines Agency in 2011,

•  Available in France 2011, Portugal 2012, rejected by the US FDA in 2012, and approved in Japan in 2013

•  stabilizes the correctly folded tetrameric form of the transthyretin (TTR)

protein by binding in one of the two thyroxine-binding sites of the tetramer •  likely to affect availability of drugs including methotrexate, rosuvastatin, and

imatinib, likely to interact with NSAIDs and other drugs that rely on those transporters.

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

Bulawa CE et al, PNAS June 12, 2012. 109 (24) 9629-‐9634

Falk R et al, Heart Failure Soc of America Annual Scientific Meeting; September 18-21, 2011; Boston, MA.

Tafamidis for transthyretin familial amyloid polyneuropathy A randomized, controlled trial

•  N=125 early V30Met •  higher-than-anticipated liver transplantation

dropout rate •  This study provides Class II evidence that 20

mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score.

•  Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

Coelho T et al, Neurology® 2012;79:785–792

Fig. 1 Changes of neurological function during Tafamidis treatment.a Change from baseline of NIS over 18 months of treatment in early(stage 1, N = 21) and late (stage 2 & 3, N = 13) stages of the disease.b Progression of neurological impairment in patients followed up over36 months of treatment (note that patients with longer follow up hadmore severe disease due to inclusion of patients in stage 2–3 in the

early phases of the study). c Six-month change of NIS over 18 monthsof treatment (N = 35). d Percentage of responders (change of NISfrom baseline NIS-LL\2 points) over 36 months of treatment. NIS-LL neuropathy impairment score, NIS-LL NIS-lower limb, F-Ufollow-up

926 J Neurol (2016) 263:925–926

123

ORIGINAL COMMUNICATION

Monitoring effectiveness and safety of Tafamidis in transthyretinamyloidosis in Italy: a longitudinal multicenter study in a non-endemic area

A. Cortese1 • G. Vita2,3 • M. Luigetti4 • M. Russo3 • G. Bisogni4 • M. Sabatelli4 •

F. Manganelli5 • L. Santoro5 • T. Cavallaro6 • G. M. Fabrizi6 • A. Schenone7 •

M. Grandis7 • C. Gemelli7 • A. Mauro8 • L. G. Pradotto8 • L. Gentile2 •

C. Stancanelli2,9 • A. Lozza1 • S. Perlini10 • G. Piscosquito11 • D. Calabrese11 •

A. Mazzeo2 • L. Obici12 • D. Pareyson11

Received: 3 December 2015 / Revised: 8 February 2016 / Accepted: 9 February 2016! Springer-Verlag Berlin Heidelberg 2016

Abstract Tafamidis is a transthyretin (TTR) stabilizerable to prevent TTR tetramer dissociation. There have been

a few encouraging studies on Tafamidis efficacy in early-

onset inherited transthyretin amyloidosis (ATTR) due toVal30Met mutation. However, less is known about its

efficacy in later disease stages and in non-Val30Met

mutations. We performed a multi-center observationalstudy on symptomatic ATTR patients prescribed to receive

Tafamidis. We followed up patients according to a stan-

dardized protocol including general medical, cardiologicaland neurological assessments at baseline and every

6 months up to 3 years. Sixty-one (42 males) patients were

recruited. Only 28 % of enrolled subjects had the commonVal30Met mutation, mean age of onset was remarkably late

(59 years) and 18 % was in advanced disease stage at studyentry. Tafamidis proved safe and well-tolerated. One-third

of patients did not show significant progression along

36 months, independently from mutation type and diseasestage. Neurological function worsened particularly in the

first 6 months but progression slowed significantly there-

after. Autonomic function remained stable in 33 %, wors-ened in 56 % and improved in 10 %. Fifteen percent of

patients showed cardiac disease progression and 30 % new

onset of cardiomyopathy. Overall, Tafamidis was not ableto prevent functional progression of the disease in 23

(43 %) subjects, including 16 patients who worsened in

their walking ability and 12 patients who reached a higherNYHA score during the follow-up period. A higher mBMI

at baseline was associated with better preservation of

neurological function. In conclusion, neuropathy and car-diomyopathy progressed in a significant proportion of

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00415-016-8064-9) contains supplementarymaterial, which is available to authorized users.

& D. [email protected]

1 C. Mondino National Neurological Institute, IRCCS, Pavia,Italy

2 Department of Neurosciences, University of Messina,Messina, Italy

3 NEMO SUD Center for Neuromuscular Disorders,Fondazione Aurora Onlus, Messina, Italy

4 Department of Geriatrics, Neurosciences and Orthopedics,Institute of Neurology, Catholic University of Sacred Heart,Rome, Italy

5 Department of Neurosciences, Reproductive andOdontostomatological Sciences, University Federico II ofNaples, Naples, Italy

6 Department of Neurological, Neuropsychological,Morphological and Motor Sciences, University of Verona,Verona, Italy

7 Department of Neurosciences, Rehabilitation,Ophthalmology, Genetics and Maternal Health Sciences,University of Genoa, Genoa, Italy

8 Division of Neurology and Neurorehabilitation, Ospedale SanGiuseppe, Istituto Auxologico Italiano, IRCCS, Piancavallo,Verbania, Italy

9 Biomedical Department of Internal and SpecialisticMedicine, University of Palermo, Palermo, Italy

10 Clinica Medica II, Department of Internal Medicine,Fondazione Policlinico IRCCS San Matteo, University ofPavia, Pavia, Italy

11 Clinic of Central and Peripheral Degenerative NeuropathiesUnit, Department of Clinical Neurosciences, IRCCSFoundation, ‘‘C. Besta’’ Neurological Institute, via Celoria11, 20133 Milan, Italy

12 Amyloidosis Research and Treatment Center, IRCCSFondazione Policlinico San Matteo, Pavia, Italy

123

J Neurol

DOI 10.1007/s00415-016-8064-9

J Neurol 2016, 263 (5):916-924

§  61 patients, 62 ans (31-81), 44 non Val30Met / Stade 1=44, 2=12, 3=5 / NIS moyen 53 ± 38

§  A 18 mois: ΔNIS= 15.6 ± 25.7, mBMI stable, 1/3 patients stables à 36 mois §  Frs prédictifs “répondeurs” à 1 an: mBMI, NIS, age début, durée, variant TTR, age §  35% des patients (8/23) naifs d’atteinte cardiaque ont développé une

cardiomyopathie

§  Bonne tolérance (13% EI), 1 décès

Cortese A et al, J Neurol 2016, 263 (5):916-924 Merci Violaine !

J Neurol 2017, 264:264-268

!  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%

§  43 patients, 59 ans (31-79), 23 non V30M / Stade 1=23, 2=15, 3=5 / NIS moyen 34.5 ± 38 §  A 24 mois ΔNIS= 12.6 ± 44.7, mBMI stable, 15% stables (répondeurs ΔNIS ≤4) §  Frs prédictifs “répondeurs”: mBMI, age, variant V30M (sous groupe Portugais)

§  Bonne tolérance, 6 décès imputables à la maladie dont 2 d’origine cardiaque

(p<0.0001)

Merci Violaine !

Falk R et al, Heart Failure Soc of America Annual Scientific Meeting; September 18-21, 2011; Boston, MA.

•  31 pts amylose sénile, 77 ans, •  NYHA 1-2 •  Suivi 55 mois •  1an: 3 arrêts de ttt, 2 décès, 7 hospitalisations,

20 NYHA stables, •  48% avaient des signes de progression de la

maladie (HF, AF, syncope) •  NT pro BNP stable, Tn petite augmentation, •  Épaisseur stable en écho

Maurer M et al, Circ Heart Fail. 2015;8:519-‐526.

Maurer M et al, Circ Heart Fail. 2018;11:e004769

13 = Diflunisal 16= Tafamidis

Maurer M et al, Circ Heart Fail. 2018;11:e004769

ATTR-ACT Study

AG10 exhibits best-in-class TTR binding, TTR stabilization, and inhibition of amyloid fibril formation

Penchala S. et al. Proc Natl Acad Sci USA 2013, 110:9992-7 27

Inhibition of WT- and V122I-TTR fibril formation in purified protein assay

Binding of TTR ligands in human serum and stabilization of TTR tetramers

Wild

type

TTR

V1

22I T

TR

Qu’est ce qu’une amylose cardiaque ? Criteres AL applicables à mTTR ou wTTR ???

62 y old woman, Ser77 mutation carrier NYHA cl II Normal ECG BNP = 36, troponin <0.1 TTE : IVS 12 mm, reduced strain -14%

Trigger for treatment ?

Mr G…. 59 y old man, Hypertension TYR77 mutation minor TTR FAP NYHA cl I Normal ECG BNP = 25, troponin <0.05 DPD scintigraphy: no cardiac uptake TTE : IVS 11 mm, strain -20% CMR: Mid septum LGE


61 y old man, asthma, DVT, uncle and aunt died of FAP VAL107 mutation decreased sensibility of fingers and toes, impotency, constipation NYHA cl I Normal ECG Biopsy: ASGbiopsy: negative; skin = denervation, no amyloid deposits BNP = 25, troponin <0.05 TTE : IVS 8 mm, strain -18%, EF 50%= strictly normal CMR: normal DPD scintigraphy: positive cardiac uptake


Les stabilisateurs

•  Avantage: traitement oral •  Limite: diffusion systémique ? •  Effet positif ?

•  Diflunisal: limites = peu de données, tolérance médiocre et disponibilité de la molécule

•  Tafamidis: Détails de ATTR-ACT sous embargo •  AG 10 ?

La JFMA est organisée avec le soutien institutionnel de

jfma, session 5 - 8e amylose

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