Download - 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.
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
Trigger for treatment ?
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
Trigger for treatment ?
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