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Martin Bortlík
Klinické a výzkumné centrum pro střevní záněty ISCARE
Interní klinika 1.LF UK a UVN, Praha
Farmakologický ústav 1. LF UK a VFN, Praha
Originální a biosimilární léky v léčbě
IBD
Zaměnitelnost biosimilárního
infliximabu CT-P13 v graviditě
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• CN a UC jsou chronické záněty tenkého a (nebo) tlustého střeva, neznámé příčiny
- rizikové faktory: RA, kouření (CN)
- začátek v mladém věku
• Komplexní choroby s lokálními a celkovými projevy
- pestrá symptomatologie, mimostřevní projevy, individuální průběh
• Prevalence 0,3-0,5%, incidence 4-6(CN) 8-12 (UC)
- severo-jižní a západo-východní gradient
• Medikamentózně (a chirurgicky) nevyléčitelné choroby
- cílem terapie je dlouhodobá remise
• Časté chirurgické intervence (80-90% CN, 10-15%UC)
- moderní terapie snižuje potřebu chirurgických výkonů
Charakteristika IBD
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IBD – komplexní choroby
3
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• While the exact cause of IBD is not entirely understood, it is known to involve an interaction
between genes, the immune system and environmental factors.
lBD - result from alterations in the interaction between
resident microbes and the host’s intestinal immune system
• Sokol H & Seksik P. Current Opinion in Gastroenterol. 2010;26:327–31.
Host
(genetic
susceptibility,
epithelial
dysfunction)
Environment
(gut microbiota)
Inappropriate
immune
response
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Current medical therapy in IBD
Conventional Biological terapy• low-cost high cost• easily available access restricted• lower effectivity higher effectivity
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Historie BL IBD v ČR
• 1998 – infliximab (CN), „expanded access programmme“
• 2006 – infliximab (UC)
• 2007 – adalimumab (CN)
• 2012 – adalimumab (UC)
• 2013 – golimumab (UC), biosimilární infliximab (CN, UC)
• 2014 – vedolizumab (CN, UC)
• 2016 – ustekinumab (CN)
• Organizace BL v ČR:
- do 2006 – individuální preskripce
- od 2006 – specializovaná centra pro podávání BL*
*od r. 2011 Centra vysoce specializované péče dle § 112 Zák. 272/2011 Sb. (Zákon o zdravotních službách)
6
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Současná situace7
• Anti-TNFα protilátky: infliximab (CN, UC), adalimumab
(CN, UC), golimumab (UC), certolizumab-pegol (CN)1)
• Antiintegrinové protilátky: vedolizumab (UC, CN),
natalizumab (CN)1)
• Protilátka proti IL 12/23: ustekinumab
Pozitiva
• efektivita a rychlost indukční léčby
• kortikoidy šetřící efekt
• redukce hospitalizací a operací
• snášenlivost
Negativa
• nižší účinnost u UC
• ztráta odpovědi (10-20% ročně)
• nežádoucí účinky (alergie, kožní
projevy, infekce, nádory?)
1)Pouze mimo EU
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Registr CREdIT
Český REgistr IBD pacientů na biologické Terapii
• Zřizovatelem Registru je Česká gastroenterologická společnost ČLS JEP
• Zahájení činnosti: březen 2016
• Aktuálně: 3 376 pacientů
– Crohnova choroba 72%
– Ulcerózní kolitida 26%
– IBD-U 2%
8
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MoA of the current and approveddrugs in CD
Anti-TNFamonoclonal antibodies
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Induction of T-cell apoptosis
Levin AD et al. J Crohn Colitis 2016
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Anti-TNFs: mechanisms of action in IBD
Induction of M2-type macrophages
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Induction of T-cell apoptosis
Levin AD et al. J Crohn Colitis 2016
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Anti-TNFs: mechanisms of action in IBD
Induction of M2-type macrophages
inflammation mucosal healing
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12
FcγRIIIa binding activity of Remicade, Flixabi, and Remsima.
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13
Ben-Horin S, et al, Gut 2016
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14
Magro F et al. Ther Adv Gastroenterol 2018
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Biosimilar IFX (CT-P13)
Clinical data
• Biosimilar IFX (CT-P13) is effective and safe in patients with CD and UC1,2
• Biosimilar IFX (CT-P13) induces mucosal healing in UC3
• Switching from Remicade® to CT-P13 for the treatment of IBD is feasible in
adult and paediatric population4,5,6
• Similar immunogenicity and shared immunodominant epitopes on both
infliximab versions (Remicade® and CT-P13)7
• Usefulness of ELISA assays for TL and ATI in pts treated with CT-P138
15
1. Gecse KB, et al. J Crohns Colitis. 2016 Feb;10(2):133-40
2. Jahnsen J, et al. Expert Rev Gastroenterol Hepatol. 2015;9 Suppl 1:45-52
3. Farkas K, et al. J Crohns Colitis. 2016 Apr 21. pii: jjw085. [Epub ahead of print]
4. Smits LJ, et al. J Crohns Colitis. 2016 Apr 19. pii: jjw087. [Epub ahead of print]
5. Kolar M, et al. ECCO Congress 2016, DOP 032
6. Sieczkowska J, et al. J Crohns Colitis. 2016 Feb;10(2):127-32
7. Ben-Horin S, et al. Gut. 2015 Apr 20. pii: gutjnl-2015-309290. doi: 10.1136/gutjnl-2015-309290. [Epub ahead of print]
8. Malickova K, et al. Biologicals. 2016 Jan;44(1):33-6
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CT-P13 in IBD patients previously treated with
anti-TNF: therapeutic switch
Moots R, et al. Curr Rheumatol Rep 2017
16
• Overview of „switch“ studies: reference IFX → CT-P13
• 12 studies, predominantly open-label, observational
• Various sizes (9-143 patients)
• In total, 826 patients
• Summary of results:
– No difference in terms of efficacy
– No difference in safety profile
– No increase in immunogenicity after switch
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CT-P13 in IBD patients previously treated with
anti-TNF: therapeutic switch
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NOR-SWITCH study: Design
• Prospective, randomised, non-inferiority, double-blind, phase 4 study
• 482 pts
- CD 155
- UC 93
- other 233
• Inclusion: at least 6 months stable therapy with originator IFX
• Randomization 1:1 (originator vs. CT-P13)
• Primary endpoint: disease worsening at W 52
Jørgensen KK, et al. Lancet 2017
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CT-P13 in IBD patients previously treated with
anti-TNF: therapeutic switch
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NOR-SWITCH study: Results
Jørgensen KK, et al. Lancet 2017
Risk of disease worsening difference according to diagnosis
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CT-P13 in IBD patients previously treated with
anti-TNF: therapeutic switch
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NOR-SWITCH study: Results
Jørgensen KK, et al. Lancet 2017
outcome originator IFX CT-P13 P-value
Disease worsening 26% 30% n.s.
Remission 61% 61% n.s.
AE 70% 68% n.s.
SAE 10% 9% n.s.
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Aim of the study
21
• To evaluate efficacy and safety of switching to biosimilar IFX in patients
with Crohn′s disease (CD) and ulcerative colitis (UC) on maintenance
treatment with original IFX
• Clinical response at W56
• Biologic response at W56 (CRP, FC)
• Pharmacokinetics (TL, ATI)
• Adverse events
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Methods
22
• Consecutive IBD patients (January 2015 – March 2015)
• At least induction treatment with original IFX
• Therapy with CT-P13 (Remsima®)
• Retrospective efficacy assessment based on clinical and biologic markers
• PK parameters: TL and ATI, ELISA (Matriks Biotek)
• Standard descriptive statistics, Mann-Whitney test, Wilcoxon signed-rank
test, ANOVA
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Baseline patients characteristics (Week 0)
N 74
Age 34.3±9.0 [21-57]
CD 75.7% (56/74)
UC 24.3% (18/74)
The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.
PATIENTS SWITCHED TO REMSIMA FROM ORIGINAL INFLIXIMAB
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Baseline disease characteristics (Week 0)
Disease (Montreal) classification
- B1 64.3% (36/56 CD patients)
The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.
PATIENTS SWITCHED TO REMSIMA FROM ORIGINAL INFLIXIMAB
- B2 28.6% (16/56 CD patients)
- B3 7.1% (4/56 CD patients)
- E1 16.7% (3/18 UC patients)
- E2 38.9% (7/18 UC patients)
- E3 44.4% (8/18 UC patients)
- L1 23.2% (13/56 CD patients)
- L2 23.2% (13/56 CD patients)
- L3 51.8% (29/56 CD patients)
- L4 12.5% (7/56 CD patients)
Disease duration [years] 10.1±6.7 [1-28]
Perianal disease 42.9% (24/56 CD patients)
Extraintestinal manifestations 28.4% (21/74)
- Skin 14.9% (11/74)
- Joint 16.2% (12/74)
- Eye 4.1% (3/74)
Crohn‘s disease
Ulcerative colitis
- A1 14.3% (8/56 CD patients)
- A2 85.7% (48/56 CD patients)
- A3 0.0% (0/56 CD patients)
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• Dose and interval 2.7% (2/74)
Baseline therapy characteristics (Week 0)
IFX treatment
duration [years] 3.0±2.2 [0.3-7.6]
IFX intensification
• Dose 1.4% (1/74)
The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.
PATIENTS SWITCHED TO REMSIMA FROM ORIGINAL INFLIXIMAB
• Interval 9.5% (7/74)
- Immunosupressive
• AZA 43.2% (32/74)
• MTX 2.7% (2/74)
• Other 1.4% (1/74)
- Corticosteroids
• Systemic 1.4% (1/74)
• Topical 0.0% (0/74)
Concomitant medication
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Clinical response
26
SCCAI (Ulcerative colitis)
18 16* 54 47Patients
total
HBISCCAI
66.7%
87.5%
11.1%
12.5%22.2%
0.0%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
W0 W56
74.1%
74.5%
14.8%
10.6%
11.1%
14.9%
W0 W56
0.0% 0.0%
HBI (Crohn‘s disease)
No disease activity 0-2
No disease activity 0-4
Mild/moderate 3-4
Mild 5-7
Severe 5+
Moderate 8-15
16+Severe
Median difference of HBI/SCCAI between week 0 and week 56
Median
Interquantile range
Median
(range)0 (-5, 1) 0 (-9, 5)
SC
CA
Idelt
a
HB
Idelt
a
-1 0
-5
0
5
1 0
Ab
so
lute
dif
fere
nc
e
* Two UC patients failed on therapy
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C-reactive protein
27
Week 0
Week 8
Week 1
6
Week 2
4
Week 3
2
Week 4
0
Week 4
8
Week 5
6
0
5
1 0
1 5
2 0
CR
P [
mg
/L]
ns – not significant
CRP≤5
mg/L
77.0%
(57/74)
77.6%
(52/67)
p=ns
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Fecal calprotectin
28
p=ns
ns – not significant
Week 0
Week 8
Week 1
6
Week 2
4
Week 3
2
Week 4
0
Week 4
8
Week 5
6
0
2 0 0
4 0 0
6 0 0
FC
[
g/g
]
FC≤250
μg/g
84.0%
(42/50)
75.0%
(36/48)
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IFX trough levels
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IFX≥2.8
μg/mL45.9%
(34/74)
64.2%
(43/67)
p=0.0128*
Week 0
Week 8
Week 1
6
Week 2
4
Week 3
2
Week 4
0
Week 4
8
Week 5
6
0
2
4
6
8
1 0
IFX
tro
ug
h [
µg
/mL
]
ADA
positive9.5%
(7/74)
6.0%
(4/67)
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Intensification
30
Crohn‘s
disease
Ulcerative
colitis
Dose
Interval
Dose
Interval
Week 0 Week 56
2/18 (11.1%)
4/18 (22.2%)
5/56 (8.9%)
1/56 (1.8%)
1/16 (6.3%)
3/51 (5.9%)
5/16 (31.3%)
9/51 (17.6%)
Patients with both dose and interval intensification are included in both categories
x (x.x%)
12 (23.5%)
5 (27.8%) 6 (37.5%)
Individual patients with
intensified therapy
5 (8.9%)
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Adverse events and treatment discontinuation
31
• 2 patients failed (both UC)
• 1 patient terminated treatment due to arthralgia, however, on the background of
endoscopic remission
• 1 patient discontinued due to maxillar firbrous dysplasia
• Follow-up lost in 1 patient
• 2 patients temporarily discontinued due to pregnancy
AE until week 56
12
7
2
5
2
2
1
0 2 4 6 8 10 12 14
Joint pain
Skin lesions
Herpetic lesions
Repeated infections
Abscess formation
Hospitalization
Surgery
Treatment discontinuation until week 56
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Summary
32
• No clinical or biological sign of efficacy change in patients one year after
the switch
• No increase in immunogenicity observed
• No safety concerns raised by switching
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CT-P13 in pregnant IBD patients
33
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Aim and methods
35
• Observational study evaluating pregnancy outcomes in women with IBD treated with CT-P13 during
pregnancy
• Data on treatment and pregnancy and newborn outcome were recorded
• Disease activity at conception, during pregnancy and 6 weeks after delivery was evaluated
• Cord blood levels of anti-TNF were measured (ELISA, Shikari, Matriks Biotek, Turkey)
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Patient and disease characteristics – overview
36
The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.
20
6.0±5.3 [0-19] years
Number of cases
Age at
pregnancy
Diagnosis
Perianal disease
28.7±4.1 [23-38] years
Disease
localization and
type
Crohn‘s disease
0
10
20
L1 L2 L3 L4
L1 3/16 (20.0%)
L2 5/16 (10.0%)
L3 12/16 (70.0%)
L4 1/16 (10.0%)
0
10
20
B1 B2 B3
B1 15/16 (70.0%)
B2 5/16 (30.0%)
B3 0/16 (0.0%)
Ulcerative colitis
0
2
4
E1 E2 E3
E1 0/4 (0.0%)
E2 1/4 (25.0%)
E3 3/4 (75.0%)
Disease duration
Previous
surgery
14/16 (87.5%) CD patients
1/20 (5.0%)
CD 16/20 (80.0%)
UC 4/20 (20.0%)
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Pregnancy and delivery – overview
37
The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.
Natural 5/19 (26.3%)
C-section 14/19 (73.7%)
11/20 (55.0%)Primi-gravidae
Way of delivery
Week of delivery 39.0±1.3 [36-41] weeks
Birt defects1/19 (5.3%) live births (cleft
palate)
Birth height 49.6±2.3 [45-53] cm
Birth weight 3305±493 [2210-4200] grams
Pre-term birth1/19 (5.3%) live births (with low
birth weight)
Miscarriage 1/20 (5.0%)
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Treatment characteristics – overview
38
The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.
2.2±2.7 [0-8.7] years
3/20 (15.0%)
Switch 12/20 (60.0%)
Induction 8/20 (40.0%)
Years of IFX
Switch/ Induction
with CT-P13
Infusion after
delivery
Intensifica-tion
during pregnancy
Newborn IFX
levels
Concomitant
medication
None 9/20 (45.0%)
5-ASA 2/20 (10.0%)
AZA 9/20 (45.0%)
Corticosteroids 1/20 (5.0%)
Interruption 16/20 (80.0%)
Continuous 3/20 (15.0%)
Rescue 1/20 (5.0%)
IFX treatment
modus in
pregnancy
Last infusion
before del.12.1±6.6 [2.1-33.6] weeks
6.9±4.0 [1.0-18.4] weeks
11.2±15.0 [0.2-60.0] µg/mL
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Disease course – overview
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Partial remission 6/19 (31.6%)
Complete remission 13/19 (68.4%)
At conception
Improvement 3/20 (15.0%)
Stable 15/20 (75.0%)
Worsening 1/20 (5.0%)
Severe new onset 1/20 (5.0%)
Stable 10/17 (66.7%)
Worsening 7/17 (33.3%)
During pregnancy
After delivery (within 6 weeks)
• Including 1 patient who didn‘t continue IFX after
delivery due to skin adverse effects
• Excluding 3 patients
– 1 abortion
– 2 follow-up after delivery not long enough
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Hladiny CRP u žen v remisi a s aktivní chorobou
v průběhu a po skončení gravidity
Kolář M: GH 2018
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Hladiny fekálního kalprotektinu v průběhu a
po ukončení gravidity
Kolář M: GH 2018
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Průměrná hmotnost novorozenců: matky v
remisi vs v aktivní fázi choroby
Kolář M: GH 2018
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Spearmanova korelace mezi hladinou IFX v pupečníkové
krvi a časovým intervalem od poslední dávky
Kolář M: GH 2018
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Souhrn:
CT-P13 v graviditě
• Má vysokou protizánětlivou efektivitu v graviditě
• Nejsou žádné negativní signály ohledně toxicity vůči
matce a/nebo plodu/novorozenci
• Na rozdíl od nových biologických léčiv jsou dlouhodobé
pozitivní zkušenosti s léčbou
infliximabem/adalimumabem v graviditě
• Ve výjimečných případech je možné podat záchrannou
léčbu infliximabem v graviditě u žen, které mají vysokou
aktivitu nemoci a selhaly na i.v. kortikoidech
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Závěr
• Biosimilární IFX je stejné efektivní a bezpečný v terapii
IBD jako originální IFX
• BS IFX je bezpečný i v terapii gravidních pacientek s IBD
• Zavedení BS infliximabu vedlo k navýšení počtu
léčených pacientů cca na dvojnásobek v posledních 3
letech
• Zavedení BS IFX je potvrzením použitelnosti procesu
extrapolace dat při zavádění BS biologik