Prezentace aplikace PowerPoint · 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

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

• 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

IBD – komplexní choroby

3

• 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

Current medical therapy in IBD

Conventional Biological terapy• low-cost high cost• easily available access restricted• lower effectivity higher effectivity

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

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

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

MoA of the current and approveddrugs in CD

Anti-TNFamonoclonal antibodies

Induction of T-cell apoptosis

Levin AD et al. J Crohn Colitis 2016

10

Anti-TNFs: mechanisms of action in IBD

Induction of M2-type macrophages

Induction of T-cell apoptosis

Levin AD et al. J Crohn Colitis 2016

11

Anti-TNFs: mechanisms of action in IBD

Induction of M2-type macrophages

inflammation mucosal healing

12

FcγRIIIa binding activity of Remicade, Flixabi, and Remsima.

13

Ben-Horin S, et al, Gut 2016

14

Magro F et al. Ther Adv Gastroenterol 2018

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

http://www.ncbi.nlm.nih.gov/pubmed/26661272







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



17

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



18

NOR-SWITCH study: Results


Risk of disease worsening difference according to diagnosis



19

NOR-SWITCH study: Results


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.

ISCARE data

20

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

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

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

Baseline disease characteristics (Week 0)

Disease (Montreal) classification

- B1 64.3% (36/56 CD patients)



- 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)

• 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)



• 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

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

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

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)

IFX trough levels

29

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)

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%)

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

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

CT-P13 in pregnant IBD patients

33

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)

Patient and disease characteristics – overview

36


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%)

Pregnancy and delivery – overview

37


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%)

Treatment characteristics – overview

38


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

Disease course – overview

39

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

Hladiny CRP u žen v remisi a s aktivní chorobou

v průběhu a po skončení gravidity

Kolář M: GH 2018

Hladiny fekálního kalprotektinu v průběhu a

po ukončení gravidity

Kolář M: GH 2018

Průměrná hmotnost novorozenců: matky v

remisi vs v aktivní fázi choroby

Kolář M: GH 2018

Spearmanova korelace mezi hladinou IFX v pupečníkové

krvi a časovým intervalem od poslední dávky

Kolář M: GH 2018

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

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

Documents

Prezentace aplikace PowerPoint · 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