Originální a biosimilární léky v léčbě IBD Zaměnitelnost biosimilárního infliximabu CT-P13 v graviditě

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1 Originální a biosimilární léky v léčbě IBD Zaměnitelnost biosimilárního infliximabu CT-P13 v graviditě 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

2 Charakteristika IBD 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

3 3 IBD komplexní choroby

4 lbd - result from alterations in the interaction between resident microbes and the host s intestinal immune system 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. Host (genetic susceptibility, epithelial dysfunction) Environment (gut microbiota) Inappropriate immune response Sokol H & Seksik P. Current Opinion in Gastroenterol. 2010;26:

5 Current medical therapy in IBD Conventional low-cost easily available lower effectivity Biological terapy high cost access restricted higher effectivity

6 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 Centra vysoce specializované péče dle 112 Zák. 272/2011 Sb. (Zákon o zdravotních službách) 6

7 7 Současná situace 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

8 8 Registr CREdIT Český REgistr IBD pacientů na biologické Terapii Zřizovatelem Registru je Česká gastroenterologická společnost ČLS JEP Zahájení činnosti: březen 2016 Aktuálně: pacientů Crohnova choroba 72% Ulcerózní kolitida 26% IBD-U 2%

9 MoA of the current and approved drugs in CD Anti-TNFa monoclonal antibodies

10 10 Anti-TNFs: mechanisms of action in IBD Induction of T-cell apoptosis Induction of M2-type macrophages Levin AD et al. J Crohn Colitis 2016

11 11 Anti-TNFs: mechanisms of action in IBD Induction of T-cell apoptosis Induction of M2-type macrophages inflammation mucosal healing Levin AD et al. J Crohn Colitis 2016

12 12 FcγRIIIa binding activity of Remicade, Flixabi, and Remsima.

13 13 Ben-Horin S, et al, Gut 2016

14 14 Magro F et al. Ther Adv Gastroenterol 2018

15 Biosimilar IFX (CT-P13) Clinical data Biosimilar IFX (CT-P13) is effective and safe in patients with CD and UC 1,2 Biosimilar IFX (CT-P13) induces mucosal healing in UC 3 Switching from Remicade to CT-P13 for the treatment of IBD is feasible in adult and paediatric population 4,5,6 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-P Gecse KB, et al. J Crohns Colitis Feb;10(2): Jahnsen J, et al. Expert Rev Gastroenterol Hepatol. 2015;9 Suppl 1: Farkas K, et al. J Crohns Colitis Apr 21. pii: jjw085. [Epub ahead of print] 4. Smits LJ, et al. J Crohns Colitis Apr 19. pii: jjw087. [Epub ahead of print] 5. Kolar M, et al. ECCO Congress 2016, DOP Sieczkowska J, et al. J Crohns Colitis Feb;10(2): Ben-Horin S, et al. Gut Apr 20. pii: gutjnl doi: /gutjnl [Epub ahead of print] 8. Malickova K, et al. Biologicals Jan;44(1):

16 CT-P13 in IBD patients previously treated with anti-tnf: therapeutic switch 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 Moots R, et al. Curr Rheumatol Rep

17 CT-P13 in IBD patients previously treated with anti-tnf: therapeutic switch NOR-SWITCH study: Design Prospective, randomised, non-inferiority, double-blind, phase 4 study 482 pts - CD 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

18 CT-P13 in IBD patients previously treated with anti-tnf: therapeutic switch NOR-SWITCH study: Results Risk of disease worsening difference according to diagnosis Jørgensen KK, et al. Lancet

19 CT-P13 in IBD patients previously treated with anti-tnf: therapeutic switch 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. Jørgensen KK, et al. Lancet

20 ISCARE data 20

21 Aim of the study 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 21

22 Methods 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 22

23 Baseline patients characteristics (Week 0) PATIENTS SWITCHED TO REMSIMA FROM ORIGINAL INFLIXIMAB 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.

24 Baseline disease characteristics (Week 0) PATIENTS SWITCHED TO REMSIMA FROM ORIGINAL INFLIXIMAB Extraintestinal manifestations 28.4% (21/74) - Skin 14.9% (11/74) Disease duration [years] 10.1±6.7 [1-28] - Joint 16.2% (12/74) Perianal disease 42.9% (24/56 CD patients) - Eye 4.1% (3/74) Disease (Montreal) classification Crohn s disease - A1 14.3% (8/56 CD patients) - A2 85.7% (48/56 CD patients) - A3 0.0% (0/56 CD patients) - B1 64.3% (36/56 CD patients) - B2 28.6% (16/56 CD patients) - B3 7.1% (4/56 CD patients) Ulcerative colitis - 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) The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.

25 Baseline therapy characteristics (Week 0) PATIENTS SWITCHED TO REMSIMA FROM ORIGINAL INFLIXIMAB IFX treatment duration [years] 3.0±2.2 [ ] Concomitant medication - Immunosupressive AZA 43.2% (32/74) MTX 2.7% (2/74) IFX intensification Dose 1.4% (1/74) Interval 9.5% (7/74) Dose and interval 2.7% (2/74) Other 1.4% (1/74) - Corticosteroids Systemic 1.4% (1/74) Topical 0.0% (0/74) The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.

26 A b s o lu te d iffe r e n c e Clinical response SCCAI HBI Median difference of HBI/SCCAI between week 0 and week 56 Patients total 18 16* Interquantile range Median 100% 90% 80% 70% 60% 22.2% 11.1% 0.0% 12.5% 0.0% 0.0% % % 14.8 % 10.6 % % 40% 30% 66.7% 87.5% 74.1 % 74.5 % % % 0% W0 W56 SCCAI (Ulcerative colitis) Severe 5+ Mild/moderate 3-4 W0 W56 HBI (Crohn s disease) Severe 16+ Moderate 8-15 Median (range) S C C A Id e lta H B Id e lta 0 (-5, 1) 0 (-9, 5) No disease activity 0-2 Mild 5-7 * Two UC patients failed on therapy No disease activity

27 C R P [m g /L ] C-reactive protein ns not significant p=ns W e e k 0 W e e k 8 W e e k 1 6 W e e k 2 4 W e e k 3 2 W e e k 4 0 W e e k 4 8 W e e k 5 6 CRP 5 mg/l 77.0% (57/74) 77.6% (52/67) 27

28 Fecal calprotectin ns not significant p=ns F C [ g / g ] W e e k 0 W e e k 8 W e e k 1 6 W e e k 2 4 W e e k 3 2 W e e k 4 0 W e e k 4 8 W e e k 5 6 FC 250 μg/g 84.0% (42/50) 75.0% (36/48) 28

29 IFX trough levels IF X t r o u g h [ µ g /m L ] p=0.0128* W e e k 0 W e e k 8 W e e k 1 6 W e e k 2 4 W e e k 3 2 W e e k 4 0 W e e k 4 8 W e e k 5 6 IFX 2.8 μg/ml 45.9% (34/74) 64.2% (43/67) ADA positive 9.5% (7/74) 6.0% (4/67) 29

30 Intensification x (x.x%) Week 0 Week 56 Individual patients with intensified therapy Crohn s disease Dose Interval 1/56 (1.8%) 5/56 (8.9%) 3/51 (5.9%) 9/51 (17.6%) 5 (8.9%) 12 (23.5%) Ulcerative colitis Dose Interval 2/18 (11.1%) 4/18 (22.2%) 1/16 (6.3%) 5/16 (31.3%) 5 (27.8%) 6 (37.5%) Patients with both dose and interval intensification are included in both categories 30

31 Adverse events and treatment discontinuation AE until week 56 Surgery Hospitalization Abscess formation Repeated infections Herpetic lesions Skin lesions Joint pain Treatment discontinuation until week 56 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 patients temporarily discontinued due to pregnancy 31

32 Summary 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 32

33 CT-P13 in pregnant IBD patients 33

34

35 Aim and methods 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) 35

36 Patient and disease characteristics overview Number of cases Age at pregnancy Diagnosis ±4.1 [23-38] years CD 16/20 (80.0%) UC 4/20 (20.0%) Disease localization and type Crohn s disease L1 L2 L3 L4 B1 B2 B3 L1 3/16 (20.0%) L2 5/16 (10.0%) L3 12/16 (70.0%) L4 1/16 (10.0%) B1 15/16 (70.0%) B2 5/16 (30.0%) B3 0/16 (0.0%) Disease duration 6.0±5.3 [0-19] years Ulcerative colitis Perianal disease 14/16 (87.5%) CD patients 4 2 E1 0/4 (0.0%) E2 1/4 (25.0%) Previous surgery 1/20 (5.0%) 0 E1 E2 E3 E3 3/4 (75.0%) The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given. 36

37 Pregnancy and delivery overview Primi-gravidae 11/20 (55.0%) Birth weight 3305±493 [ ] grams Week of delivery 39.0±1.3 [36-41] weeks Birth height 49.6±2.3 [45-53] cm Birt defects 1/19 (5.3%) live births (cleft palate) Pre-term birth 1/19 (5.3%) live births (with low birth weight) Way of delivery Miscarriage 1/20 (5.0%) Natural 5/19 (26.3%) C-section 14/19 (73.7%) The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given. 37

38 Treatment characteristics overview Years of IFX 2.2±2.7 [0-8.7] years Switch/ Induction with CT-P13 Switch 12/20 (60.0%) Induction 8/20 (40.0%) Concomitant medication Corticosteroids 1/20 (5.0%) 5-ASA 2/20 (10.0%) AZA 9/20 (45.0%) None 9/20 (45.0%) Intensifica-tion during pregnancy 3/20 (15.0%) Last infusion before del. Infusion after delivery Newborn IFX levels 12.1±6.6 [ ] weeks 6.9±4.0 [ ] weeks 11.2±15.0 [ ] µg/ml IFX treatment modus in pregnancy The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given. Interruption 16/20 (80.0%) Continuous 3/20 (15.0%) Rescue 1/20 (5.0%) 38

39 Disease course overview At conception During pregnancy Partial remission 6/19 (31.6%) Complete remission 13/19 (68.4%) After delivery (within 6 weeks) Improvement 3/20 (15.0%) Stable 15/20 (75.0%) Worsening 1/20 (5.0%) Severe new onset 1/20 (5.0%) 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 Stable 10/17 (66.7%) Worsening 7/17 (33.3%) 39

40 Hladiny CRP u žen v remisi a s aktivní chorobou v průběhu a po skončení gravidity Kolář M: GH 2018

41 Hladiny fekálního kalprotektinu v průběhu a po ukončení gravidity Kolář M: GH 2018

42 Průměrná hmotnost novorozenců: matky v remisi vs v aktivní fázi choroby Kolář M: GH 2018

43 Spearmanova korelace mezi hladinou IFX v pupečníkové krvi a časovým intervalem od poslední dávky Kolář M: GH 2018

44 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

45 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