Biosimilar Infliximab (CT-P13) is not Inferior to Originator Infliximab: Explorative IBD Subgroup-Analyses in Crohn's Disease and Ulcerative Colitis from the Nor-Switch Trial

Table 1. Efficacy Results at Week 6 for Per-Protocol Population

AGA Abstracts

of interest were measured. These included demographic characteristics, medications, diagnostic tests, comorbidities, and healthcare utilization measures. Marginal structural models were used to determine odds ratios (OR) and 95% confidence intervals (CI) for death with antiTNF use relative to corticosteroids. An additional model censored follow-up at the time of any of the secondary outcomes to determine whether these events explained the association between treatment and mortality.. Results: Among patients with Crohn's disease (CD), 7,694 entered the cohort as prolonged corticosteroid users and 1,879 as new anti-TNF users. Among patients with ulcerative colitis (UC), 3,224 and 459 entered the cohort as prolonged CS users and new anti-TNF users, respectively. The weighted annual incidence of death per 1000 treated patients was 21.4 and 30.1 in the anti-TNF and prolonged CS groups with CD and 23.0 and 30.9 in the anti-TNF and prolonged CS groups with UC, respectively. The risk of death was statistically significantly lower in patients treated with anti-TNF therapy for CD (OR 0.78, 95% CI 0.65-0.93) but not statistically significantly reduced with anti-TNF therapy for UC (OR 0.87, 95% CI 0.63-1.22). Among the CD cohort, anti-TNF therapy was also associated with lower rates of major adverse cardiovascular events (OR 0.68, 0.55-0.85) and hip fracture (OR 0.54, 0.34-0.83) (Figure). In the model censoring for any of the secondary outcomes, the reduced risk for death was attenuated and very close to a null result (OR 0.97, 95% CI 0.63-1.47). Conclusions: Compared to prolonged corticosteroid exposure, anti-TNF drug use was associated with reduced mortality in patients with CD, which may be explained by lower rates of major adverse cardiovascular events and hip fracture.

*95% confidence interval

249 BIOSIMILAR INFLIXIMAB (CT-P13) IS NOT INFERIOR TO ORIGINATOR INFLIXIMAB: EXPLORATIVE IBD SUBGROUP-ANALYSES IN CROHN'S DISEASE AND ULCERATIVE COLITIS FROM THE NOR-SWITCH TRIAL Kristin K. Joergensen, Inge C Olsen, Guro L Goll, Merete Lorentzen, Nils Bolstad, Ingrid P. Berset, Espen A Haavardsholm, Knut E. Lundin, Cato Mørk, Tore K Kvien, Jorgen Jahnsen Background: TNF-inhibitors have improved treatment of Crohn's disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and chronic plaque psoriasis (Ps). The aim of the government funded NOR-SWITCH study was to examine switching from originator to biosimilar infliximab regarding efficacy, safety and immunogenicity. Methods: The study was designed as a 52-week randomised, double-blind, non-inferiority trial. Adult patients with a diagnosis of CD, UC, SpA, RA, PsA or Ps on stable maintenance treatment with the originator infliximab (Remicade®, INX) were randomized 1:1 to either continued INX or switch to biosimilar infliximab (Remsima®, CT-P13), using unchanged dosing regimen. The primary endpoint was disease worsening according to disease activity indices during follow-up. Results: In total, 481 patients at 40 Norwegian study centres were randomised with 202/206 patients in the INX/CT-P13 treatment arms (Per Protocol Set). There were 129 (32%) and 75 (18%) patients with CD and UC diagnoses. Overall disease worsening occurred in 26.2% and 29.6% of patients in the INX and CTP13 arms, respectively, and the 95% confidence interval (CI) of the adjusted difference was within the pre-specified non-inferiority margin (-4.4; 95% CI -12.7, 3.9%) (figure). In CD, disease worsening occurred in 21.2% and 36.5% and in UC 9.1% and 9% of patients (figure). The estimated difference for CD was close to the non-inferiority margin for CTP13, but disease specific analyses were pre-specified as exploratory and NOR-SWITCH was not powered for demonstrating non-inferiority in the single diagnoses. The baseline characteristics in CD and UC showed no difference between treatment arms regarding, age, gender, disease duration, previous biologic therapy, use of immunosuppressives, trough drug levels, disease duration, distribution, behaviour and activity (Harvey-Bradshaw Index (HBI) and Partial Mayo Score (PMS)), bowel surgery, smoking, CRP, fecal calprotectin, and EQ-5D. Changes in disease measures from baseline to study end showed similarity between treatment arms (adjusted difference, (95% CI)) in CD and UC, respectively, regarding HBI, PMS, HBI and PMS remission, CRP and fecal calprotectin (table). Changes in Patient's and Phycician's global assessment of disease activity showed some larger improvement in the INX compared to the CT-P13 arm in the CD group (table). Comparable results were also seen for through serum levels, presence of anti-drug antibodies and reported adverse events. Conclusion: Explorative subgroup analyses of CD and UC in the NOR-SWITCH study showed similarity between patients treated with INX and CT-P13 with regard to efficacy, safety and immunogenicity. Further studies are needed to examine multiple sequenced as well as back- and-forth switches involving originator and biosimilar infliximab. Change in disease measures in Crohn's disease and ulcerative colitis during 52-weeks followup (Per Protocol Set)

Adjusted odds ratios for primary and secondary outcomes in Crohn's disease. All odds ratios are for anti-TNF therapy with corticosteroid therapy as the reference group. Numbers in parentheses represent the total number of outcomes in the study cohort. Weighted incidence rates (IR) are reported per 1000 person-years.

248 PHASE III RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL TO COMPARE BIOSIMILAR INFLIXIMAB (CT-P13) WITH INNOVATOR INFLIXIMAB (INX) IN PATIENTS WITH ACTIVE CROHN'S DISEASE: EARLY EFFICACY AND SAFETY RESULTS Young Ho Kim, Byong Duk Ye, Marina Pesegova, Olga Alexeeva, Marina Osipenko, Adi Lahat, Andrey Dorofeyev, Agnes Salamon, Sigal Fishman, Olena Levchenko, Jae Hee Cheon, Maria L. Scribano, Radu-Bogdan Mateescu, Kang-Moon Lee, Chang Soo Eun, Sang Joon Lee, Sung Young Lee Background: CT-P13 is a biosimilar of innovator infliximab (INX) and has been approved for all indications by the European Medicines Agency in 2013 and Food and Drug Administration in 2016. Methods: This study was a randomized, double-blind, parallel-group, phase III study conducted in patients with moderate to severe CD. The primary objective of the study was to compare efficacy between CT-P13 and INX in terms of Crohn's Disease Activity Index (CDAI)-70 response rates at Week 6. CDAI-70 response and CDAI-100 response were defined as reductions from baseline in the CDAI score of at least 70 and 100 points, respectively. Clinical remission was defined as an absolute CDAI score of less than 150 points1. Comparisons between the 2 treatment groups up to Week 6 were evaluated. Results: Of 220 patients randomized in 58 study centers across 16 countries, 214 patients completed study up to Week 6. At Week 6, CDAI-70 response rate of CT-P13 was quite similar to that of INX (CT-P13, 71.4%; INX, 75.2%; p-value= 0.5613). Similar and consistent trends were observed in proportion of patients achieving CDAI-100 response (CT-P13, 61.9%; INX, 64.4%; p-value= 0.7744) and clinical remission rate of 42.9% and 44.6% (p-value= 0.8329) in CT-P13 and INX treatment group, respectively (Table 1). The number of patients with at least one treatment-emergent adverse event (TEAE) showed a similar proportion in the 2 treatment groups (CT-P13, 30.6% [34/111]; INX, 35.8% [39/109]). The proportion of number of patients with at least one treatment-emergent serious adverse event (TESAE) was also comparable between treatment groups (CT-P13, 1.8% [2/111]; INX, 1.8% [2/109]). TEAEs of special interest including infusion-related reactions and infections related to study drug were reported in similar between the 2 treatment groups (CT-P13, 5.4% [6/111]; INX, 5.5% [6/109] as infusion-related reactions, CT-P13, 2.7% [3/111]; INX, 1.8% [2/109] as infections). Conclusion: The efficacy of CT-P13 was similar to INX in terms of CDAI-70, CDAI-100 and clinical remission up to Week 6 in patients with CD. In addition, CT-P13 was well tolerated with a similar safety profile to that of INX up to Week 6. These results are consistent with randomized controlled studies of INX and other published studies and further reinforced now within the randomized controlled settings1, 2, 3. Reference 1. Colombel JF, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362(15):1383-95. 2. Gecse KB, et al. Efficacy and safety of biosimilar infliximab after one-year: results from a prospective nationwide cohort. United European Gastroenterol J. 2016;4(5S):A59-60. 3. Jørgensen KK, et al. Biosimilar infliximab (CT-P13) is not inferior to originator infliximab: results from the 52-week randomized nor-switch trial. United European Gastroenterol J. 2016;2(Supplement 1).

S-65

AGA Abstracts

between MRI and US findings was 80% (p<0.001). Conclusions: US was as accurate as the combination CS + MRI in assessing disease activity and complications. Therapeutic decisions based on US findings alone were appropriate in the vast majority of CD patients. US is a non-invasive, easy-to-use tool to manage CD patients in clinical practice. Table 1. Performance of US in assessing disease activity and complications.

AGA Abstracts

Data are in mean (SD), 95% CI, 95% confidence interval of the adjusted treatment difference or n (%)*

Figure. Occurrence of disease worsening during 52 weeks follow-up, overall and within the diagnoses in the Per Protocol Set. 252 DECREASED EXPRESSION OF SLC26A3 PROTEIN IN A TOXIGENIC MOUSE MODEL AND PATIENTS WITH CLOSTRIDIUM DIFFICILE INFECTION Hayley Coffing, Melinda A. Engevik, Sangeeta Tyagi, Shubha Priyamvada, Arivarasu Natarajan Anbazhagan, Seema Saksena, Ravinder K. Gill, Waddah A. Alrefai, James Versalovic, Pradeep K. Dudeja

250 UNCHANGED INFLIXIMAB SERUM CONCENTRATIONS AFTER SWITCHING FROM THE ORIGINATOR INFLIXIMAB TO THE BIOSIMILAR CT-P13 IN PATIENTS WITH QUIESCENT CROHN'S DISEASE: A PROSPECTIVE STUDY Anne S. Strik, W van de Vrie, Yvonne Megen, Joanne Minekus, Theo Rispens, Geert R. D'Haens

Background: Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and the most common cause of nosocomial infection in the U.S. C. difficile produces two primary cytotoxins, TcdA and TcdB, that are known to be the causative agents of CDI. However, the pathophysiology of toxin-induced diarrhea remains poorly understood. DRA (Down-Regulated in Adenoma) or SLC26A3 is a Cl-/HCO3- (OH-) exchanger protein involved in vectorial Cl- absorption in the human intestine. It has been shown that reduced DRA function and/or expression contributes to the diarrheal phenotype in intestinal inflammation and enteric infectious. Our previous studies showed that DRA protein, but not mRNA, is decreased upon exposure to toxins A and B in intestinal epithelial cell lines (Caco2, T84). However, the effects of purified C. difficile toxins on DRA in a mouse model of CDI have not been investigated. Whether DRA expression is altered in patients with CDI is also not known. Methods: Purified toxins TcdA (10 ug/mouse), TcdB (10 ug/mouse) or both TcdA and TcdB (5 ug of each/mouse) were prepared in PBS and intrarectally administered to C57BL/6 mice. Mice were sacrificed at 4h post-toxin administration. Immunoblotting/immunohistochemistry, real-time PCR and myeloperoxidase (MPO) were used to evaluate protein level, mRNA, and inflammatory changes in the colon of C57BL/6 mice, respectively. Additionally, CDI patient colon biopsy slides were stained for DRA protein. Results: Our results showed that administration of TcdA resulted in higher colonic MPO levels (5-fold) than mice treated with TcdB, TcdA + TcdB, and controls (p<0.001). Additionally, mice administered TcdA, TcdB, and TcdA + TcdB had increased mRNA levels of pro-inflammatory markers IL-1b (5-20 fold), IL-6 (10-40 fold), CXCL1 (5-25 fold), and COX2 (5-10 fold) compared to control mice (p<0.05). Administration of purified toxins A and B significantly decreased DRA protein by 50% (p<0.0001) and 30% (p<0.01), respectively. However, neither TcdA nor TcdB treatment significantly altered DRA mRNA levels indicating that, similar to our in vitro model using Caco2 cells, the toxin-decreases DRA expression potentially via a posttranscriptional mechanism. Finally, DRA protein immunostaining was significantly reduced in colonic biopsies from patients with CDI versus healthy controls (p<0.01). Conclusion/ Speculation: Taken together, our data show that DRA protein expression is decreased both in patients with CDI and in a toxigenic mouse model of CDI. Thus, DRA may represent as a novel therapeutic target in the treatment of CDI associated diarrhea. (Supported by NIH & Dept. of Veterans Affairs)

Background The biosimilar infliximab (IFX) can reduce healthcare costs when patients are switched from the originator to the biosimilar IFX; however this switch has raised concerns about potential immunogenicity. The objective of the SECURE study was to demonstrate that the IFX serum concentrations of the biosimilar IFX were non-inferior to the IFX concentrations of the originator 16 weeks after switch in subjects with rheumatoid arthritis, ulcerative colitis and Crohn's disease (CD) in stable remission for > 30 weeks. This abstract presents the preliminary results of CD patients only. Methods In this prospective, openlabel, interventional, non-inferiority, multicentre, phase IV trial, adult CD patients in clinical remission >30 weeks (Harvey Bradshaw Index; HBI ≤ 4) were switched from the reference IFX to biosimilar IFX at stable doses. Patients were followed for 16 weeks after switch (2 infusions at 8 week interval). The primary endpoint was the serum IFX trough level concentration measured by a bridging enzyme-linked immunosorbent assay (ELISA) 16 weeks after switch (non-inferiority margin of 15%). Secondary endpoints included antibodies to IFX (ATI), clinical disease activity (HBI score), C-reactive protein (CRP), fecal calprotectin and quality of life (EQ-5D score) 16 weeks after switch compared to reference IFX. Results In total 61 CD patients were enrolled in 9 centers and 44 patients were included in the per protocol analysis (PP); 17 patients were excluded due to violation of eligibility criteria (4), not compliant with the study protocol (5), early termination of the study (3) and missing IFX serum samples (5). Mean age of the patients was 42±16 years (50% male) and mean duration on IFX treatment 4.9±3.8 years. The LS mean serum IFX concentration (90% CI) was 2.97 (2.78-3.18) for the reference IFX and 3.25 (3.04-3.48) 16 weeks after switch, with an IFX ratio of 109.6% (99.7%-120.6%) demonstrating non-inferiority of the biosimilar IFX to the reference IFX. One patient developed ATI's after 2 infusions. At the end of the study 38 (86%) patients were still in remission (HBI ≤ 4). The CRP, fecal calprotectin and EQ-5D were not significantly different for the biosimilar at week 16 compared to the reference IFX. In the enrolled population (61 patients) 2 SAEs (3.2%) were reported (both perianal abscess). The adverse event profile was not changed compared to the reference IFX. Conclusion This prospective, interventional study demonstrated that the IFX serum concentration of the biosimilar IFX was non-inferior to the IFX concentration of the reference IFX 16 weeks after switching in patients with CD. Efficacy and tolerability were also similar.

253 251 HEPATOCYTE NUCLEAR FACTOR 1Î' UPREGULATES P-GLYCOPROTEIN EXPRESSION IN HUMAN INTESTINAL EPITHELIAL CELLS Shubha Priyamvada, Mumtaz Anwar, Anoop Kumar, Arivarasu Natarajan Anbazhagan, Ravinder K. Gill, Waddah A. Alrefai, Pradeep K. Dudeja, Seema Saksena

COMPARATIVE ACCURACY OF US VERSUS MRI AND COLONOSCOPY IN ASSESSING DISEASE ACTIVITY AND COMPLICATIONS AND INFLUENCING THE DECISION-MAKING PROCESS IN CROHN'S DISEASE Mariangela Allocca, Gionata Fiorino, Cristiana Bonifacio, Federica Furfaro, Simona Radice, Daniela Gilardi, Laurent Peyrin-Biroulet, Silvio Danese

P-glycoprotein (P-gp/ MDR1), an apical efflux transporter is involved in the defense mechanisms of intestinal epithelial cells (IECs) through the excretion of xenobiotics and bacterial toxins. Decrease in Pgp expression and function has been implicated in the reduced intestinal epithelial integrity associated with diseases like IBD. Therefore, strategies to increase P-gp expression and/or activity could have therapeutic potential in restoring epithelial integrity. P-gp has been shown to be regulated by transcriptional mechanisms. In this regard, hepatocyte nuclear factors (HNFs) constitute a group of phylogenetically unrelated transcription factors (HNF1α, 1β and 4α) that play a crucial role in maintaining intestinal epithelial homeostasis. It was previously shown that HNF4α had no effect on P-gp promoter activity in human epithelial placental cell lines. However, the role of HNF1α and/or 1β on P-gp promoter activity and expression has not yet been investigated. Therefore, current studies were aimed at examining the potential transcriptional regulation of P-gp by HNF1α and 1β in Caco-2 cells. Our results showed that siRNA mediated knock down of HNF1β but not HNF1α markedly suppressed P-gp mRNA levels (~57%) in Caco-2 cells, thereby suggesting that only HNF1β is pivotal in regulating endogenous P-gp expression. Further, transfection studies showed that overexpression of HNF1β resulted in a significant increase in P-gp mRNA levels (~4 fold) with a concomitant increase in P-gp protein expression (~4 fold) as compared to the empty vector. Interestingly, over-expression of HNF1β transactivated Pgp promoter by 9 fold (P<0.01). Furthermore, co-transfection of HNF1β with 5′-progressive deletion constructs of P-gp promoter revealed that the stimulatory effect of HNF1β was retained in the smallest P-gp promoter construct (p-428/+703). These results suggest that

Background: Bowel ultrasound (US) and MRI are accurate in assessing disease activity and complications in Crohn's disease (CD) patients. The comparative accuracy of US versus MRI + endoscopy in assessing disease activity and complications and influencing the decisionmaking process in Crohn's disease is unknown. Methods: Ileo-colonic CD consecutive patients seen in a tertiary referral Center (Humanitas Research Hospital, Milan, Italy) were prospectively assessed by magnetic resonance imaging (MRI), colonoscopy (CS), and US, within 1 week. Sensitivity, specificity, accuracy, positive and negative predictive values (PPV and NPV) of US in assessing localization and extension, bowel wall enhancement (increase of vascularization at color Doppler), bowel wall thickening (>3 mm), strictures (narrowing of the lumen), fistulas and abscesses, and active disease (presence of ulcers at colonoscopy) were calculated using CS in combination with MRI findings as a reference standard. Two independent blinded IBD specialists reviewed separately MRI and US findings, and were asked to decide the therapeutic strategy (continue therapy vs. optimize/change therapy). Kappa agreement between MRI and US was also investigated. Results: Forty-one consecutive CD patients, irrespectively of disease activity and current therapy, were enrolled. Twentyfive patients had active disease as assessed by MRI and colonoscopy (60.9%), 16/41 (39.1%) had CD-related complications. Sensitivity, specificity, accuracy, PPV and NPV of US are showed in Table 1. Based on US findings alone when compared to MRI and CS, the management of IBD patients (continuing or changing/optimizing therapy) was judged accurate in 85% of patients compared to 75% managed by MRI only (p<0.001). Agreement

AGA Abstracts

S-66