M. Lowenberg

Biosimilars in IBD: hope or expectation?

A biosimilar is a biological medicine that enters the market subsequent to expiration of the patent of an original reference product and its similarity to the reference medicine exhibits ‘no clinically meaningful differences in terms of quality, safety and efficacy’.1 In practice, patents protect a reference product for 10 years after its approval before registration for a similar biological medicine can be applied for.1 The term ‘biosimilar’ is recognised by all regulators, but synonyms include ‘similar biotherapeutic product’ (WHO) and ‘subsequent-entry biologic’ (Canada).2 Biopharmaceutical agents are derived from living cells or organisms and are usually complex proteins. Therefore, regulators are establishing novel specific approval pathways for biosimilars that differ from those for chemical generics. Since the first approval in 2005, several biosimilars of somatropin (human growth hormone), filgrastim (granulocyte colony-stimulating factor, G-CSF) and epoetin (erythropoietin) have become available in Europe. Currently, 12 biosimilars are authorised in the European market, and numerous others, including monoclonal antibodies (mAbs), have applied for authorisation.3 ,4 This subject has received increasing attention in gastroenterology, because the patent on infliximab is due to expire and regulatory approval for two biosimilar infliximabs have already been filed for to the European Medicines Agency (EMA). One of these molecules is already available for patient care in South Korea.4 ,5 Biological agents are currently in widespread use for the treatment of chronic inflammatory diseases. As recently as in 2000, only two of the worlds top 10 grossing drugs were biological agents. In 2012, estimates are that seven are biological agents, of which adalimumab and infliximab lead the list.6 The long duration of development and high manufacturing costs are cited as the main contributors to the high cost of biological agents. For example, the average yearly cost of infliximab treatment for Crohns disease in …

157 Fecal Loss of Infliximab As a Cause of Lack of Response in Severe Inflammatory Bowel Disease

Background: The degree of association between homocysteine metabolism and inflammatory bowel diseases (IBD) remains unknown and the association between hyperhomocysteinemia and thrombosis and oncogenesis remains controversial in IBD. The aim of this study was to investigate the serum homocysteine levels in patients with Crohn’s disease (CD) and ulcerative colitis (UC) and the potential folate therapeutic regimen against hyperhomocysteinemia. Methods: Serum levels of homocysteine were measured in 55 patients with (IBD) (28/55 CD and 31/55 UC patients). Patients with hyperhomocysteinemia received 15mg folate/day for 2 12 months. Levels of serum homocysteine were measured during folate treatment. Results: Hyperomocysteinemia was prevalent in 28/55 (50.90%) of patients studied (13 CD and 15 UC patients). Mean homocysteine levels among the patients with hyperhomocysteinemia were 17.72mmol/L with range 14.23 29.88mmol/L (normal values 3.7 13.9mmol/L) (Table 1). Folate was administered in 24/28 patients and serum levels of homocysteine were re-measured in 17 patients. In 14/17 patients lower levels of homocysteine were observed with a mean reduction of 5.25mmol/L by folate treatment. The baseline levels of homocysteine in these patients were 17.01 mmol/L and posttreatment 11.75mmol/L.

Serial magnetic resonance imaging for monitoring medical therapy effects in Crohn's disease.

Background:Tumor necrosis factor (TNF) antagonists can induce mucosal healing in patients with Crohn’s disease (CD), but the effects on transmural inflammation and stenotic lesions are largely unknown. Methods:We performed a retrospective study in 50 patients (54% female, median age 37 yr) with CD who had undergone serial magnetic resonance imaging (MRI) examinations while receiving infliximab or adalimumab. Patients were grouped as clinical responders or nonresponders based on physician’s assessment, laboratory, and endoscopic appearance. MRI scoring was performed by 2 radiologists in consensus blinded to clinical data using a validated MRI scoring system. In total, 64 lesions on MRI were identified for analysis. Analyses were performed using paired t test and Wilcoxon rank test. Results:During anti-TNF treatment, MRI inflammation scores improved in 29 of 64 lesions (45.3%), remained unchanged in 18 of 64 lesions (28.1%), or deteriorated in 17 of 64 lesions (26.6%) over time. In the anti-TNF responder group, the mean intestinal inflammation score of all lesions improved from 5.19 to 3.12 (P < 0.0001). The mean inflammation scores in stenotic lesions in anti–TNF responders also improved significantly, from 6.33 to 4.58 (P = 0.01). In contrast, the mean inflammation scores did not change significantly (5.55–5.92, P = 0.49) in nonresponders. Diagnostic accuracy of anti–TNF response on MRI was 68%. Conclusions:Improved inflammatory activity on serial MRI scans was observed in patients with clinical response to medical therapy with anti-TNF agents in luminal CD. MRI can be used as a complementary approach to measure transmural inflammation in patients with CD and guide the optimal use of TNF antagonists in daily clinical practice.

Impact of disease location on fecal calprotectin levels in Crohn’s disease

Abstract Objective. The correlation between the Simple Endoscopic Score for Crohn’s Disease (SES-CD) and fecal calprotectin is well established in (ileo)colonic Crohn’s disease (CD). However, for ileal CD, existing data are conflicting. The aim of this study is to evaluate the biomarker profile in CD patients with varying severity and location of mucosal ulceration. Materials and methods. An electronic patient database search identified CD patients in whom ileocolonoscopy, fecal calprotectin (CALPRO), serum C-reactive protein (CRP) and blood leukocyte counts (LEU) were measured within a 4-week interval without changes in medication. Ileocolonoscopies were scored for the presence of ulcers in each segment as defined by the SES-CD and the sum of segmental ulcer scores resulted in a partial SES-CD (pSES-CD). Results. Fourty-four patients were identified, of whom 9/44 had ileal CD, 20/44 colonic and 15/44 ileocolonic CD based on the Montreal classification. In the total study population CALPRO correlated best with pSES-CD (r = 0.76, p < 0.0001), followed by LEU (r = 0.54, p = 0.0004) and CRP (r = 0.45, p = 0.0026). Patients with ileal CD had significantly lower CALPRO level than those with (ileo)colonic disease even in the presence of large and/or very large ulcers (mean ± SEM: 297 ± 81 μg/g vs. 1523 ± 97 μg/g, p < 0.0001). LEU was also significantly lower in the presence of large and/or very large ulcers in ileal CD compared to those with (ileo)colonic disease (mean ± SEM: 6.7 ± 0.9 × 109/l vs. 10.6 ± 0.8 × 109/l, p = 0.02). A similar trend was identified regarding CRP levels. Conclusions. Even in the presence of large or very large ulcers, patients with ileal Crohn’s may not have markedly elevated fecal calprotectin levels.

Effects of infliximab retreatment after consecutive discontinuation of infliximab and adalimumab in refractory Crohn's disease.

Background:Switches between anti–tumor necrosis factor agents in the treatment of Crohns disease (CD) occur in case of treatment failure, intolerance, or patient preference. No data are currently available on the usefulness of a second infliximab treatment after earlier discontinuation and previous switch to an alternative anti–tumor necrosis factor agent. In this study, we evaluated the clinical benefit of infliximab retreatment in patients with CD after sequential use of both infliximab and adalimumab. Methods:Twenty-nine patients with CD who had received earlier treatments with sequential infliximab and adalimumab and were then restarted on infliximab were retrieved from a multicenter registry designed for the follow-up of adalimumab treatment for CD. Short-term and sustained effects of infliximab retreatment were evaluated retrospectively by reviewing clinical records. Follow-up was 18 months for all patients. Results:In 13/29 (45%) patients, infliximab was reintroduced at intensified dosing schedule (>5 mg/kg or <8 wk) for 23/29 (79%) of patients similar to the schedule who were on at time of previous discontinuation. During the second infliximab treatment course, dosing was further intensified in 11 out of 29 (38%) patients. After 18 months 18/29 (62%), patients were still on continued therapy of their second infliximab treatment. Infliximab was discontinued (after a median of 7 mo) in 11 out of 29 patients for loss of response (n = 7 [24%]), intolerance (n = 3 [10%]), or non-compliance (n = 1 [3%]). Use of induction schedule or concomitant immunomodulators were not significantly associated with treatment benefit. Conclusions:The majority of patients with CD benefit from a second treatment with infliximab after previous treatment with infliximab and adalimumab, which offer a meaningful therapeutic option in often highly refractory patients.

Safety and Feasibility of Using the Second-Generation Pillcam Colon Capsule to Assess Active Colonic Crohn's Disease.

BACKGROUND & AIMS The second-generation Pillcam Colon Capsule Endoscope (PCCE-2; Given Imaging Ltd, Yoqneam, Israel) is an ingestible capsule for visualization of the colon. We performed a multicenter pilot study to assess its safety and feasibility in evaluating the severity of Crohns disease (CD). METHODS In a prospective study, 40 patients with active colonic CD underwent PCCE-2 and optical colonoscopy procedures. Using both techniques, we generated values for the Crohns Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for CD, and global evaluation of lesion severity. In the first stage of the study, we calculated the correlation between PCCE-2 and optical colonoscopy scores. In the second stage, we performed interobserver agreement analysis for a random subset of 20 PCCE-2 recordings, graded in duplicate by 2 independent readers. RESULTS There was substantial agreement between PCCE-2 and optical colonoscopy in the measurement of the CDEIS (intraclass correlation coefficient [ICC], 0.65; 95% confidence interval [CI], 0.43-0.80). There was substantial interobserver agreement between 2 independent PCCE-2 readers for the CDEIS (ICC, 0.67; 95% CI, 0.35-0.86) and the Simple Endoscopic Score for CD (ICC, 0.66; 95% CI, 0.32-0.85). However, the PCCE-2 scoring systematically underestimated the severity of disease compared with optical colonoscopy; based on our results, PCCE-2 detected colonic ulcerations with 86% sensitivity and 40% specificity. No adverse events were observed and PCCE-2 was better tolerated than colonoscopy. CONCLUSIONS PCCE-2 is feasible, safe, and well tolerated for the assessment of mucosal CD activity in selected populations. Larger studies are needed to assess its operating characteristics further. European clinical trials database number: 2014-003854-15.

Golimumab for the treatment of ulcerative colitis

The introduction of therapeutic antibodies against tumor necrosis factor (TNF) had a major impact on the treatment of ulcerative colitis (UC). Infliximab and adalimumab are powerful agents that are used for remission induction and maintenance therapy in UC and have an acceptable safety profile. However, a proportion of UC patients for whom therapy with anti-TNF agents is indicated fail or become intolerant to treatment with infliximab or adalimumab. Hence, there remains an unmet need for novel anti-TNF agents. Golimumab (Simponi®), a human anti-TNF antibody that is administered by monthly subcutaneous injections, is the most recently introduced TNF blocker for the treatment of UC. Here, we will discuss recent literature on clinical efficacy and safety of golimumab induction and maintenance treatment in patients with UC. Furthermore, we will discuss the positioning of golimumab for UC in current treatment algorithms.

Sa1198 Agreement Among Experts in the Endoscopic Evaluation of Postoperative Recurrence in Crohn's Disease Using the Rutgeerts Score

Geboes-Structural 0.70 (0.60 0.79) 0.80 (0.74 0.86) Geboes-Chronic inflammatory infiltrate 0.64 (0.54 0.74) 0.81 (0.75 0.86) Geboes-Lamina propria eosinophils 0.26 (0.18 0.37) 0.59 (0.52 0.66) Geboes & Modified Riley-Lamina propria neutrophils 0.37 (0.27 0.49) 0.59 (0.51 0.68) Modified Riley-Neutrophils in epithelium 0.47 (0.37 0.59) 0.71 (0.64 0.78) Geboes-Crypt destruction 0.34 (0.24 0.47) 0.61 (0.54 0.69) Geboes-Erosion or ulceration 0.56 (0.45 0.67) 0.78 (0.73 0.84)

786 The Pharmacokinetics of Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis

G A A b st ra ct s of anti-inflammatory M2 BMDM, determined by expression of Arg1 and Fizz1 that are classical M2 markers, was impaired in Il10rb-/mice. These Mφ also expressed significantly higher levels of pro-inflammatory cytokines following LPS stimulation, suggesting that IL10R signaling regulates TLR4-dependent responses in murine anti-inflammatory Mφ. Il10rb-/M2 Mφ also produced less IL10 and promoted less generation of Tregs in-vitro, perhaps due to decreased surface expression of PD-L1 and PD-L2. Moreover, transfer of WT but not Il10rb-/M2 Mφ ameliorated CD4+-induced colitis in Il10rb-/-Rag2-/mice. Similar to murine studies, the generation of M2 Mφ was severely impaired in human IL10R deficient patients. These Mφ also secreted significantly higher levels of TNF, IL6 and IL12 following LPS stimulation, and promoted less generation of Tregs. Conclusion: IL10R-dependent signals play a critical role in the generation and function of blood borne and tissue resident anti-inflammatory Mφ in mice and humans. Therapeutics and cell-based therapies aimed at augmenting anti-inflammatory Mφ may have clinical utility.

Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.