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Medical Treatment of IBD
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Naveen Sharma, Michael R.B. Keighley, Severine Vermeire
Other compounds have been developed in this class and are currently in phase 3 of drug development after promising phase-1 and 2 studies. Etrolizumab, a humanised monoclonal anti-β7 antibody showed in a phase-2 trial significant clinical improvement and comparable adverse events (as compared to the placebo arm) in patients with moderate-to-severe UC and failure to conventional treatments.6 Finally, anti-MadCAM antibodies also passed phase-1 and -2 studies and showed a good safety profile and a promising efficacy and are entering phase-3 programs.7 Furthermore, oral delivery systems for targeting gut-specific integrins are being developed.
The Small Intestine
Published in Professor Sir Norman Williams, Professor P. Ronan O’Connell, Professor Andrew W. McCaskie, Bailey & Love's Short Practice of Surgery, 2018
Professor Sir Norman Williams, Professor P. Ronan O’Connell, Professor Andrew W. McCaskie
Third-generation monoclonal antibody therapies include integrin antibodies vedulizumab and etrolizumab. Both prevent leucocyte migration preferentially in the gastrointestinal tract and may therefore have fewer side effects than the earlier monoclonal antibodies, although they are both currently in limited use.
Probiotics in the Management of Inflammatory Bowel Disease and Irritable Bowel Syndrome
Published in Marcela Albuquerque Cavalcanti de Albuquerque, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Raquel Bedani, Lactic Acid Bacteria, 2020
Larissa S Celiberto, Bruce A Vallance, Daniela CU Cavallini
At present, the traditional therapies for IBD follow a step-up approach that starts with immunosuppresives such as 5-aminosalicylic acid (5-ASA), moving to immunomodulators (azathioprine and methotrexate), and finally to biologics (infliximab, adalimumab, vedolizumab, etrolizumab, ustekinumab) [reviewed in (Burger and Travis (2011), and Celiberto et al. (2018)]. The drug type, dosage and possible combination of therapies must be managed through an individualized approach for each patient, considering important factors such as age, clinical background and/ or associated co-morbidities, as well as disease severity. At present, conventional treatments for IBD focus on suppressing the pathological immune response rather than targeting potential root causes of the disease. Moreover, several limitations and side effects have been reported when using these approaches (Stallmach et al. 2010). For instance, the efficacy of biologics and steroids often reduces over time in most patients, while some patients do not respond at all to these treatments (Renna et al. 2014, Ben-Horin et al. 2015, Roda et al. 2016). Notably, a resulting increase in susceptibility to cancer and infectious disease has been described following steroid and biologic regimes (Renna et al. 2014, Ben-Horin et al. 2015), which represents a significant concern especially for pediatric patients, since they will be on medications for many years following diagnosis. Therefore, studies investigating potential causal factors of IBD, as well as therapies targeting them, are extremely important to improve the quality of life for these patients.
IL-36: a therapeutic target for ulcerative colitis?
Published in Expert Opinion on Therapeutic Targets, 2022
Yasmina E. Hernandez Santana, Naoise Irwin, Patrick T. Walsh
Another biotherapeutic that limits the migration of lymphocytes to the gut is the sphingosine 1-phosphate (S1P) receptor modulator, ozanimod. The results of phase II and III clinical trials have shown that ozanimod enhances clinical remission in patients with moderate to severe UC and has a satisfactory long-term safety profile [26,27]. Similar approaches, currently under clinical development include anti-adhesion molecules such as AJM347 (α4β7-integrin inhibitor), AJM300 (anti-α4-integrin antibody), ontalizumab (anti-MadCAM1 antibody), and etrolizumab (anti-β7-integrin antibody) [28]. The efficacy and safety of etrolizumab as a treatment for UC has been evaluated in phase 3 clinical trials enrolling over 3,000 patients [25]. Recently reported findings indicate that while treatment with etrolizumab can provide benefit to patients during the induction phase, such improvements were less evident in maintenance studies [26,27,29–31].
Antibodies to watch in 2018
Published in mAbs, 2018
Hélène Kaplon, Janice M. Reichert
Etrolizumab (RH7413) is a humanized mAb that binds the β7 subunit of α4β7 and αEβ7 integrin heterodimers, thereby inhibiting interactions with their ligands MAdCAM-1 and E-cadherin, respectively. The safety and efficacy of etrolizumab are being evaluated in six Phase 3 studies of patients with ulcerative colitis (UC) and 2 Phase 3 studies of patients with Crohn's disease. Of the 6 studies in UC, 2 (NCT02163759 and NCT02171429) have primary completion dates in March 2018. In both of these placebo-controlled studies, the efficacy and safety of etrolizumab in induction of remission in patients with moderately to severely active UC who are naïve to TNF inhibitors and refractory to or intolerant of prior immunosuppressant and/or corticosteroid treatment are being evaluated. Etrolizumab (105 mg) will be administered SC every 4 weeks, and the effects will be compared to those of an active comparator, adalimumab (160 mg) administered SC at week 0; 80 mg SC at week 2; 40 mg SC at weeks 4, 6 and 8. For both studies, the primary outcome measure is the percentage of participants with induction of remission compared with placebo as determined by the Mayo Clinic Score (MCS) by week 10, and the estimated enrollment is 350 patients.
How not to discover a drug - integrins
Published in Expert Opinion on Drug Discovery, 2021
Vedozilumab is an anti-α4β7 monoclonal antibody [142] that has been approved for both ulcerative colitis [143] and Crohn’s disease [144]. It appears to be safe with no evidence of PML [145]. Etrolizumab is an anti-β7 monoclonal antibody under investigation for both Crohn’s and ulcerative colitis [146]. This antibody targets both αEβ7 and α4β7. Rather than simply blocking β7 it appears to cause internalization of β7 [147]. An alternative approach is to block the ligand for α4 integrins – mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). However, PII studies of an anti-MAdCAM-1 antibody have shown little evidence of benefit [148,149].