Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis

Sandborn, William J.; Feagan, Brian G.; Wolf, Douglas C.; D’Haens, Geert R.; Vermeire, Séverine; Hanauer, Stephen B.; Ghosh, Subrata; Smith, Heather; Cravets, Matthew; Frohna, Paul; Aranda, Richard; Gujrathi, Sheila; Olson, Allan

doi:10.1056/nejmoa1513248

Cited by 382 publications

(322 citation statements)

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“…For instance, ozanimod is an oral agonist of S1PR subtypes 1 and 5 that induces peripheral lymphocyte sequestration. A phase II trial indicated that ozanimod (daily dose of 1 mg) results in a slightly higher clinical remission rate in ulcerative colitis than placebo, suggesting that such drugs might be therapeutically effective in human ulcerative coli tis 73 . However, further prospective studies are needed to determine efficacy and safety of ozanimod treatment in ulcerative colitis.…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

507

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

507

403

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“…Ozanimod was studied in a phase 2 randomized controlled trial in patients with active ulcerative colitis [35] . Adults with moderate to severe UC defined by a Mayo score of 6-12 with endoscopic subscore ≥ 2 were enrolled.…”

Section: Ozanimodmentioning

confidence: 99%

“…Subjects were randomized to receive placebo 0.5 or 1 mg daily by mouth. The primary outcome was clinical remission (Mayo score ≤ 2 and no score greater than 1) at week 8, and was achieved by 13.8, 16.4 and 6.2% with ozanimod 0.5, 1 mg and placebo, respectively (p = 0.048 for ozanimod 1 mg vs. placebo) [35] . Secondary analysis included clinical response (decrease in Mayo score by ≥ 3 from baseline and decrease in rectal bleeding score by ≥ 1 or rectal bleeding score ≤ 1), seen in placebo (36.9%), 0.5 mg (53.8%) and 1.0 mg (58.2%, p = 0.01 for comparison to placebo) [35] .…”

Section: Ozanimodmentioning

confidence: 99%

“…The primary outcome was clinical remission (Mayo score ≤ 2 and no score greater than 1) at week 8, and was achieved by 13.8, 16.4 and 6.2% with ozanimod 0.5, 1 mg and placebo, respectively (p = 0.048 for ozanimod 1 mg vs. placebo) [35] . Secondary analysis included clinical response (decrease in Mayo score by ≥ 3 from baseline and decrease in rectal bleeding score by ≥ 1 or rectal bleeding score ≤ 1), seen in placebo (36.9%), 0.5 mg (53.8%) and 1.0 mg (58.2%, p = 0.01 for comparison to placebo) [35] . In addition, Mayo endoscopic subscore ≤ 1 was observed in 34.3% of patients receiving ozanimod 1 mg, which was significantly greater than the rates observed for 0.5 mg (27.7%, p = 0.04) or placebo (12.3%, p = 0.002) [35] .…”

Section: Ozanimodmentioning

confidence: 99%

“…Secondary analysis included clinical response (decrease in Mayo score by ≥ 3 from baseline and decrease in rectal bleeding score by ≥ 1 or rectal bleeding score ≤ 1), seen in placebo (36.9%), 0.5 mg (53.8%) and 1.0 mg (58.2%, p = 0.01 for comparison to placebo) [35] . In addition, Mayo endoscopic subscore ≤ 1 was observed in 34.3% of patients receiving ozanimod 1 mg, which was significantly greater than the rates observed for 0.5 mg (27.7%, p = 0.04) or placebo (12.3%, p = 0.002) [35] . The investigators concluded that the 1 mg dose was most optimal for future study [35] .…”

Section: Ozanimodmentioning

confidence: 99%

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Leukocyte Anti-Trafficking Strategies: Current Status and Future Directions

Sands

2017

Dig Dis

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Background: In inflammatory bowel diseases (IBD), a pivotal step in the initiation and perpetuation of mucosal inflammation entails the recruitment of inflammatory leukocytes to the gut. Understanding the carefully coordinated series of molecular events that culminate in the recruitment of leukocytes to the gut has resulted in novel interventions with new capabilities in treating both Crohn's disease and ulcerative colitis. Key Messages: Natalizumab, an anti-α4 integrin antibody, was the first agent to demonstrate the efficacy of this approach for the induction and maintenance of response and remission in Crohn's disease. Widespread adoption was mitigated by the previously unknown risk of progressive multifocal leukoencephalopathy (PML) with this approach. Current approaches employ a more selective inhibition of adhesion molecules targeting the gut to avoid broad suppression of surveillance for JC virus, the causal pathogen of PML. Subsequently, vedolizumab, a humanized anti-α4β7 integrin antibody, has demonstrated efficacy in patients with IBD and has an excellent safety profile. To date, there have been no cases of PML in patients treated with vedolizumab, suggesting that this more selective agent does not have the same risk for PML as natalizumab. Other agents target β7 integrin (etrolizumab) and mucosal addressin cellular adhesion molecule-1, the endothelial ligand of α4β7 integrin. Efforts to inhibit the chemokine receptor CCR9 using the agent CCX282-B in Crohn's disease were not successful. An orally administered anti-α4 integrin compound showed some promise in a phase 2 trial but raises concern for PML. Finally, the S1P1 receptor agonist ozanimod showed promise in early trials in ulcerative colitis. Conclusions: In summary, anti-trafficking agents have the potential to provide safe and effective therapy for IBD, and are a burgeoning class of novel agents.

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Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis

Jairath

Zou

Parker

et al. 2017

Cochrane Database of Systematic Reviews

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Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.

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Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis

Cited by 382 publications

References 20 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Leukocyte Anti-Trafficking Strategies: Current Status and Future Directions

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis

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