A Randomized Trial of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Moderate-to-Severe Crohn's Disease

Sandborn, William J.; Feagan, Brian G.; Fedorak, Richard N.; Scherl, Ellen; Fleisher, Mark R.; Katz, Seymour; Johanns, Jewel; Blank, Marion; Rutgeerts, Paul

doi:10.1053/j.gastro.2008.07.014

Cited by 681 publications

(468 citation statements)

References 35 publications

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“…Subsequently, various antibodies against IL 12-IL 23 p40 and IL 23 p19 subunits were developed for clinical trials (such as ABT 874, ustekinumab, risanki zumab, LY 2525623, AMG139/MEDI2079 and guselku mab) [105][106][107] . Studies with ABT 874 and ustekinumab as p40 blockers demonstrated higher response rates in patients with Crohn's disease than placebo.…”

Section: T Cellmentioning

confidence: 99%

“…Studies with ABT 874 and ustekinumab as p40 blockers demonstrated higher response rates in patients with Crohn's disease than placebo. Initial studies also revealed that ustekinumab was particularly effective for therapy in patients with Crohn's disease who had previously taken anti TNF agents 105,106 . On the basis of successful phase III studies in both anti TNF agent naive and anti TNF agent experienced patients (UNITI 1 and UNITI 2 programmes), ustekinumab was recently approved for Crohn's disease therapy in the USA and in Europe) 108 .…”

Section: T Cellmentioning

confidence: 99%

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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: T Cellmentioning

confidence: 99%

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

507

403

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“…In addition to leukocyte adhesion, IL-12 and IL-23 have emerged as therapeutic targets in IBD. Ustekinumab is a human antibody targeting the p40 subunit of both IL-12 and IL-23 that has demonstrated efficacy for treating moderate-severe Crohn's disease [77,78]. It was originally FDA approved for use in psoriasis and recently achieved regulatory approval for Crohn's disease [79].…”

Section: Currently Available Therapeutic Antibodies In Digestive Disementioning

confidence: 99%

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions

Sofia

Rubin

2017

Dig Dis Sci

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The development of therapeutic antibodies represents a revolutionary change in medical therapy for digestive diseases. Beginning with the initial studies that confirmed the pathogenicity of cytokines in inflammatory bowel disease, the development and application of therapeutic antibodies brought challenges and insights into their potential and optimal use. Infliximab was the first biological drug approved for use in Crohn's disease and ulcerative colitis. The lessons learned from infliximab include the importance of immunogenicity and the influence of pharmacokinetics on disease response and outcomes. Building on this foundation, other therapeutic antibodies achieved approval for inflammatory bowel disease and many more are in development for several digestive diseases. In this review, we reflect on the history of therapeutic antibodies and discuss current practice and future directions for the field.

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“…In an earlier phase 2a study, intravenous injection reportedly resulted in improved clinical remission and response [72]. However, it has been postulated that a reduced amount of the drug is generally required to maintain efficacy.…”

Section: Interleukin Inhibitor Ustekinumabmentioning

confidence: 99%

Emerging biologics in inflammatory bowel disease

Chan

2016

J Gastroenterol

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Early biologic therapy is recommended in patients with inflammatory bowel disease and poor prognostic factors and in those refractory to conventional medications. Anti-tumor necrosis factor (anti-TNF) agents are the most commonly used biologic agents. However, some patients may not have an initial response to anti-TNF therapy, and one-third will develop loss of response over time. Anti-TNF drugs can also be associated with side effects. In addition, the use of biologics is currently limited by their cost, especially in developing countries. A number of new therapeutic targets, including novel small molecules, and cellular therapy are available or under investigation. These novel molecules include oral Janus kinase (JAK) inhibitor (tofacitinib), interleukin inhibitor (ustekinumab), oral SMAD7 antisense oligonucleotide (mongersen), and anti-integrin inhibitors (vedolizumab). Here, we review the mechanisms of action, the efficacy, and the safety data of these novel agents. Biological products that are highly similar to reference biologic products whose patents have expired-also known as ''biosimilars''-can be produced at lower cost with similar efficacy, and are also available for the treatment of IBD. We review the efficacy data for such agents as well.

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A Randomized Trial of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Moderate-to-Severe Crohn's Disease

Cited by 681 publications

References 35 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions

Emerging biologics in inflammatory bowel disease

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