Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

Feagan, Brian G.; Sandborn, William J.; Gasink, Christopher; Jacobstein, Douglas; Lang, Yinghua; Friedman, Joshua R.; Blank, Marion; Johanns, Jewel; Gao, Lei; Miao, Yi; Adedokun, Omoniyi J.; Sands, Bruce E.; Hanauer, Stephen B.; Vermeire, Séverine; Targan, Stephan R.; Ghosh, Subrata; Villiers, Willem J. de; Colombel, Jean–Frédéric; Tulassay, Zsolt; Seidler, Ursula; Salzberg, Bruce; Desreumaux, Pierre; Lee, Scott D.; Loftus, Edward V.; Dieleman, Levinus A.; Katz, Seymour; Rutgeerts, Paul

doi:10.1056/nejmoa1602773

Cited by 1,339 publications

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“…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 . Potentially, p19 blockers such as risankizu mab will also be available for Crohn's disease therapy in the future, as the latest phase II data presented as a late breaker abstract suggested efficacy for this antibody in patients with active Crohn's disease 109 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

484

367

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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%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

484

367

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“…Among them, calcineurin inhibitors (cyclosporine and tacrolimus) [14,15] and biologics [16][17][18][19][20][21][22][23][24] have been highly effective in refractory cases, and the advent of the biologic anti-tumor necrosis factor alpha antibody in particular has revolutionized the treatment of IBD [25]. Drugs with other targets such as non-tumor necrosis factor alpha cytokines and adhesion molecules have also been developed [26][27][28][29], and several clinical trials are underway [30]. Despite the increased number of IBD drugs available, there are still disparities between those approved and available in different areas globally, a phenomenon referred to as "drug lag".…”

Section: Introductionmentioning

confidence: 99%

Drug Lag for Inflammatory Bowel Disease Treatments in the East and West

Okabayashi

Hibi²

2018

Inflamm Intest Dis

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Background: Inflammatory bowel disease (IBD), though historically common in the West, is now increasingly prevalent in industrializing countries. A simultaneous dramatic increase in IBD drug options has enabled most patients to achieve remission. Nevertheless, worldwide disparities in the approval of IBD drugs, or “drug lag”, remain problematic. Summary: Drug lag for major IBD drugs before March 31, 2018 (12 for Crohn’s disease [CD] and 13 for ulcerative colitis [UC]) was compared between that of the United States (US), European Union (EU), and Asia (Japan, China, South Korea, Taiwan, and the Philippines) to assess current trends. In the US, unapproved IBD drugs accounted for 16.7% (2/12) for CD and 23.1% (3/13) for UC; approval lag was 3.8 (0–80.5) months for CD and 3.6 (0–88) months for UC. In the EU, unapproved drugs accounted for 16.7% (2/12) for CD and 15.4% (2/13) for UC; approval lag was 0.03 (0–13.9) months for CD and 0 (0–13.9) months for UC. This demonstrates the short drug lag in both regions, although one drug developed in a joint US/EU clinical trial had around a 350-day approval lag. In Asia, the proportion of unapproved IBD drugs was the lowest in Japan at 33.3% (4/12) for CD and 23.1% (3/13) for UC; South Korea had the shortest lag for CD at 13.2 (0–133.1) months and the Philippines had the shortest lag for UC at 9.9 (0.6–176.2) months, but these countries still had longer lag periods than the West. However, a proportion of unapproved drugs and approval lag has decreased considerably in Asia since the start of the biologics era. Key Messages: Despite the recent shortening drug lag between different countries and regions, this study shows that disparities persist. With globalization, eliminating these disparate drug lags is necessary to manage IBD and may require efforts toward international adoption of a more standardized approval process.

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“…However, as the interpretation of the investigators conducting the phase II trial of ustekinumab [27] illustrates, explanations may be primarily driven by the results obtained at that time point and not necessarily by a critical review of the available overall evidence. Initially, a presumable superiority of this agents in patients previously exposed to infliximabat that time explained by an alternate immunological pathway (i.e., for instance rather TH17 than TNF-α) in this subgroup of patients -was refuted in the subsequent phase III study [28] , revealing significantly superior efficacy rates in anti-TNF naïve CD patients, leading to a renaissance of the traditional explanation (previous anti-TNF exposure = indicative of a generally more severe course of disease). Interestingly, the phase II ustekinumab had an identical number of participating patients as our long-term observational study (104 patients).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: The FACTS III Survey

Vavricka

Spasojevic

Rogler

et al. 2017

Dig Dis

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Background: Long-term data of certolizumab pegol (CZP) in Crohn's disease (CD) from pivotal registry trials are limited. We therefore aimed to evaluate the long-term efficacy of CZP in clinical practice in Switzerland. Methods: In the First Approved Certolizumab Therapeutic Experience in Switzerland-III phase IV multicenter cohort, patients receiving CZP were prospectively included all over Switzerland in (non-) academic hospitals and private practice. Results: We included 104 CD patients (52 male; only 22.1% anti-tumor necrosis factor (TNF) naïve, CZP as third anti-TNF agent in 46.2%) with follow-up time between 6 weeks up to 5 years. During treatment with CZP, we observed a significant decrease of the Harvey Bradshaw Index from a median of 7 at baseline (interquartile range 4-11) to 4, 5, 4, 3, 3, and 2 at weeks 6, 26, 52, 78, 104, and 156, respectively. While anti-TNF naïve patients showed a significantly better response at the end of induction, during CZP maintenance therapy response was similar as compared to anti-TNF experienced patients as well as between patients with a short (0-5 years) vs. long duration of disease (>5 years). Conclusions: CZP is an effective long-term treatment option, including CD patients with long disease duration and prior treatment with 1 or 2 anti-TNF agents.

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Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

Cited by 1,339 publications

References 16 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Drug Lag for Inflammatory Bowel Disease Treatments in the East and West

Long-Term Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: The FACTS III Survey

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