A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients With Crohn’s Disease

Sandborn, William J.; Ghosh, Subrata; Panés, Julián; Vranić, Ivana; Wang, Wenjin; Niezychowski, Wojciech; Vermeire, Séverine; Dewit, Olivier; Peeters, Harald; Stehlík, J; Vaňásek, Tomáš; Laharie, David; Colombel, Jean Fréd́eric; Bigard, Marc‐André; Varga, Márta; Zeher, Margit; Novák, János; Hunyady, Béla; Salamon, Ágnes; Rácz, I; Gionchetti, Paolo; Kohn, Anna; Prantera, Cosimo; Stokkers, Pieter; Słomka, Maria; Paradowski, Leszek; Arłukowicz, Tomasz; Kuzela, L; Baricky, Boris; Hlavatý, Tibor; Vera, María Isabel Paredes; Guardiola, Jordi; Probert, Christopher S.; Shaffer, Jonathan; Fleisher, Mark R.; Pruitt, Ronald E.; Goff, John S.; Weber, John T.; Bell, R.; Zwick, Andrew; Gutierrez, Alexandra; Levine, Robert; Hanauer, Stephen B.; Lavelle, Lori Ann; Kottoor, Ravindranath; Dryden, Gerald W.; Hardi, Robert; Glorioso, David; Swaroop, Prabhakar; Lee, Scott D.; Patrick, Teressa; Scheinert, Sheldon; Sninsky, Charles A.; Katz, Seymour; Noar, Mark D.; Gaspari, Michael; Gordon, Glenn; Dalton, Thomas A.; Homoky, Douglas Edward; Kilgore, William; Levien, Joel A.; Schneider, H.R.; Moola, S. A. H.; Kruger, Frederik Cornelius; Wright, John Paul; Aboo, Nazimuddin

doi:10.1016/j.cgh.2014.01.029

Cited by 258 publications

(155 citation statements)

References 15 publications

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“…In phase 2 and phase 3 studies of up to 52 wk of tofacitinib for patients with moderate to severe chronic plaque psoriasis (2,4,50,51,58), tofacitinib 5 mg bid and tofacitinib 10 mg bid have been well tolerated, with no new safety findings observed with respect to the RA program. In phase 2 studies of UC and CD (66,67), dose-dependent increases in low-density lipoprotein and high-density lipoprotein cholesterol levels were observed with tofacitinib, consistent with observations in tofacitinib RA and psoriasis studies; however, the UC and CD studies had relatively short durations and sample sizes.…”

Section: Jak Inhibition With Tofacitinibsupporting

confidence: 56%

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Danese¹,

Grisham

Hodge

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

145

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Section: Jak Inhibition With Tofacitinibsupporting

confidence: 56%

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Danese¹,

Grisham

Hodge

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

145

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“…As individual JAKs mediate cell activation via sev eral cytokines (for example, JAK3 is activated via IL 2, IL 4, IL 7, IL 9, IL 15 and IL 21) with proposed pro inflammatory roles in colitis [110][111][112][113] , this approach opens the possibility to block the activity of several pro inflammatory cytokines simultaneously. Indeed, several JAK inhibitors (tofacitinib, ABT494 and filgo tinib) have been developed for clinical therapy 114,115 . Interestingly, the JAK1-JAK3 blocker tofacitinib, a sup pressor of T cell, natural killer cell and B cell activ ation, yielded very promising results in a phase II study in patients with ulcerative colitis, but was not effective in patients with Crohn's disease 114,115 .…”

Section: T Cellmentioning

confidence: 99%

“…Indeed, several JAK inhibitors (tofacitinib, ABT494 and filgo tinib) have been developed for clinical therapy 114,115 . Interestingly, the JAK1-JAK3 blocker tofacitinib, a sup pressor of T cell, natural killer cell and B cell activ ation, yielded very promising results in a phase II study in patients with ulcerative colitis, but was not effective in patients with Crohn's disease 114,115 . Moreover, filgotinib, a selective JAK1 inhibitor, showed increased remission rates in patients with moderate to severe Crohn's dis ease 116 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

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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“…Therefore blocking JAK kinases is able to inhibit the inflammatory process via many different ways. However; a phase II study investigating the efficacy and safety of tofacitinib; a JAK3 inhibitor in moderate-to severe CD; was negative and there was no difference in the rate of clinical response and remission in the patients receiving tocafitinib compared to placebo [59]. Moreover; a significant elevation of low-density lipoprotein cholesterol levels was observed requiring further long term safety observations.…”

Section: Anti-cytokine Therapiesmentioning

confidence: 99%