Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial

Vermeire, Séverine; O’Byrne, Sharon; Keir, Mary E.; Williams, Marna; Lu, Timothy T.; Mansfield, John C.; Lamb, Christopher A; Feagan, Brian G.; Panés, Julián; Salas, Antonio; Baumgart, Daniel C.; Schreiber, Stefan; Dotan, Iris; Sandborn, William J.; Tew, Gaik W.; Luca, Diana; Tang, Meina; Diehl, Lauri; Eastham-Anderson, Jeffrey; Hertogh, Gert De; Perrier, Clémentine; Egen, Jackson G.; Kirby, John A.; Assche, Gert Van; Rutgeerts, Paul

doi:10.1016/s0140-6736(14)60661-9

Cited by 418 publications

(363 citation statements)

References 28 publications

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“…Prospective studies comparing vedolizumab with TNF blockers such as infliximab in anti TNF agent naive patients will determine the precise position ing of vedolizu mab in the treatment algorithm for IBD. On the basis of the success of the anti α4β7 integrin approach with vedolizumab, further therapies target ing T cell homing are currently tested in clinical trials including anti MAdCAM1 antibodies (PF 00547659) and the anti β7 integrin antibody etrolizumab [66][67][68] (FIG. 1).…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

“…1). The latter drug is particularly interesting, as it blocks not only α4β7 mediated homing but additionally T cell retention via inhibition of αE(CD103)β7 mediated bind ing to E cadherin on gut epithelial cells 66,67 . Consistently, in a humanized mouse model of colitis with ulcerative colitis T cells, etrolizumab was superior to vedolizumab in reducing T cell trafficking in the inflamed tissue due to effects on ulcerative colitis T cell retention 66 .…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

“…Consistently, in a humanized mouse model of colitis with ulcerative colitis T cells, etrolizumab was superior to vedolizumab in reducing T cell trafficking in the inflamed tissue due to effects on ulcerative colitis T cell retention 66 . However, phase III clinical data on clinical efficacy and safety of etrolizumab are still missing, although phase II data indicated efficacy for induction of remission in ulcerative colitis 67 .…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

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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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Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

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Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

512

403

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“…Etrolizumab is a humanized antibody targeting the b-7 subunit of a-4-b-7 and a-E-b-7 integrins delivered by self-injection. It is efficacious and safe for ulcerative colitis according to phase I and II studies [87,88]. It is now in phase III clinical trials for Crohn's disease (NCT02394028) and ulcerative colitis (NCT02165215, NCT02171429, NCT02100696).…”

Section: Future Directions Inflammatory Bowel Diseasementioning

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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“…RO measurements have been successfully developed in bone marrow, synovial fluid, and colonic tissue matrices (35,36). This approach presents additional challenges related to more invasive specimen collection procedures as well as post-collection processing.…”

Section: Specimen Typementioning

confidence: 99%

Recommendations for the development and validation of flow cytometry‐based receptor occupancy assays

Green

Stewart

Högerkorp

et al. 2016

Cytometry Part B Clinical

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Receptor occupancy measurements demonstrate the binding of a biotherapeutic agent to its extracellular target and represent an integral component of the pharmacodynamic (PD) portfolio utilized to advance the development and commercialization of a therapeutic agent. Coupled with traditional pharmacokinetic (PK) assessments derived from serum drug concentration, receptor occupancy data can be used to model PK/PD relationships and validate dose selection decisions throughout the drug development lifecycle. Receptor occupancy assays can be even more challenging to develop than other flow cytometric methods (e.g. surface immunophenotyping). In addition to typical considerations regarding stability of the cell type of interest, stability of the target-bound therapeutic agent and stability of the target receptor must be taken into account. Reagent selection is also challenging as reagents need to be evaluated for the potential to compete with the therapeutic agent and bind with comparable affinity. This article provides technical guidance for the development and validation of cytometry-based receptor occupancy assays. V C 2016 International Clinical Cytometry Society

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Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial

Abstract: Genentech.

Cited by 418 publications

References 28 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

Recommendations for the development and validation of flow cytometry‐based receptor occupancy assays

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