A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn’s Disease

Targan, Stephan R.; Feagan, Brian G.; Vermeire, Séverine; Panaccione, Remo; Melmed, Gil Y.; Landers, Carol J.; Li, Dalin; Russell, Chris B.; Newmark, Richard; Zhang, Nan; Chon, Yun; Hsu, Yi‐Hsiang; Lin, Shao-Lee; Klekotka, Paul

doi:10.1038/ajg.2016.298

Cited by 309 publications

(233 citation statements)

References 20 publications

Supporting

Mentioning

214

Contrasting

Unclassified

Order By: Relevance

“…These observations highlight that the presence of a cytokine in diseased tissue does not necessarily equate to an irreplaceable role in pathogenesis. Furthermore, both secukinumab20 and brodalumab21 have been demonstrated to worsen Crohn’s disease (CD). Thus, in contrast to its pro-inflammatory role in other diseases and locations, IL-17A may function as a negative regulator of immunity in the gut mucosa, perhaps via interaction with fungal elements of the intestinal microbiome 22 23.…”

Section: The Th17 Axismentioning

confidence: 99%

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017

View full text Add to dashboard Cite

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

show abstract

Section: The Th17 Axismentioning

confidence: 99%

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017

View full text Add to dashboard Cite

show abstract

“…It has been suggested that the principal function of IL-17A and IL-17RA in experimental colitis is the maintenance of intestinal barrier integrity rather than driving pathogenic inflammation. Clinical trials of anti-IL-17A (secukinumab) and anti-IL-17RA (brodalumab) Abs in patients with moderate-to-severe CD have reported no improvement, or even a worsening of disease, on treatment 97, 98 . The high levels of mRNA for T H 17 signature cytokines, including IL-17A, IL-17F, IL-22, and IL-26, in the intestinal mucosa of patients with IBD may therefore be beneficial 99–102 .…”

Section: Il-17 In the Intestinementioning

confidence: 99%

Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation

2018

View full text Add to dashboard Cite

Interleukin (IL)-17A is a pro-inflammatory cytokine in mice and humans. It is recognized as a key factor for the protection of mice against various pathogens, but it also underlies pathogenic inflammatory responses in numerous mouse models. The inborn errors of IL-17A- and IL-17F-mediated immunity identified in humans in the last decade have revealed that IL-17A and IL-17F are key players in mucocutaneous immunity to Candida albicans, and, to a lesser extent, Staphylococcus aureus. By contrast, there is currently no genetic evidence for a causal link between excess of IL-17 and autoimmunity, autoinflammation, or allergy in humans. We discuss here the physiological and pathological roles of mouse and human IL-17A and IL-17F in host defense and excessive inflammation. We highlight recent advances in our understanding of the consequences deficient or excessive IL-17 immunity at various mucocutaneous sites, including the oral cavity, skin, intestine, lungs, and vagina.

show abstract

“…In contrast to the benefit evident in neutralising TNF, a contributing role for IL-17 in IBD is still uncertain, and IL-12/IL-23 are likely not the driver cytokines as there is only marginal efficacy from ustekinumab (anti-12/IL-23) in CD patients, and no benefit was evident in initial trials with briakinumab (anti-IL-12/IL-23 p40-neutralising mAbs) [54]. Indeed, brodalumab (anti-IL-17RA-neutralising mAb) caused worsening symptoms in CD [55]. Clearly, further investigation into the complex interactions between the normal and altered microbiome, and the endogenous intestinal cells, including resident innate and adaptive immune cells, is required to better understand these IBD pathologies.…”

Section: Inflammatory Cytokines In Psoriasis (And Psoriatic-type Arthmentioning

confidence: 99%

“…Brodalumab, an IL-17RA-specific mAb, is one such reagent that acts by preventing IL-17-family cytokines from binding to the IL-17 receptor (Box 4). Recent Brodalumab data, derived from phase II and III clinical trials, have demonstrated effectiveness in the treatment of psoriasis [32], and reportedly with superior skin clearance than the anti-IL-12/ IL-23 mAb ustekinumab [55,82]. These are long-awaited treatment for a skin condition that has previously proven to be difficult to treat.…”

Section: Cytokine-neutralising Mabsmentioning

confidence: 99%

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

Sedger¹,

Ranasinghe²,

McDermott³

et al. 2017

Immunotherapy - Myths, Reality, Ideas, Future

View full text Add to dashboard Cite

Inflammation causes debilitating human conditions and older treatments rely on global immunosuppression that non-specifically alleviates symptoms. Currently, several monoclonal antibodies (mAbs) are available that specifically block pro-inflammatory cytokines. These include mAbs specific to tumour necrosis factor (TNF), interleukin (IL)-1β,I L -6 , IL-17 and IL-12/IL-23. The chapter summarises the key elements in human inflammatory disease conditions, including various forms of arthritis, psoriasis, Crohn's disease and ulcerative colitis, plus pyrin-associated inflammatory syndromes and periodic fevers, to explain the benefit of cytokine neutralisation through mAb-type reagents. The chapter reviews the efficacy and safety of the current repertoire of anti-cytokine/cytokine receptor mAbs. It also discusses the known side effects and adverse events that are sometimes associated with systemic blockade of cytokines in vivo, and concludes that the accumulating knowledge of treatment failures can reveal unappreciated aspects of cytokine biology and even new treatment opportunities. The chapter includes mention of the rapidly expanding cohort of biosimilar mAbs and the mAbs to IL-4, IL-5 and IL-13 that are now emerging, in addition to the need for treatments for disorders that remain refractory to the current repertoire of anti-cytokine mAbs and conventional treatments. Thus, here we summarise the current status of anti-cytokine mAbs for human inflammatory diseases.

show abstract

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn’s Disease

Abstract: Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD.

Cited by 309 publications

References 20 publications

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

Contact Info

Product

Resources

About