Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Ulcerative Colitis

Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, Tuttle JL, Klekotka P, Friedrich S, Durante M, Morgan-Cox M, Laskowski J, Schmitz J, D'Haens GR

Gastroenterology. 2019;doi: https://doi.org/10.1053/j.gastro.2019.08.043. [Epub ahead of print]

Introduction

Hajir Ibraheim © Hajir Ibraheim

Interleukin-23 (IL23) contributes to the pathogenesis of chronic inflammatory diseases, including Ulcerative Colitis (UC), by maintaining and amplifying T helper 17 cells and stimulating many innate immune cells. IL-23 is a heterodimeric cytokine composed of a p40 subunit (shared by IL12) and a p19 subunit (IL-23p19). Ustekinumab, a monoclonal antibody targeting the shared p40 subunit, is effective for treatment of Crohn’s Disease (CD) and psoriasis [1–3]. However, studies in patients with psoriasis have suggested that selective targeting of the IL23 pathway by blocking IL-23p19 is more effective than ustekinumab [4, 5]. Whilst promising phase 2 results have been observed in CD patients following treatment targeting IL-23p19 [6, 7], the role of this therapeutic strategy in UC is unknown. Mirikizumab (LY3074828) is a humanised immunoglobulin G4 (IgG4)-variant monoclonal antibody that binds to the IL-23p19 subunit. The current study evaluated the efficacy and safety of mirikizumab for the treatment of patients with moderate-to-severely active UC. 

Tight control for Crohn’s Disease with adalimumab-based treatment is cost-effective: An economic assessment of the CALM trial

Panaccione R, Colombel J-F, Travis SPL, Bossuyt P, Baert F, Vaňásek T, Danalıoğlu A, Novacek G, Armuzzi A, Reinisch W, Johnson S, Buessing M, Neimark E, Petersson J, Lee W-J, D’Haens GR GR

Gut 2019 Jul 8. doi: 10.1136/gut-jnl-2019-318256 [Epub ahead of print].

Introduction

Jennie Clough © Jennie Clough

It is widely accepted that a ‘treat-to-target’ (T2T) approach of continual assessment against established biomarkers and early treatment optimisation is important in preventing progression in Crohn’s Disease (CD) [1], and in 2015 the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) programme was initiated to define a T2T approach for CD [2].

CALM was an open-label, multicentre, randomised controlled phase 3 study comparing the outcome of a ‘tight control’ (TC) adalimumab-based treatment strategy against standard clinical symptom-based management (CM) for patients with early CD [3]. Treatment of patients in the TC arm was escalated in a stepwise manner in response to elevated C reactive protein (CRP) or faecal calprotectin, even in the absence of symptoms. A significantly higher proportion of patients in the TC group achieved the primary endpoint of mucosal healing (CDEIS<4) at 48 weeks compared to the CM group (46% vs 30%).

Perhaps unsurprisingly, a TC approach led to higher rates of adalimumab usage than a conventional approach [3]. Biologics constitute a significant cost in managing Inflammatory Bowel Disease, with other major cost drivers being hospital admission and surgical management [4]. As rates of surgery and hospitalisation have decreased with the advent of biologics [5, 6], costs have shifted to outpatient care, drug acquisition and infusion unit management [7].

This study sought to model the costs of a TC versus a conventional approach, to determine whether the increased biologic costs could be offset by a reduction in hospital attendance and need for surgery, and enhanced economic outputs associated with increased wellbeing.  

Infliximab induction regimens in steroid‐refractory acute severe colitis: A multicentre retrospective cohort study with propensity score analysis

Sebastian S, Myers S, Argyriou K, Martin G, Los L, Fiske J, Ranjan R, Cooper B, Goodoory V, Ching HL, Jayasooriya N, Brooks J, Dhar A, Shenoy AH, Limdi JK, Butterworth J, Allen PB, Samuel S, Moran GW, Shenderey R, Parkes G, Lobo A, Kennedy NA, Subramanian S, Raine T

Aliment Pharmacol Ther. 2019;50:675–683. doi: 10.1111/apt.15456..

Introduction

Joshua McGuire © Joshua McGuire

Acute Severe Ulcerative Colitis (ASUC) is a medical emergency which necessitates a colectomy in up to 30% of cases on index presentation [1]. The first-line treatment is with intravenous corticosteroids but up to 40% of patients will fail to respond [2]. Ciclosporin and infliximab are then well-recognised options for rescue therapy to avert the need for a colectomy and, whilst there appear to be no difference in response rates between these two choices [3], many experts favour infliximab owing to convenience and familiarity [4]. Up to 55% of patients do not respond to the standard dosing regimen of infliximab extrapolated from the outpatient setting [5]. The exaggerated clearance of infliximab in ASUC is increasingly better characterised [6]; this has led to the concept of accelerated dosing regimens although the efficacy of such regimens has yet to be evaluated by randomised controlled trials. A recent meta-analysis [7] of the available cohort studies showed no benefit of accelerated induction in reducing colectomy rates in steroid‐refractory disease; however, provider bias represents a significant barrier to answering this question. Propensity score matching seeks to address this provider bias.

No association between pseudopolyps and colorectal neoplasia in patients with inflammatory bowel diseases

Mahmoud R, Shah SC, Ten Hove JR, Torres J, Mooiweer E, Castaneda D, Glass J, Elman J, Kumar A, Axelrad J, Ullman T, Colombel JF, Oldenburg B, Itzkowitz SH; Dutch Initiative on Crohn and Colitis

Gastroenterology. 2019;156:1333–44.e3.

Introduction

Sailish Honap © Sailish Honap

Patients with Inflammatory Bowel Disease (IBD) are at an increased risk of developing high-grade dysplasia and colorectal carcinoma [1, 2]. The risk of carcinogenesis, driven by chronic inflammation, increases with several factors, including duration and anatomic extent of colitis, family history and the presence of primary sclerosing cholangitis (PSC). European clinical guidelines for colonoscopy surveillance in this high-risk cancer population also suggest a shorter surveillance interval for those with post-inflammatory polyps (PIPs), also known as pseudopolyps [3–5]. PIPs are a common finding, more so in Ulcerative Colitis (UC) than in Crohn’s Disease, and are formed after alternating cycles of inflammation and regeneration of the epithelial mucosa. However, data are conflicting and evidence is lacking in this field as previous case control studies have reported up to a 2.5-fold increased risk [6, 7] whereas a more recent cohort study showed no significant association between PIPs and colorectal neoplasia (CRN) [8]. The authors of this study aimed to use a large cohort study to further define the risk of CRN and PIPs in patients with Inflammatory Bowel Disease.  

Crohn’s Disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial

Levine A, Wine E, Assa A, Boneh RS, Shaoul R, Kori M, Cohen S, Peleg S, Shamaly H, On A, Millman P, Abramas L, Ziv-Baran T, Grant S, Abitbol G, Dunn KA, Bielawski JP, Van Limbergen J

Gastroenterology. 2019;157:440–50.

Introduction

Paul Harrow © Paul Harrow

Exclusive enteral nutrition (EEN) is a safe and effective induction treatment for Crohn’s Disease (CD). It is recommended as first-line induction therapy in children and adolescents [1]. However, enteral nutrition is less well tolerated than other options like corticosteroids. A recent meta-analysis found three times as many patients withdrew from enteral nutrition therapy compared to corticosteroids even in the supported setting of clinical trials [2]. There is a clear need for a more acceptable dietary intervention. However, our understanding of the role of diet in CD is incomplete and to date specific diets have not been proven to induce remission. 

Ustekinumab exposure-outcome analysis in Crohn’s Disease only in part explains limited endoscopic remission rates

Verstockt B, Dreesen E, Noman M, Outtier A, Van den Berghe N, Aerden I, Compernolle G, Van Assche G, Gils A, Vermeire S, Ferrante M

J Crohns Colitis. 2019;13:864–72.

Introduction

Samantha Campbell © Samantha Campbell

Ustekinumab is licenced to treat moderate-severe Crohn’s Disease (CD) [1]. Ustekinumab induction is administered via intravenous (IV) infusion at a dose of 6 mg/kg at week 0, followed by a subcutaneous (SC) maintenance injection of 90 mg at week 8.

The UNITI programme demonstrated that ustekinumab can induce and maintain clinical remission. However, there is a paucity of real-life data in patients with CD receiving the mentioned IV induction and SC maintenance dosing of ustekinumab. Real-life data on therapeutic drug monitoring and biomarkers, such as faecal calprotectin, remain a relatively unexplored area with ustekinumab, with discrepancies in the literature [2, 3]. . 

Rates and characteristics of postcolonoscopy colorectal cancer in the Swedish IBD population: What are the differences from a non-IBD population?

Stjärngrim J, Ekbom A, Hammar U, Hultcrantz R, Forsberg AM

Gut 2018 Dec 15; doi: 10.1136/gutjnl-2018-316651

Introduction

Rohit Rao  © Rohit Rao

Individuals with IBD have an increased risk of colorectal cancer (CRC) [1, 2]. In an effort to address this, societal guidelines recommend surveillance colonoscopy 8–10 years after diagnosis and at varying intervals thereafter, depending on risk [3, 4]. A 2017 Cochrane systematic review [5] demonstrated a benefit in this strategy, noting reductions in the development of both CRC and the rate of CRC‐associated death. Despite this, dysplasia detection is challenging and CRC still accounts for 10%–15% of all IBD deaths [6, 7]. Of further concern is the reported increased rate of post-colonoscopy colorectal cancer (PCCRC) in IBD. 

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: A prospective, multicentre, cohort study

Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A, Nice R, Perry MH, Bouri S, Chanchlani N, Heerasing NM, Hendy P, Lin S, Gaya DR, Cummings JRF, Selinger CP, Lees CW, Hart AL, Parkes M, Sebastian S, Mansfield JC, Irving PM, Lindsay J, Russell RK, McDonald TJ, McGovern D, Goodhand JR, Ahmad T, UK Inflammatory Bowel Disease Pharmacogenetics Study Group*

Lancet Gastroenterol Hepatol. 2019;4:341–53

Introduction

Misha Kabir  © Misha Kabir

The anti-TNF monoclonal antibodies infliximab and adalimumab have been integral to the management of Crohn’s Disease over the past two decades. However, primary non-response and secondary loss of response in the first year of treatment remain common, at 10%–40% [1–3] and 23%–46% [4] respectively. Immunogenicity has been implicated as an important predictive factor for anti-TNF therapy failure. However, target-to-treat drug and anti-drug antibody concentrations have not yet been validated in an adequately powered prospective study. The Personalised Anti-TNF Therapy in Crohn’s Disease Study (PANTS) aimed to investigate the factors that predict primary non-response, non-remission and adverse events with anti-TNF therapy in luminal Crohn’s Disease.

Early combined immunosuppression may be effective and safe in older patients with Crohn’s disease: post hoc analysis of REACT

Singh S, Stitt LW, Zou G, et al.

Aliment Pharmacol Ther. 2019;49:1188–94.

Introduction

Georgina Cunningham  © Georgina Cunningham

Due to the ageing population and the chronicity of the disease, increasing numbers of patients with Inflammatory Bowel Disease (IBD) are now over the age of 60 [1]. The management of IBD in this group poses some challenges, mainly centered on the balance between risk of immunosuppression and the burden of active disease [2]. Although older IBD patients usually display a more indolent disease course, they are more likely to be hospitalised and have higher in-hospital mortality than their younger counterparts [3]. There is no doubt that there is room for improvement in our management of IBD in elderly patients, and guidance is needed to help physicians decide whether more aggressive treatment strategies, widely accepted in certain younger IBD patients [4], are also warranted in this cohort, and especially those at high risk of disease complications.

Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in Inflammatory Bowel Disease

Drobne D, Kurent T, Golob S, Švegl P, Rajar P, Hanžel J, Koželj M, Novak G, Smrekar N, Ferkolj I, Štabuc B

Aliment Pharmacol Ther. 2019;49:880–9

Aravind Gokul Tamilarasan  © Aravind Gokul Tamilarasan

Introduction

Since the publication of the landmark SONIC trial in 2010 [1], the use of combination biologic–immunomodulator therapy has been considered best standard practice for patients with Inflammatory Bowel Disease (IBD) who have failed topical therapies or immunomodulators (thiopurines or methotrexate). More recently, real-world data from the PANTS (Personalised anti-TNF therapy in Crohn’s Disease) study demonstrated the benefit of combination therapy (particularly for infliximab) in the form of higher week 54 remission rates and prevention of immunogenicity [2]. Notably, the week 54 remission rates were independent of infliximab trough levels or immunogenicity status, suggesting additional benefits apart from improving the pharmacokinetics of infliximab. This study aimed to provide further real-world data on the effect of combination therapy on clinical and pharmacokinetic outcomes.