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Abstract

Crohn’s disease (CD) is an inflammatory bowel disease (IBD) with uncertain etiology. Biologic agents have revolutionized the treatment of CD but nonresponders remain a challenge. Ustekinumab is an interleukin 12/23p40 inhibitor that was recently found effective in treating CD. We reviewed the current literature regarding the efficacy of ustekinumab in treating CD and concluded that ustekinumab is a novel, promising and relatively safe agent for the treatment of moderate to severe CD. Additional data from randomized controlled studies and real-life cohorts are pending.

Keywords

Crohn’s disease interleukin 12/23p40 inhibitor ustekinumab

Introduction

Crohn’s disease (CD) is an inflammatory bowel disease (IBD) characterized by transmural inflammation of the gastrointestinal (GI) tract. It may involve any part of the GI tract from the mouth to the perianal area and typically manifests a relapsing and remitting course [Cosnes et al. 2011]. The etiology remains uncertain but it is hypothesized that genetic, environmental, endogenous gut bacteria and immunological factors all play important roles [Cosnes et al. 2011; Hugot, 2004; Shanahan, 2001; Neuman, 2007; Fiocchi, 1998; Papadakis and Targan, 2000; Sartor, 1997; Podolsky, 2002; Ben-Horin and Chowers, 2008]. Biologic agents have revolutionized the treatment of IBD and gained an important place for the treatment of moderate to severe IBD and CD. Tumor necrosis factor α (TNFα) antagonists became the mainstay of treatment for moderate and severe disease [Sandborn, 2012; Sands et al. 2004; Colombel et al. 2007, 2010; Hanauer et al. 2006; Sandborn et al. 2007, 2012, 2013; Ghosh et al. 2003; Côté-Daigneault et al. 2015]. Nevertheless a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponders to anti-TNFα therapy hold a clinical challenge and require dose adjustment or switch to another medication [Yanai and Hanauer, 2011]. There is a growing demand for novel therapeutic agents targeting alternative disease mechanisms. Current treatment options include selective anti-integrin therapy with vedolizumab (anti-α4β7), etrolizumab (anti-β7 antibody) anti-interleukin (IL)-12/23p40 therapy with ustekinumab and Janus kinase 1, 2 and 3 inhibition with tofacitinib [Sandborn, 2012]. Importantly, the efficacy of vedolizumab for treatment of anti-TNF-resistant CD appears to be quite modest [Sandborn et al. 2013, Côté-Daigneault et al. 2015]. In real-world cohorts of patients with CD or ulcerative colitis (UC) whose disease has failed to respond to previous anti-TNF therapy, approximately one third of patients achieved steroid-free clinical remission after 14 weeks of treatment with vedolizumab [Amiot et al. 2016; Baumgart et al. 2016]. This emphasizes the need for novel and effective agents.

Mode of action, principle, pharmacology and pharmacokinetics

Inflammatory changes in CD are associated with excess cytokine activity driven by activated T cells. T helper 1 (Th1) and Th2 CD4+ effector subsets, each with unique cytokine profiles, are essential for the development of disease. The paradigm regarding T cells has shifted from the classical Th1/Th2 to that of TH1-Th17/Treg [Ueno et al. 2015]. IL-17 secreting helper T (Th17) cells have been implicated in tissue-specific immune pathology of murine models of IBD, human CD and UC [Fujino et al. 2003]. IL-17 is linked to promoting barrier function of the gut and neutrophil chemotaxis and plays an important role in the clearance of extracellular bacterial and fungal infections. Th17 cells express heterogeneous cytokine profiles and are capable of producing other cytokines, including IL-21 and IL-22 and more [Ueno et al. 2015; Fujino et al. 2003; Duerr et al. 2006]. The proinflammatory cytokine IL-12 family, which includes IL-22, IL-23, IL-25 and IL-27, is responsible for the differentiation of T helper (Th) cells into Th1 cells and has been recently linked to the pathophysiology of CD as well as other immune-mediated disorders. IL-23, secreted mainly by innate myeloid cells, monocytes and macrophages, is critical for Th17 proliferation and maintenance [Ueno et al. 2015]. Mutations within the il23r locus, which encodes a receptor subunit unique to IL-23, are associated with psoriasis, ankylosing spondylitis and IBD, and thus may be an important target for therapy and intervention, although previous attempts with a human anti-IL-17 monoclonal antibody (secukinumab) for the treatment of CD failed to show efficacy. Failure might be explained by the complexity of the cytokine network on the one hand and the heterogeneous causes of the disease on the other [Ueno et al. 2015; Hueber et al. 2012].

IL-12 and IL-23 are heterodimeric proteins composed of a unique subunit linked to a shared p40 subunit [Strober and Fuss 2011; Duerr et al. 2006]. Overexpression of the IL-12p35 and IL-12/23p40 subunits was demonstrated in patients with CD [Berrebi et al. 1998; Tuskey and Behm, 2014; Scherl et al. 2010; Marafini et al. 2015; Settesoldi et al. 2014]. Ustekinumab is a fully human immunoglobulin G1κ monoclonal antibody that targets the standard p40 subunit of the cytokines IL-12 and IL-23 (IL-12/23p40), which are involved in the pathogenesis of CD [Baumgart et al. 2016; Strober and Fuss, 2011; Duerr et al. 2006; Berrebi et al. 1998; Tuskey and Behm, 2014; Scherl et al. 2010; Marafini et al. 2015; Settesoldi et al. 2014]. Ustekinumab can be administered intravenously or subcutaneously as a weight-based infusion or a fixed-dose injection. The median half life of ustekinumab is approximately 3 weeks. The pharmacokinetic profile is affected by body weight, but not by age. The effect of sex and albumin levels on the pharmacokinetics of ustekinumab has not been well studied [Tuskey and Behm, 2014; Scherl et al. 2010; Marafini et al. 2015; Settesoldi et al. 2014; Croxtall, 2011].

The latest results from the UNITI-1 and UNITI-2 studies showed that serum ustekinumab concentrations over time were dose proportional and were similar between patients who were TNF antagonist refractory and those who were TNF antagonist naïve. Moreover, ustekinumab sera concentrations were positively associated with remission at week 8 and inversely related to C-reactive protein levels [ClinicalTrials.gov identifier: NCT01369329, NCT01369342].

Data from randomized controlled trials

Currently, ustekinumab is approved for the treatment of psoriasis and psoriatic arthritis [Scherl et al. 2010; Leonardi et al. 2008]. Ustekinumab was evaluated in several phase III studies and real-life, ongoing cohorts for the treatment of CD [ClinicalTrials.gov identifier: NCT01369329, NCT01369342] [WIls 2015; Kopylov et al. 2014]. Ustekinumab is pending approval by MHRA, the UK Medicines and Healthcare products Regulatory Agency and European Medicines Agency (EMA) for use in patients with IBD.

A phase IIa study of ustekinumab use in patients with CD was published in 2008 [Sandborn et al. 2008]. This phase II, double-blind, placebo-controlled, parallel-group, multicenter crossover trial included two populations: the first population consisted of 104 patients with moderate to severe CD who were assigned to one of four groups: subcutaneous placebo at weeks 0, 1, 2 and 3, then 90 mg ustekinumab at weeks 8, 9, 10 and 11; 90 mg ustekinumab subcutaneously at weeks 0, 1, 2 and 3, then placebo at weeks 8, 9, 10 and 11; intravenous placebo at week 0, then 4.5 mg/kg ustekinumab at week 8; or 4.5 mg/kg ustekinumab intravenously at week 0, then placebo at week 8. The second population enrolled in an open-label study comprised 27 patients who were either nonresponders to infliximab induction treatment (primary nonresponders) or patients who lost response to infliximab maintenance therapy (secondary nonresponders) and were randomized to either 90 mg ustekinumab subcutaneously at weeks 0, 1, 2 and 3, or 4.5 mg/kg ustekinumab intravenously at week 0. The study did not meet the primary endpoint (reduction of at least 25% and 70 points from baseline Crohns Disease Activity Index (CDAI)); nevertheless, in a subgroup analysis, a significantly higher clinical response rate was noted among patients with previous exposure to infliximab over 8 weeks. Numerically higher rates of clinical response were found with intravenous administration compared with subcutaneous administration [Tuskey and Behm, 2014, Sandborn et al. 2008].

In 2012 a phase IIb clinical trial of ustekinumab for CD was published (Crohn’s Evaluation of Response to Ustekinumab Anti–Interleukin-12/23 for Induction (CERTIFI) trial). The study population comprised 526 patients with moderate to severe CD resistant to anti-TNF treatment (primary or secondary nonresponders or intolerance) who were randomized to an 8-week induction trial and 26-week maintenance trial with either a weight-based dose of intravenous ustekinumab (1, 3 or 6 mg/kg) or placebo. Treatment with intravenous ustekinumab (6 mg/kg) resulted in a significantly higher clinical response rate than placebo (primary endpoint, a reduction of at least 100 points in CDAI). However, the rate of clinical remission in the group receiving a single 6 mg/kg intravenous dose did not differ significantly from the placebo group at 6 weeks, possibly due to high median baseline CDAI score (330). In patients who responded to the intravenous induction therapy, maintenance with subcutaneous ustekinumab (90 mg at weeks 8 and 16) resulted in clinically significant response and remission at week 22. For nonresponders to ustekinumab induction, further treatment with ustekinumab did not result in a significant clinical response [Sandborn et al. 2012].

Following these results, three phase III clinical trials were conducted but are not yet published. These studies are expected to fill the existing gaps in regards to dosing, mucosal response, pharmacokinetics and pharmacodynamics, patient-reported outcomes and more.

UNITI-1 is a study evaluating the safety and efficacy of ustekinumab in patients with moderately to severely active CD have failed to respond to or are intolerant of TNF antagonist therapy, evaluating ustekinumab (6 mg/kg intravenously, 130 mg subcutaneously) versus placebo.

In patients with moderately to severely active disease who have previously failed to respond to one or more TNF antagonists, intravenous ustekinumab significantly induced clinical response and clinical remission and was well tolerated throughout induction, confirming the previous positive induction data from CERTIFI. The magnitude of treatment effects was greater at a higher dose than for the lower 130 mg induction dose, particularly at the final week 8 induction endpoint [ClinicalTrials.gov identifier: NCT01369329, NCT01369342].

UNITI-2 is a study evaluating the safety and efficacy of ustekinumab induction therapy in patients with moderately to severely active CD. It evaluated two intravenous ustekinumab induction dose regimens (130 mg or weight-based dose 6 mg/kg) in a CD population who were not refractory to TNF antagonist therapy. Preliminary results have already been presented in abstract form [Feagan, 2015; Sandborn et al. 2016] (UEGW 2015 Abstract). A total of 628 patients with moderate to severe CD were randomized to a single dose of ustekinumab 130 mg intravenously, 6 mg/kg ustekinumab intravenously or intravenous placebo. The primary endpoint was clinical response at week 6 (reduction in CDAI score of >100 points). At week 6 and at week 8 both ustekinumab dose groups achieved a significantly higher clinical response in comparison to the placebo group. At week 8, 40.2% and 30.6% of patients (6 mg/kg and 130 mg respectively) achieved clinical remission compared with 19.6% in the placebo group (p < 0.009). Moreover both ustekinumab doses showed significant improvements compared with placebo in quality of life measurements also known as Inflammatory Bowel Disease Questionnaire (IBDQ) and in inflammation surrogate markers. Induction efficacy has been demonstrated in patients with moderately to severely active disease, including patients who are TNF antagonist naïve or those whose disease has failed to respond to this treatment [Feagan, 2015].

IM-UNITI is a study evaluating the safety and efficacy of ustekinumab maintenance therapy in patients with moderately to severely active CD. The primary outcome is defined as clinical remission at week 44; secondary outcomes are clinical remission in anti-TNF nonresponders and corticosteroid-free remission at week 44 [ClinicalTrials.gov identifier: NCT01369329, NCT01369342, NCT01369355] [Feagan, 2015; Leung and Panaccione, 2014].

Similar to ustekinumab, the anti-IL-12/23 antibody briakinumab showed a favorable safety and tolerability profile but failed to meet the primary endpoint of clinical remission at week 6. Failure was suggested to be related to a carryover effect in patients rerandomized to placebo who had received briakinumab during induction [Panaccione et al. 2015].

Real-life experience with ustekinumab in Crohn’s disease

Currently existing real-life data are still sparse. In the first real-life cohort of 38 patients with severe CD [Kopylov et al. 2014], anti-TNF nonresponders who were treated with subcutaneous ustekinumab showed an initial clinical response of 73.7% and was maintained by the majority of patients for the duration of the follow up (7.9±5.2 months). Multiple dosing schemes were used, the most frequent being an induction dose of 90 mg at weeks 0, 1 and 2, followed by a maintenance dose of 90 mg every 8 weeks. Dose escalation was required in almost half of the patients and was successful in 61.1%. Thirteen patients had perianal disease, of which 69.2% achieved clinical response. Endoscopic improvement was reported in 76.9% (10/13) and two patients achieved mucosal healing similar to the mucosal healing rates reported in the CERTIFI trial [Baumgart et al. 2016; Kopylov et al. 2014]. A retrospective observational study that was recently published by the Groupe d’Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) reported the results for 122 patients with active CD who lost response to anti-TNF therapy and received subcutaneous ustekinumab. A clinical benefit was demonstrated in almost two thirds of patients. Similar to the Canadian study, the dosing schemes were very heterogeneous. Concomitant immunosuppressant therapy at study inclusion increased the odds of a clinical benefit from ustekinumab (odds ratio 5.43), adding preliminary data on combination therapy [Wils et al. 2015].

The association of ustekinumab trough concentrations with clinical, biochemical and endoscopic outcomes in 59 anti-TNF nonresponders was recently evaluated and will be presented in abstract form. In this study, subcutaneous ustekinumab induced and maintained steroid-free clinical remission in a large proportion of patients with anti-TNF refractory CD. Patients with colonic disease had significantly improved clinical and endoscopic outcomes. Adequate ustekinumab concentrations (>4.5 µg/ml) were associated with endoscopic and clinical response. Interestingly, anti-ustekinumab antibodies were undetectable in all patients’ available sera [Battat et al. 2015].

Safety profile

More than 3000 patients enrolled in clinical trials provide the safety profile of ustekinumab that appears to be favorable. To date most of the data are driven from psoriasis studies follow by multiple sclerosis and CD. The incidence of serious adverse events was not significantly different from placebo [Toussirot et al. 2013]. In the two published CD trials no increase in the rate of adverse events and serious adverse events from induction to week 8 was found compared with placebo. Two patients (4%) in the phase II trial had serious adverse events (small bowel obstruction and coronary event). Through week 28 of follow up, 10 patients (5.5%) experienced one or more serious adverse events (worsening CD, colonic stenosis and pneumothorax, small bowel obstruction, prostate cancer, viral gastroenteritis, nephrolithiasis, disseminated histoplasmosis) [Sandborn et al. 2008]. Likewise, in the CERTIFI trial, during the induction phase the total rate of infection and serious adverse events was similar for ustekinumab and placebo. Serious infections were reported in five patients receiving 6 mg/kg ustekinumab (Clostridium difficile infection, viral gastroenteritis, urinary tract infection, anal abscess and vaginal abscess) and in one patient receiving 1 mg/kg (staphylococcal infection of a central line) during the induction phase. In the maintenance phase at week 25 there were no serious adverse events or infections, with one patient diagnosed with basal cell carcinoma [Sandborn et al. 2012]. Only one serious infection was reported in the McGill real-life cohort (C. difficile infection) in a patient who was also receiving corticosteroids and methotrexate [Kopylov et al. 2014]. In the UNITI-1 study one significant opportunistic infection (listeria meningitis) was reported in the group receiving 6 mg/kg ustekinumab. No malignancies, deaths, major adverse cardiovascular events or tuberculosis (TB) occurred in ustekinumab-treated patients through week 20. Similar results were reported from the UNITI-2 study, in which proportions of adverse events and serious adverse events and infections (including serious infections) were similar to placebo. No malignancies, deaths, opportunistic infections or TB occurred [ClinicalTrials.gov identifier: NCT01369329, NCT01369342, Sandborn et al. 2016].

Ustekinumab responders at week 44 were eligible to continue to receive treatment in the 3-year long-term extension study. No anaphylaxis or serious infusion reactions were reported. Ten cases of serious infection were reported, most of them (seven patients) in the weight dose adjustment group (6 mg/kg). No malignancy or adverse cardiac events were reported [ClinicalTrials.gov identifier: NCT01369329, NCT01369342] [Feagan, 2015; Leung and Panaccione, 2014].

The most common adverse events reported, not including worsening of CD, were nonserious infections (39.2%) followed by abdominal pain (7.2%), nausea (6/1%) and nasopharyngitis (6.1%). Infusion reactions were similar to placebo (~4%) [ClinicalTrials.gov identifier: NCT01369342] [Sandborn et al. 2012; Leung and Panaccione, 2014]. There has been one case report of central demyelination diagnosed 1 year after ustekinumab treatment in a 63-year-old patient who was also previously treated with an immunomodulator, infliximab, adalimumab and certolizumab [Badat et al. 2014].

Long-term safety data are available from trials of ustekinumab in patients with psoriasis. Similar to studies in CD, most reported that adverse events with ustekinumab were mild and did not require treatment withdrawal. Common adverse events with long-term use (up to 5 years) are headache, nasopharyngitis and upper respiratory tract infections. The incidence of malignancy (excluding nonmelanoma skin cancers) was no higher than in the general population. The most frequent serious adverse events were serious infections; no TB infection was reported, probably due to the high-quality screening process before initiation. The second most common serious adverse events were cardiac [Tuskey and Behm, 2014; Scherl et al. 2010; Croxtall, 2011; Leonardi et al. 2008; Leung and Panaccione, 2014]. Certain concern has been raised regarding the use of ustekinumab and the risk of major cardiac events. Numerical imbalance (without statistical significance) between the groups receiving ustekinumab and placebo was observed in the incidence of major cardiovascular events (nonfatal myocardial infarction and cerebrovascular accident and cardiovascular death) during the controlled periods of clinical trials including patients with psoriasis [Reich et al. 2011; Papp et al. 2013]. A meta-analysis of randomized controlled clinical trials concluded that there was no significant difference in the rate of major cardiac events observed in patients receiving anti-IL-12/IL-23 antibodies or anti-TNFα treatments, although the analysis may have been underpowered to identify a significant difference [Ryan et al. 2011]. No cardiac events were reported in the phase III UNITI studies [ClinicalTrials.gov identifier: NCT01369329, NCT01369342] [Adedokun et al. 2014; Feagan, 2015; Leung and Panaccione, 2014].

There was no relationship found between serum concentrations and the incidence of infections, serious infections or other serious adverse effects following induction treatment with ustekinumab [ClinicalTrials.gov identifier: NCT01369342].

Immunogenicity

Like with safety, most immunogenicity data are available from psoriasis trials. Higher rates of antibodies to ustekinumab were reported in pooled data analysis including the sera of more than 3000 patients, ranging from 3.8% to 5.4% [Reich et al. 2011]. As opposed to these reports, the sera of only 0.7% of 427 patients with CD available from the CERTIFI trial had antibodies to ustekinumab, however only for 36 weeks [Sandborn et al. 2012]. Likewise the incidence of antibodies to ustekinumab in the UNITI studies was 0.2% across both dose groups [ClinicalTrials.gov identifier: NCT01369329, NCT01369342]. No data are currently available on the development of antibodies during maintenance and long-term treatment and no information is available regarding the effect of concomitant immunomodulators on antibody development.

Conclusion

Ustekinumab is a novel, promising and relatively safe biological fully human monoclonal antibody for the treatment of moderate to severe CD. Ustekinumab is an appealing therapeutic option, especially for patients whose disease has failed to respond to anti-TNF, with encouraging results according to the latest reports from phase III clinical trials. Ustekinumab has a favorable safety profile and a significant body of safety data is available from psoriasis studies. Some significant data gaps such as optimal dosing, impact of perianal disease and extraintestinal manifestations, and efficacy in induction of mucosal healing still exist and are expected to be covered in the results of the forthcoming clinical trials. These results along with ‘real-life’ cohorts and registry studies are eagerly anticipated and will add important information on this promising agent that will soon be added to the CD treatment tool box.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Dr Kopylov has received lecture and consultancy fees from JNJ, lecture fees from Takeda, Abbvie and CTS. Dr Engel has no conflicts of interest.

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Ustekinumab in Crohn’s disease: evidence to date and place in therapy

Abstract

Keywords

Introduction

Mode of action, principle, pharmacology and pharmacokinetics

Data from randomized controlled trials

Real-life experience with ustekinumab in Crohn’s disease

Safety profile

Immunogenicity

Conclusion

Footnotes

Funding

Conflict of interest statement

References