Ustekinumab (originally known as CNTO 1275) is a human monoclonal antibody (IgG1) that targets the IL-12/23 shared p40 subunit. The result is the inhibition of IL-12 and IL-23 binding to their receptor on the surface of T cells, natural killer cells, and antigen-presenting cells (see Fig. 35.3).

Ustekinumab has been shown to be clinically effective in the treatment of moderate to severe CD in phase II studies. There were two groups studied with population 1 being double-blind, placebo-controlled, parallel-group, crossover at week 8 study and population 2 being an open-label study [10]. Both groups were followed up for 28 weeks. Group 1 comprised of 104 patients with moderate to severe Crohn’s disease despite treatment with 5-ASA, antibiotics, corticosteroids, infliximab, and/or immunomodulators who were randomly assigned to one of four arms of treatment: subcutaneous placebo at weeks 0–3 followed by subcutaneous ustekinumab 90 mg at weeks 8–11; subcutaneous ustekinumab 90 mg at weeks 0–3 followed by subcutaneous placebo at weeks 8–11; intravenous placebo at week 0 followed by intravenous ustekinumab 4.5 mg/kg at week 8; or intravenous ustekinumab 4.5 mg/kg at week 0 followed by intravenous placebo at week 8. Group 2 consisted of 27 patients who previously failed to respond to a three-dose induction of infliximab 5 mg/kg or lost response to infliximab maintenance every 8 weeks despite dose escalation to 10 mg/kg who were randomly assigned to open-label therapy with either 4 weekly subcutaneous injections ustekinumab 90 mg at weeks 0–3 or single intravenous ustekinumab 4.5 mg/kg at week 0. The primary endpoint was clinical response at week 8 (a reduction of at ≥25 % and 70 points in the CDAI score from baseline). In group 1 the primary endpoint was assessed for combined subcutaneous and intravenous ustekinumab administered before crossover to placebo (n = 51) versus combined subcutaneous and intravenous placebo administered before crossover to ustekinumab (n = 53). There was no significant difference in rates of clinical response between ustekinumab and placebo at week 8 (49 % vs. 40 %, P = 0.34). However, superiority of ustekinumab over placebo was observed in achieving clinical response at week 4 and at week 6 (53 % vs. 30 % at both time points, P = 0.02). Of note, among patients in group 1 who had prior exposure to infliximab given at submaximal infliximab doses or regimens ustekinumab was significantly superior to placebo with clinical response rates of 59 % and 26 %, respectively (P = 0.022). Among group 2, clinical response rates at week 8 were 43 % and 54 % for subcutaneous and intravenous route of administration of ustekinumab, respectively. It was thus concluded that ustekinumab has the potential of inducing clinical response in patients with moderate to severe active Crohn’s disease with the most prominent effect at weeks 4 through 6 and in patients with prior exposure to infliximab.

Ustekinumab in CD was further studied in a phase IIb randomized, double-blind, placebo-controlled trial with an 8-week induction and 26-week maintenance evaluation period for patients previously exposed to anti-TNF therapy who either had primary nonresponse, secondary nonresponse or intolerance to anti-TNF treatment [11]. During the induction phase, 526 patients were randomly assigned to receive a weight-based dose of intravenous (IV) ustekinumab (1, 3, or 6 mg/kg) or placebo. Responders and nonresponders were separately randomized to subcutaneous (SC) ustekinumab 90 mg or placebo at weeks 8 and 16. The primary endpoint was clinical response (≥100-point decrease from baseline CDAI) at week 6. 39.7 % of patients at 6 mg/kg vs. 23.5 % of patients receiving placebo achieved clinical response at week 6 (P = 0.005). Clinical remission rates at week 6, however, were similar between the ustekinumab and placebo groups. Among patients with a response to ustekinumab in the induction phase, 69.4 % vs. 42.5 % and 41.7 % vs. 27.4 % of patients receiving 90 mg of ustekinumab vs. placebo in the maintenance phase continued to have a clinical response and clinical remission at week 22. In addition, 30.6 % vs. 17.8 % of patients in the ustekinumab vs. placebo group were in glucocorticoid-free remission at week 22 (p = 0.048). Of note, for those patients who did not achieve clinical response after induction with ustekinumab, further therapy with the drug was no different than placebo in terms of clinical response at week 22.

Mucosal healing was also evaluated in the phase IIb trial. Fifty patients were evaluated and 1 out of 9 vs. 8 out of 41 patients achieved mucosal healing in the placebo vs. ustekinumab group respectively (P = 1.00) [11].

Having had promising results with the phase II trials, two phase III trials are completed and a third is underway. UNITI-1 (NCT01369329) is a multicenter, double-blind, placebo-controlled study of ustekinumab for induction of remission in moderate to severe CD in patients with prior failure or intolerance to TNF antagonist therapy [12]. Patients with moderate-severely active CD (defined as a CDAI 220–450) who previously failed or were intolerant to at least 1 TNF-antagonist were randomized (1:1:1) to receive a single dose of IV placebo (PBO), ustekinumab 130 mg, or weight-based tiered ustekinumab dosing approximating 6 mg/kg (260 mg [weight ≤55 kg], 390 mg [weight >55 kg and ≤85 kg], and 520 mg [weight >85 kg]) at week 0. The primary endpoint was clinical response at week 6, defined as reduction from baseline in the CDAI score of >100 points; patients with baseline CDAI score 220–248 were considered to have had a clinical response if a CDAI score of <150 was present. At week 8, patients either transitioned to the UNITI maintenance study (see below) or were followed to week 20. Seven hundred and forty-one patients had had a history of anti-TNF therapy failure either primary nonresponse, secondary nonresponse or intolerance to at least one anti-TNF agent. Primary and secondary endpoints were met at both intravenous doses of ustekinumab. 33.7 % of the ∼6 mg/kg and 34.3 % of the 130 mg ustekinumab groups versus 21.5 % in placebo (P = 0.003 and 0.002, respectively) achieved clinical response at week 6. 20.9 % of the ∼6 mg/kg group and 15.9 % of the 130 mg ustekinumab group versus 7.3 % on placebo (P < 0.001, P = 0.003, respectively) were found to be in clinical remission (CDAI <150) at week 8. 37.8 % of the ∼6 mg/kg and 33.5 % of the 130 mg ustekinumab groups, versus 20.2 % on placebo (each P ≤ 0.001) had a clinical response at week 8. Both intravenous ustekinumab induction doses compared to placebo resulted in significant improvements in CDAI, IBDQ, CRP, fecal lactoferrin, and calprotectin. AEs, SAEs, and infections were similar in the treated and placebo groups. One opportunistic infection (Listeria meningitis) was reported in the ∼6 mg/kg UST group; otherwise no tuberculosis, malignancies, deaths, or major adverse cardiovascular events occurred in ustekinumab treated patients through the week 20 observation.

UNITI-2 (NCT01369342) is identical in design to UNITI-1 and involves patients who have failed conventional treatment (corticosteroids, immunomodulators) or who are corticosteroid dependent without previous failure or intolerance to TNF antagonist therapy. The data were recently presented at the American College of Gastroenterology (Oct 2015 [13]). Six hundred and twenty-eight patients with moderate to severely active Crohn’s disease were randomized to receive a single dose of IV placebo (n = 210), 130 mg of ustekinumab (n = 209) or weight-based tiered dosing of 6 mg/kg of ustekinumab (n = 209). The primary endpoint was clinical response at 6 weeks and at 8 weeks, patients either transitioned to the maintenance study or were followed through to 20 weeks. 51.7 % of patients who received 130 mg of ustekinumab and 55.5 % of patients who received 6 mg/kg of ustekinumab vs. 28 % of patients who received placebo (P < 0.001) achieved a clinical response at 6 weeks. 47 % of patients who received 130 mg of ustekinumab and 58 % of patients who received 6 mg/kg of ustekinumab vs. 32 % of patients who received placebo (P < 0.001) achieved clinical response at week 8. 31 % who received 130 mg of ustekinumab and 40 % of patients who received 6 mg/kg of ustekinumab achieved clinical remission at 8 weeks. Adverse events and serious adverse events were similar between the groups and no malignancies, deaths, opportunistic infections or tuberculosis occurred in patients treated with ustekinumab.

Patients with a clinical response to IV ustekinumab in UNITI-1 or UNITI-2 as mentioned above were eligible for enrollment in the maintenance trial, IM-UNITI (NCT01369355). This study is still ongoing [14]. Patients will be randomized to 90 mg of ustekinumab every 8 weeks, every 12 weeks, or placebo. Patients who receive placebo or ustekinumab every 12 weeks and who lose response are eligible to cross over to receive ustekinumab 90 mg every 8 weeks. The primary outcome will be clinical remission at week 44. Secondary endpoints clinical remission in patients who have previously failed TNF antagonists, clinical response, and corticosteroid-free remission at week 44. Patients who are continuing to do well at week 44 will be eligible to continue to receive ustekinumab in the long-term extension study with follow-up to 3 additional years.

In contrast to IL-12 inhibition, IL-23 inhibition has been previously shown to be associated with a decreased incidence of tumor formation [19]. In addition, there have been concerns regarding the safety of ustekinumab and/or briakinumab regarding the incidence of serious infections and major adverse cardiovascular events [19]. Therefore, it is thought that IL-23-specific antagonism may provide similar or greater efficacy than blocking IL-12/23p40 and without the potential risks associated with blocking IL-12. Accordingly, a human IgG2 monoclonal antibody called AMG139 was developed to specifically bind to the IL-23 p19 unit and block binding of IL-23 specifically to its receptor. A phase I trial was just completed assessing the safety and tolerability of AMG139 following the administration of multiple intravenous (IV) or subcutaneous (SC) doses in healthy subjects and in subjects with mild to severe CD [20].

Phase IIb studies are ongoing at the writing of this chapter.

BI 655066 is a monoclonal antibody that also targets IL-23p19. It is being investigated as a subcutaneous drug in both psoriasis and Crohn’s disease. A proof of concept, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II dose-ranging study of BI 655066 in patients with moderately to severely active Crohn’s disease is ongoing. The primary outcome measure is clinical remission at week 12, defined as a CDAI score of <150. Secondary outcome measures include CDEIS remission, CDEIS response, mucosal healing, deep remission, and clinical response at week 12 [21]. There is another ongoing an open-label, single-group, long-term safety extension trial ongoing for subjects who responded to treatment with BI 655066 in a preceding trial [22].

PF-04236921 is a monoclonal antibody against IL-6. A phase II placebo-controlled study has been completed to evaluate the safety and efficacy of this subcutaneously administrated antibody in patients with active CD (the ANDANTE study) [26]. There were limitations of the study including early termination which led to small numbers of participants and technical problems with measurement resulting in unreliable or uninterpretable data.

Phase I/II studies are ongoing at the time of writing of the chapter.

Tralokinumab (CAT-354) is an IL-13-specific human immunoglobulin G4 monoclonal antibody that binds to and neutralizes IL-13 [31, 32]. Tralokinumab is being evaluated in phase III clinical studies in patients with asthma and in a phase II study in idiopathic pulmonary fibrosis and may be a treatment for UC.

In a phase IIa, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, 111 patients with UC (total Mayo score ≥6) were randomized to tralokinumab 300 mg subcutaneous or placebo [33]. The primary endpoint of clinical response at week 8 was 38 % (21/56) for tralokinumab vs. 33 % (18/55) for placebo (P = 0.406). Clinical remission rate at week 8 was 18 % (10/56) vs. 6 % (3/55) (P = 0.033) and mucosal healing rate was 32 % (18/56) vs. 20 % (11/55) (P = 0.104) for tralokinumab vs. placebo.

QAX576 is a highly potent and specific inhibitor of human IL-13 activity in cell-based in vitro assays. It has been used to treat eosinophilic esophagitis with success [34] and studied in asthma and idiopathic pulmonary fibrosis.

A phase II study to assess the safety and efficacy of intravenously administered QAX576 in patients with fistulizing Crohn’s disease has been completed [35]. Another phase II study to test the safety and efficacy of the drug in the treatment of perianal fistulas has also been completed [36]. Results are not available of either of the studies.

Bertilimumab is a fully human, IgG₄-type monoclonal antibody that blocks the activity of a protein called eotaxin-1. Eotaxin-1 plays an important role in inflammation and causes eosinophils to migrate towards sites of inflammation where they become activated and release substances that result in tissue damage and enhance inflammation.

A randomized, double blind, placebo-controlled, parallel-group, multicenter study in adult patients with active moderate to severe UC is ongoing. Patients are currently being and eligible patients will be randomly assigned in a 2:1 ratio to one of two treatment groups, bertilimumab 10 mg/kg intravenously or matching placebo, respectively [37].

Vidofludimus (4SC-101) is a novel oral immunomodulatory drug that inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro and inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation [38].

ATR-107 is a fully human anti-IL-21 receptor (IL-21R) monoclonal antibody designed to block IL-21 from binding and activating the receptor as a novel approach to treatment of systemic lupus erythematosus and other autoimmune diseases [39–41]. The ATR-107 target, IL-21R, is expressed on many lymphoid cells, including B cells, activated T cells, natural killer cells, monocytes and dendritic cells and thus ATR-107 is expected to block the effects of IL-21 activation of its receptor (enhanced proliferation of lymphoid cells, B cell differentiation to memory cells and plasma cells, and development of T helper type 17 (Th17) cells) [42, 43]. In addition, anti-inflammatory efficacy resulting from IL-21R blockade has been observed in animal models [44].

Phase I studies are ongoing at the writing of this chapter.

NNC0114-0006 is an anti-IL-21-antibody. A randomized, double-blind, placebo-controlled, parallel-group trial phase II study to assess clinical efficacy and safety of NNC0114-0006 in subjects with active Crohn’s disease has been completed. Results are not yet known.

Tofacitinib (CP-690,550) is an oral small molecule inhibitor of JAK 1 and 3. In vitro studies have shown that it interferes with Th2 and Th17 cell differentiation and blocks the production of IL-17 and IL-22 [48].

In a phase II, double-blind, placebo-controlled trial, the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis was evaluated [49]. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks and occurred in 32 %, 48 %, 61 %, and 78 % of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.39), 3 mg (P = 0.55), 10 mg (P = 0.10), and 15 mg (P < 0.001), respectively – compared with 42 % of patients receiving placebo. Clinical remission (Mayo score ≤2 with no subscore >1) at 8 weeks occurred in 13 %, 33 %, 48 %, and 41 % of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.76), 3 mg (P = 0.01), 10 mg (P < 0.001), and 15 mg (P < 0.001), respectively, as compared with 10 % of patients receiving placebo. Treatment with the drug resulted in reduced C-reactive protein and fecal calprotectin levels.

Tofacitinib was also evaluated in patients with moderate to severe active CD. Patients were randomized to receive tofacitinib twice daily for 4 weeks at doses of 1 mg, 5 mg, 15 mg, or placebo [50]. The primary endpoint was not met in this phase II trial in CD patients receiving tofacitinib, but the placebo response rate was high. Although no significant clinical differences were observed between actively treated patients and placebo, a reduction in CRP and fecal calprotectin levels among patients given 15 mg tofacitinib twice daily indicated its biologic activity. The primary endpoint was clinical response at week 4 and the rates were as follows: 36 % (P = 0.467), 58 % (P = 0.466), and 46 % (P ≥ 0.999) in those patients given 1, 5, or 15 mg tofacitinib twice daily versus 47 % given placebo. A secondary endpoint was clinical remission at week 4 and this was seen in 31 % (P = 0.417), 24 % (P = 0.776), and 14 % (P = 0.540) of patients given 1, 5, and 15 mg tofacitinib, versus 21 % of patients given placebo. As the clinical response was not significant, the trial was negative. However, the placebo response and remission rates were unexpectedly high and in addition, the reduction in fecal calprotectin and C-reactive protein levels among patients receiving 15 mg tofacitinib twice daily suggested biologic activity of the drug. A repeat phase II trial with stricter inclusion criteria defining active Crohn’s disease is ongoing [51].

There is currently an ongoing multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluating tofacitinib as a maintenance therapy in patients with ulcerative colitis. Patients will either be given placebo orally twice daily, tofacitinib 5 mg orally twice daily or tofacitinib 10 mg orally twice daily. The primary endpoint is the proportion of subjects in remission at week 52. Secondary outcomes that will be measured is the proportion of patients with mucosal healing at week 52 and number of patients in sustained steroid free remission [52].

GLPG0634, has been shown to selectively inhibit JAK1-dependent signaling in cellular and whole blood assays as well as showed remarkable efficacy in collagen induced arthritis disease models for RA in both mouse and rat [55].

There is currently an ongoing phase II clinical trial evaluating the efficacy, safety and tolerability and pharmacokinetics of GLP0634 on Crohn’s disease during a 20-week period of time [56].

GED0301 is an antisense oligonucleotide targeting SMAD7 and is an oral gastro-resistant compound with a pH-dependent, delayed-release of the oligonucleotide in the terminal ileum and right colon.

A phase I clinical trial was performed which showed that GED0301 in active, steroid dependent/resistant CD patients resulted in a clinical benefit in all patients [62, 63].

In a placebo-controlled phase II study in patients with active CD [64], patients were randomized to receive induction treatment with different doses of GED0301 (Mongersen) or placebo for 2 weeks. The primary endpoint was clinical remission and this was seen in 55.0, 65.1, and 9.5 % of patients receiving Mongersen 40 mg/day, 160 mg/day, or placebo (p < 0.0001, for both comparisons) at 15 days and maintained for ≥2 weeks. Adverse events were similar across the treatment groups.

This promising molecule is now being investigated in larger trials [51].

BMS-936557 (Eldelumab) is a fully human, monoclonal antibody to CXCL10. A phase I, open-label, dose-escalation study of MDX-1100 was been performed in patients with UC using MDX-1100 [54]. The primary objective of this was to evaluate the safety of single doses of the drug in patients with ulcerative colitis having exacerbation on stable doses of standard therapy. Patients were off anti-TNF therapy for at least 8 weeks prior to the study. Cohorts of patients were given a single infusion of the drug at doses of 0.3, 1.0, 3.0, or 10 mg/kg and were followed for at least 70 days post infusion. A clinical response was defined as UCDAI decrease by ≥3 points at day 29 compared to baseline. Patients who responded were allowed to receive up to three additional infusions at the time of relapse. Peripheral blood mononuclear cells and colon biopsy specimens were studied for expression of CXCL10 and CXCL10-induced proteins. Three patients in the 1.0 mg/kg and two patients in the 3.0 mg/kg cohorts had clinical responses; however, one patient in the 1.0 mg/kg cohort also was started on concomitant immunomodulator therapy 2 months prior to MDX-1100 administration. Two of three responding patients who relapsed after 50, 85, and 93 days, respectively who had then been given additional MDX-1100 doses responded to re-treatment. One patient in the 3.0 mg/kg cohort was admitted to the hospital for anemia and worsening UC requiring a colectomy but otherwise the drug was well tolerated.

Mayer, and colleagues in 2014 published data from an 8-week phase II, double-blind, multicenter, randomized study in patients with active ulcerative colitis [65]. Patients with moderately to severely active UC were given either BMS-936557 (10 mg/kg) or placebo intravenously every other week. The primary endpoint was the rate of clinical response at day 57 and secondary endpoints were clinical remission and mucosal healing rates. Fifty-five patients received the drug and 54 patients received placebo. Primary and secondary endpoints were not met. However, what was found was that with higher steady-state trough levels of BMS-936557 (108–235 μg/ml), there was an increased clinical response (87.5 % vs. 37 % p < 0.001) and histological improvement (73 % vs. 41 % P = 0.004) compared to placebo. Infections occurred in 12.7 % of BMS-936557 treated patients and 5.8 % placebo-treated patients. Two patients (or 3.6 %) discontinued due to adverse events.

In a phase IIb study of patients with ulcerative colitis [65, 72] patients (n = 121) with CDAI ≥220 and ≤450 were randomly assigned 1:1:1 to placebo or intravenous eldelumab 10 or 20 mg/kg given on days 1 and 8 and then every other week. Endoscopy videos were collected for all patients at baseline. Patients with a score of 2–3 on the ulcerated surface subscore of the Simplified Endoscopic Score for Crohn’s Disease (SES-CD) in at least 1 of 5 segments had a follow up endoscopy at 11 weeks. A central reader read endoscopies in a blinded fashion. Trial endpoints included week 11 clinical response which was defined as a reduction in CDAI 100 points from baseline or an absolute CDAI score <150, clinical remission which was defined as CDAI <150 and endoscopic improvement. There was a trend towards efficacy as remission and response rates at week 11 for the 10 mg/kg dose, 20 mg/kg and placebo groups were 22.5 and 47.5 %, 29.3 and 41.5 %, vs. 20 and 35 % and were higher in anti-TNF-naive patients versus those patients who experienced anti-TNF failures. Both drug groups achieved a greater reduction from baseline in mean endoscopy scores compared to placebo and were similar in the eldelumab-treated groups across the anti-TNF-naive and anti-TNF failure subgroups [73].