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Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract which has a significant disease burden in Ireland, affecting around 20,000, with approximately six new diagnoses per 100,000 per year and this has been increasing over the last 50 years. Usual treatment regimens consist of glucocorticoids, immunosuppressants and tumour necrosis factor (TNF) antagonists.
However, the management of inflammatory bowel disease (IBD), and Crohn’s disease in particular, has changed significantly in recent times. As recently as the late 1990s, standard therapies included mainly glucocorticosteroids, antibiotics and immunosuppression with azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate. These therapies, especially glucocorticosteroids, mainly controlled symptoms without modifying the long-term disease course.
The advent of biologics and targeted monoclonal antibody therapy has been revolutionary for keeping what can be a debilitating condition under control, effectively reducing rates of surgery. As only roughly half of Crohn’s disease sufferers maintain remission of their disease for over one year, there is a clear unmet need for further treatment options.
A recent study published in the New England Journal of Medicine (November 2016) looked at the efficacy of one of these monoclonal antibody therapies, ustekinumab, as an intravenous induction therapy in two populations with moderately to severely-active Crohn’s disease. The effectiveness of ustekinumab was also evaluated as subcutaneous maintenance therapy.
Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 that has been approved for use in the treatment of psoriasis and psoriatic arthritis. In previous trials involving patients with psoriasis in which ustekinumab was administered subcutaneously for up to five years, the drug was not associated with an increased risk of serious adverse events.
The study in question followed on from phase 2b trials. These trials showed intravenous ustekinumab induction therapy in patients with Crohn’s disease that was refractory to treatment with TNF antagonists provides a significant benefit in terms of clinical response but not remission, and subcutaneously-administered maintenance doses of ustekinumab were efficacious during a period of 22 weeks. The study concerns a phase 3 development programme for the treatment of Crohn’s disease with ustekinumab, consisting of two eight-week induction trials (UNITI-1 and UNITI-2) and one 44-week maintenance trial (IM-UNITI), representing 52 weeks of therapy.
UNITI-1 and UNITI-2 were conducted at 178 sites in 23 countries and 175 sites in 23 countries, respectively, and IM-UNITI was conducted at 260 sites in 27 countries. All were double-blind, placebo-controlled trials performed from July 2011 through June 2015.
In UNITI-1, patients were required to have received one or more TNF antagonists at approved doses and to have met the criteria for primary non-response (the absence of a response) or secondary non-response (a response that was not maintained) or to have had unacceptable side-effects.
In UNITI-2, patients were required to have had treatment failure or unacceptable side-effects when treated with immunosuppressants (ie, azathioprine, mercaptopurine or methotrexate) or glucocorticoids. Patients in UNITI-2 could have previously received one or more TNF antagonists, provided they had not had unacceptable side-effects and had not met the criteria for primary or secondary non-response to treatment. They were also required to have objective evidence of active Crohn’s disease, which was defined as either a serum level of C-reactive protein (CRP) of more than 3.0mg per litre, a faecal calprotectin level of more than 250mg/kg, or endoscopic ulcerations in the ileum, the colon, or both. Patients who completed UNITI-1 or UNITI-2 could enrol in the IM-UNITI maintenance trial.
At week 0, patients in both induction trials were randomly assigned, in a 1:1:1 ratio, to receive a single intravenous infusion of 130mg of ustekinumab, a weight-range based dose that approximated 6mg of ustekinumab per kilogram (kg) of body weight, or placebo.
In the maintenance trial, patients who had a response to ustekinumab induction therapy at week eight were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injections of 90mg of ustekinumab every eight weeks, 90mg of ustekinumab every 12 weeks, or placebo through week 40.
In both induction trials, the primary end-point was clinical response at week six, which was defined as a decrease from baseline in Crohn’s Disease Activity Index (CDAI) score of at least 100 points or a total CDAI score less than 150. Major secondary end-points were clinical remission at week eight (CDAI score <150), clinical response at week eight, and a decrease from baseline in CDAI score of at least 70 points at weeks three and six.
In the maintenance trial, the primary end-point was clinical remission at week 44 (CDAI score <150). Major secondary end-points at week 44 were clinical response (decrease in CDAI score of ≥100 points from week 0 of induction or clinical remission), maintenance of remission among patients in remission at week 0 of the maintenance trial, glucocorticoid-free remission, and remission in patients who met the criteria for primary or secondary non-response or who had unacceptable side-effects when treated with a TNF antagonist (UNITI-1 population).
In UNITI-1, the percentages of patients who had a response at week six were significantly higher in the groups that received ustekinumab at a dose of either 130mg or 6mg per kg (34.3 per cent and 33.7 per cent, respectively) than in the placebo group (21.5 per cent).
In UNITI-2, the percentages of patients who had a response at week six were also significantly higher in the groups that received ustekinumab at a dose of either 130mg or 6mg per kg (51.7 per cent and 55.5 per cent, respectively) than in the placebo group (28.7 per cent).
The rates at which patients met the criteria for all major secondary efficacy end-points were significantly higher in the two ustekinumab groups than in the placebo group.
In IM-UNITI, the percentage of patients who were in remission at week 44 was significantly higher in the groups that received 90mg of ustekinumab every eight weeks or every 12 weeks (53.1 per cent and 48.8 per cent, respectively) than in the placebo group (35.9 per cent).
In terms of adverse events or serious infections, in all three studies, there was no significant increase in risk with ustekinumab compared to placebo.
This cohort was also followed for the subsequent two years in a long-term efficacy study up to 96 weeks. Eighty per cent of patients remained on ustekinumab at two years, with efficacy maintained within study end-points. While the TNF failure and non-failure patients retained remission, the non-failure patients did so to a greater degree. There was no increase in adverse events or serious infections compared to placebo up to two years.
Concurrently with the three studies, endoscopic evaluations of response were also evaluated. Ustekinumab showed a significantly reduced Simple Endoscopic Score for Crohn’s Disease (SES-CD) than placebo at week eight of induction and in the maintenance group who received eight week dosing, though interpretation of the latter is limited by a small sample size.
This large, multi-centre study demonstrates encouraging results in the struggle against Crohn’s disease. Current biologic therapy for Crohn’s disease includes the TNF-antagonists infliximab, adalimumab and certolizumab as first-line, with the other option of the anti-integrins natalizumab and vedolizumab. Currently, certolizumab and natalizumab are licensed only in the USA.
In comparison with the agents we currently have for treatment of refractory Crohn’s disease, ustekinumab compares well. For initial response at week six, ustekinumab demonstrated rates of 33.7 per cent (6mg/kg) to 34.3 per cent (130mg) versus 21.5 per cent in placebo, which is similar to vedolizumab (39.2 per cent vs 22.3 per cent with placebo in the GEMINI-3 trial).
However, ustekinumab shows higher rates of clinical remission at week 44, with response rates of 38.6 per cent (90mg q12w) to 41.1 per cent (90mg q8w) compared to vedolizumab, with rates of 27.3 per cent (every four-week dosing) to 28 per cent (every eight-week dosing), though one has to consider that the placebo response rates were higher with ustekinumab (26.2 per cent vs 12.8 per cent).
The study shows that ustekinumab is a valuable tool for management of Crohn’s disease in patients refractory to TNF-antagonists or other immunosuppression. Given the non-response rate to anti-TNF can be as high as 33 per cent, and loss of response can be anywhere from 10 per cent to 50 per cent per year, it is imperative that we develop more and more effective tools to manage these difficult cases.
Given its proven benefit in psoriasis, it may be the preferred option in Crohn’s disease patients with concurrent psoriasis or the particular subset of patients that develop TNF antagonist-induced psoriasis. It also has been shown to have a safe profile from an adverse event and infection point of view and perhaps even superior to TNF antagonists.
Intravenous ustekinumab induces response and remission in patients with moderately-to-severely active Crohn’s disease that is refractory to either TNF antagonists or conventional therapy. Among patients who had a response to intravenous induction, subcutaneous ustekinumab administered at a dose of 90mg every eight weeks or every 12 weeks was more effective than placebo for maintaining remission.
It seems it will become an effective and safe advance in current therapeutic options.