Ustekinumab in CD
The Phase IIb CERTIFI trial evaluated the efficacy of ustekinumab in adults with moderate-to-severe active CD who had previously failed to respond to anti-TNF agents.24 The primary endpoint was clinical response (≥100 points reduction from baseline CD Activity Index [CDAI] score). At induction, 526 patients received a single IV ustekinumab infusion at doses of 1, 3, or 6 mg/kg versus placebo. The primary endpoint was reached in 36.6%, 34.1%, and 39.7% of cases receiving ustekinumab (for 1, 3, and 6 mg/kg ustekinumab, respectively), as compared with 23.5% for placebo (p=0.005 for the comparison with the 6 mg/kg group). There were no statistically significant differences in the rates of clinical remission (CDAI <150). During the maintenance phase, 145 patients with clinical response were re-randomized at week 8 to receive SC injections of ustekinumab 90 mg or placebo at weeks 8 and 16. Rates of clinical response and clinical remission were significantly increased with ustekinumab as compared with placebo (69.4% versus 42.5%, p<0.001 and 41.7% versus 27.4%, p=0.03, respectively) at week 22.
The approval of ustekinumab for the treatment of moderate-to-severe CD was based on data from three pivotal Phase III trials which showed that treatment with ustekinumab induced clinical response and maintained clinical remission in a significantly greater proportion of patients with moderate-to-severe active CD after 1-year therapy compared to placebo: two induction trials (UNITI-1 and -2) and a maintenance trial (IM-UNITI trial).25
The UNITI-1 trial included patients with CD who were refractory or intolerant to anti-TNF (n=741), and the UNITI-2 trial included patients with CD refractory or intolerant to conventional therapy, glucocorticoids, or immunomodulators (n=628). Patients were randomly assigned to receive a single IV dose of ustekinumab (130 mg), a weight-range-based dose of ustekinumab (6 mg/kg), or placebo. Clinical response at week 6 (decrease from baseline in CDAI score of ≥100 points or a CDAI score <150) was assessed. In both trials, those patients receiving ustekinumab had a significantly higher rate of response after 6 weeks than placebo: 34.3%, 33.7%, and 21.5%, respectively (p≤0.003) in UNITI-1 and 51.7%, 55.5%, and 28.7% respectively (p<0.001) in UNITI-2.
Patients who completed the induction phase and had a clinical response to ustekinumab (n=397) were included in the IM-UNITI trial. They were randomly assigned to receive SC maintenance injections of ustekinumab (90 mg either every 8 weeks or every 12 weeks) or placebo. After 44 weeks, more patients receiving ustekinumab were in remission (CDAI score <150) than those receiving placebo: 53.1% and 48.8% of patients receiving ustekinumab every 8 weeks or every 12 weeks, as compared with 35.9% of those receiving placebo (p=0.005 and p=0.04, respectively). The main results of this trial are summarized in Table 1.
Table 1 Phase III randomized controlled trial with ustekinumab in patients with moderate-to-severe Crohn’s disease
Notes: Data from Feagan et al.25 UNITI-1 and -2, two induction trials; IM-UNITI, maintenance trial.
Abbreviations: CDAI, Crohn’s Disease Activity Index; IV, intravenous; SC, subcutaneous; TNF, tumor necrosis factor.
A recent Cochrane review concluded that high-quality evidence suggests that ustekinumab, at an optimal dose of 6 mg/kg, is effective for induction of clinical remission and clinical improvement in patients with moderate-to-severe CD.26
Apart from randomized clinical trials, retrospective studies have shown the clinical efficacy of ustekinumab in around two-thirds of patients of real-life cohorts consisting of patients who had failed to respond to anti-TNF agents.27,28 Data on reduction of C-reactive protein or improvement of endoscopic lesions have also been obtained.29,30 Endoscopic (mucosal healing) or radiographic response was observed in >50% of patients with refractory CD in a retrospective study.31
Moreover, ustekinumab appears to be highly effective in the treatment of the paradoxical psoriasis-like lesions induced by the use of anti-TNF agents in patients with CD.32–35 These are the most frequent dermatologic adverse effects in CD patients receiving anti-TNF agents.