A multicentre, double-blind, placebo-controlled phase 3 study of ustekinumab, a human interleukins-12/23p40 mab, in moderate-severe Crohn's disease refractory to anti-tumour necrosis factor α: UNITI-1

Background: IL 12 and 23 are implicated in the pathophysiology of Crohn's disease (CD). These pro‐inflammatory cytokines are blocked by UST. In a phase 2b study (CERTIFI),1 UST IV induction followed by surveillance colonoscopy (SC) maintenance was shown effective in moderate‐severe CD refractory to anti‐tumour necrosis factor (TNF) therapy. This phase 3 study examined efficacy and safety of IV UST induction in these patients (pts). Methods: Pts with moderate‐to‐severely active CD(CDAI 220‐450) who previously failed or were intolerant to at least 1 TNF antagonist were randomised (1:1:1) at Wk0 to a single dose of IV placebo (PBO), UST 130 mg, or weight‐based tiered UST dosing approximating 6 mg/kg (260mg [wt ≤ 55kg], 390 mg [wt > 55kg and ≤ 85 kg]), 520 mg [wt > 85 kg]). The primary endpoint was clinical response at week 6, defined as reduction from baseline in the CDAI score of ≥ 100 points; pts with baseline CDAI score ≥ 220 to ≤ 248 points were considered in clinical response if a CDAI score of <150 was present. At week 8, patients either transitioned to the IM‐UNITI maintenance study or were followed to week 20. Results: The 741 randomised pts had a history of TNF‐antagonist failure, with baseline median CDAI of 317, C‐reactive protein (CRP) of 9.9 mg/L, and prior disease duration of 10.1 years. Of these, 51% had previously failed ≥ 2 anti‐TNFs with 29.1%, 69.4%, and 36.4% of pts, respectively. Clinical response at week 6 (primary endpoint) was observed in 33.7% of the ∼6 mg/kg and 34.3% of the 130 mg UST groups vs 21.5% in the PBO group (p = 0.003 and 0.002, respectively). Clinical remission (CDAI < 150) at week 8 was observed in 20.9% of the ∼6 mg/kg group and 15.9% of the 130 mg UST group vs 7.3% on PBO (p < 0.001, p = 0.003, respectively). Clinical response at week 8 was seen in 37.8% of the ∼6 mg/kg and 33.5% of the 130 mg UST groups vs 20.2% on PBO (each p ≤ 0.001). Proportion of patients with 70‐pt CDAI response at week 6 was 43.8% of the ∼6 mg/kg and 46.1% of the 130 mg UST groups vs 30.4% on PBO (p = 0.002 and < 0.001, respectively), and at the first post‐baseline week 3 visit, 40.6% in ∼6mg/ kg and 38.4% in the 130 mg UST groups vs 27.1% on PBO (p = 0.001 and p = 0.009, respectively), the final major secondary endpoint. Both IV UST induction doses additionally resulted in significant improvements in CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ), C‐reactive protein (CRP), faecal lactoferrin, and calprotectin vs IV PBO. Proportions of pts with adverse events (AEs), serious adverse events (SAEs), and infections were similar in the UST and PBO groups. One opportunistic infection (listeria meningitis) was reported in the ∼6 mg/kg UST group. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST‐treated pts through week 20. Conclusions: In pts with moderate‐to‐severe CD refractory to 1 or prior TNF‐antagonists, IV UST induced clinical response and remission and was well tolerated throughout induction, confirming the previous positive induction data from CERTIFI.