Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial.

BACKGROUND: Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. METHODS: We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. FINDINGS: Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). INTERPRETATION: Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. FUNDING: Janssen Research and Development.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.