Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results From the UNIFI Long-Term Extension

Introduction: Ustekinumab (UST) is approved for moderate to severe ulcerative colitis (UC) treatment. Here we report final results of the UNIFI long-term extension (LTE) study with efficacy and safety through 4 years (yrs) of subcutaneous (SC) UST treatment. Methods: Overall, 523 intravenous UST induction responders were randomized to SC maintenance therapy: 175 SC placebo (PBO); 172 UST 90mg every 12 weeks (q12w); 176 UST 90mg q8w. The nonrandomized population included UST induction nonresponders at week (wk) 8 who received SC UST, responded 8wks later and continued receiving UST q8w, and PBO induction responders continuing PBO. Patients (pts) completing wk44 were eligible to continue treatment in LTE. PBO pts discontinued after study unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Efficacy was evaluated in UST-randomized pts (n=284) using symptomatic remission (Mayo stool frequency subscore 0/1 and rectal bleeding subscore 0). Safety was evaluated for all 588 pts treated in LTE (randomized/nonrandomized populations). Results: Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk200 (biologic naïve 67.2%; biologic failure 41.6%; Table); 53.2% achieved corticosteroid-free symptomatic remission at wk200. Overall, 42.7% of biologic failure and 18.8% of biologic naïve pts randomized to UST and treated in the LTE discontinued treatment between wks44 and 200. Among randomized pts who continued UST in the LTE, 67.6% were in symptomatic remission at wk200; 72.9% of those in clinical remission at wk44 were in symptomatic remission at wk200; and 85.1% of pts with observed data at wk200 were in symptomatic remission. Safety events were similar between UST-treated pts and PBO throughout study. Maintenance wks0-220 included 1647.4 (UST) and 301.7 (PBO) pt yrs of follow-up. Safety events per 100 pt yrs of follow-up for UST vs PBO were adverse events (AEs): 214.45 vs 288.04, serious AEs: 7.22 vs 10.61, and serious infections: 2.00 vs 3.31. During the final yr of the LTE, no deaths or major cardiovascular events were reported in UST pts. Among UST pts, 2 cases of colorectal cancer and 1 case of cytomegalovirus were reported. (Figure) Conclusion: Pts receiving SC UST generally maintained clinical benefit through 4 yrs. No new safety signals were observed. (Figure)Figure 1.: Symptomatic Remission of Randomized Patients in Maintenance Who Were Treated in Long-Term Extension (LTE) Through Week 200 (a,b,c). Symptomatic remission: Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0; SC: subcutaneous; q8w: every 8 weeks; q12w: every 12 weeks. a) Patients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit. b) Randomized group at maintenance Week 0 regardless of whether patients had a dose adjustment during the long-term extension. c) Patients who had an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an adverse event of worsening of ulcerative colitis prior to the designated visit were considered not to be in symptomatic remission. Table 1. - Symptomatic remissiona rates during the LTE in randomized patients Analysis 90 mg UST SC q12w b 90 mg UST SC q8w b Overall UST Symptomatic remission in the ITT population c,d,e (treatment failure and missing data nonresponder imputation) Week 44, n/N (%) 107/172 (62.2) 119/176 (67.6) 226/348 (64.9) Week 200, n/N (%) 96/172 (55.8) 96/176 (54.5) 192/348 (55.2) Symptomatic remission in biologic naïve f patients Week 44, n/N (%) 68/95 (71.6) 57/79 (72.2) 125/174 (71.8) Week 200, n/N (%) 62/95 (65.3) 55/79 (69.6) 117/174 (67.2) Symptomatic remission in biologic failure f patients Week 44, n/N (%) 34/70 (48.6) 57/91 (62.6) 91/161 (56.5) Week 200, n/N (%) 30/70 (42.9) 37/91 (40.7) 67/161 (41.6) Corticosteroid-free symptomatic remission in the ITT population c,d,e,g Week 44, n/N (%) 105/172 (61.0) 116/176 (65.9) 221/348 (63.5) Week 200, n/N (%) 94/172 (54.7) 91/176 (51.7) 185/348 (53.2) Symptomatic remission in patients treated in the LTE (treatment failure and missing data nonresponder imputation) d,e Week 44, n/N (%) 117/141 (83.0) 119/143 (83.2) 236/284 (83.1) Week 200, n/N (%) 96/141 (68.1) 96/143 (67.1) 192/284 (67.6) Symptomatic remission up to the time of dose adjustment with treatment failure rules applied in patients treated in the LTE d (modified as observed h ) Week 44, n/N (%) 117/141 (83.0) 119/143 (83.2) 236/284 (83.1) Week 200, n/N (%) 58/65 (89.2) 73/89 (82.0) 131/154 (85.1) AE, adverse event; ITT, intent-to-treat; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; TNF, tumor necrosis factor; UC, ulcerative colitis; UST, ustekinumab.aSymptomatic remission is defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0.bRandomized group at maintenance Week 0 regardless of whether or not patients had a dose adjustment during the long-term extension.cPatients who had a prohibited change in UC medication, an ostomy or colectomy, or used a rescue medication after clinical flare, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the Week 44 visit were considered not to be in symptomatic remission at Week 44.dPatients who had an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC after Week 44 and prior to Week 200, were considered not to be in symptomatic remission at Week 200.ePatients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit.fEfficacy was evaluated only in patients with a history of biologic failure to ≥1 biologic (anti-TNFα or integrin antagonist) and those who were biologic naïve; 7 UST q12w and 6 UST q8w patients who were biologic-experienced but did not have documentation of a history of biologic failure are excluded.gPatients who had a missing value in corticosteroid use had their last value carried forward.hThe observed data excluded patients with missing data and had not had treatment failure (i.e., an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC) prior to the designated visit.