UNIFI Long-Term Extension Shows Safety, Efficacy of Ustekinumab for Ulcerative Colitis Through 4 Years

Waqqas Afif, MD

Credit: McGill University

Long-term subcutaneous maintenance therapy with ustekinumab every 8 and 12 weeks can maintain clinical and endoscopic outcomes through 4 years, according to the final efficacy and safety results of the UNIFI long-term extension study in patients with ulcerative colitis (UC).

In patients who responded to intravenous ustekinumab induction, therapy was safe and effective at maintaining symptomatic remission, providing clinical and endoscopic benefit to patients through 4 years of treatment without the need for concomitant corticosteroids and with no new safety signals reported.¹

“Due to the life-long nature of UC, long-term treatment is often required to induce and maintain remission. Advances in biologic therapies have allowed a paradigm shift in treatment goals from controlling symptoms to endoscopic healing, thus improving long-term outcomes,” wrote Waqqas Afif, MD, associate professor in the division of gastroenterology at McGill University, and colleagues.¹

A human interleukin (IL)-12 and IL-23 antagonist, ustekinumab blocks the p40 subunit shared by both cytokines and inhibits their interaction with the IL-12Rβ1 receptor, effectively reducing inflammation and altering the body's immune response. It was first granted US Food and Drug Administration (FDA) approval for the treatment of psoriasis in 2009, though it has since gained further indications for psoriatic arthritis, Crohn disease, plaque psoriasis, and most recently, UC.^2,3

A randomized, double-blind, placebo-controlled, parallel-group, phase 3 protocol, UNIFI included an 8-week induction study and a 44-week maintenance study to assess the efficacy and safety of ustekinumab as an intravenous infusion in patients with moderately to severely active UC and as a subcutaneous administration in patients who demonstrated a clinical response to induction treatment. Results from the induction and maintenance studies were used to support ustekinumab’s FDA approval for UC in 2019. The long-term extension began after week 44 of maintenance and spanned through week 220 at the final safety visit.^1,2

All ustekinumab induction responders who completed 44 weeks of maintenance treatment were eligible to continue treatment in the long-term extension. The maintenance study was unblinded after analysis of the week 44 endpoints. Of note, ustekinumab subcutaneous 90 mg was previously shown to be safe and effective in patients with moderate-to-severe UC through 3 years of maintenance therapy.^1,4

At maintenance baseline, 523 intravenous ustekinumab induction responders were randomized to subcutaneous maintenance therapy, with 175 in the subcutaneous placebo group, 172 in the ustekinumab 90 mg every 12 weeks group, and 176 in the ustekinumab 90 mg every 8 weeks group. Of these patients, 399 (76.3%) continued treatment in the long-term extension, including 284 patients who continued ustekinumab treatment: 141 in the 12-week group and 143 in the 8-week group.¹

C-reactive protein (CRP) and fecal calprotectin were assessed every 3 months in the long-term extension through week 200. The Inflammatory Bowel Disease Questionnaire (IBDQ) was used to assess disease-specific health-related quality of life every 6 months through week 200 across 4 dimensional scores: bowel, systemic, social, and emotional.¹

Efficacy endpoints related to the Mayo score, including full Mayo clinical remission, full Mayo clinical response, modified Mayo response, and endoscopic improvement, were evaluated at week 200. Adverse events, serious adverse events, infections, serious infections, and laboratory assessments were assessed from week 44 through the final safety visit during week 220.¹

Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline, 55.2% were in symptomatic remission at week 200, with similar proportions across the 8-week and 12-week treatment groups. Investigators pointed out a greater proportion of biologic naïve patients (67.2%; n = 117) were in symptomatic remission than those with a history of biologic failure (41.6%; n = 67). Additionally, 96.4% of these participants were corticosteroid-free.¹

Investigators also noted patients who remained in the study through week 200 had high rates of full Mayo clinical remission, full Mayo clinical response, and modified Mayo score response that were maintained from the earlier maintenance study. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (n = 71) in the 12-week group and 79.8% (n = 67) in the 8-week group had endoscopic improvement.¹

Absolute stool numbers remained low and the proportion of patients with an absolute stool number ≤3/day was maintained through week 200. The proportion of patients with Mayo stool frequency subscores of 0 or 1, or no rectal bleeding, and concentrations of median serum CRP, fecal calprotectin, and IBDQ remission were maintained from weeks 44 to 200.¹

From week 156 to the final safety visit at week 220, no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, ulcerative colitis worsening, and upper respiratory tract infections were the most frequently reported adverse events.¹

“In this population of patients with treatment-refractory moderate-to-severe UC, patients who responded to ustekinumab IV induction and received SC maintenance treatment generally maintained clinical benefit through 4 years. The safety profile of ustekinumab maintenance treatment was consistent with the known long-term safety profile in other approved indications,” investigators concluded.¹

References:

1. Afif W, Arasaradnam RP, Abreu MT, et al. Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results of the UNIFI Long-term Maintenance Study. Am J Gastroenterol. doi:10.14309/ajg.0000000000002621
2. Janssen. Janssen Announces U.S. FDA Approval of STELARA® (ustekinumab) for the Treatment of Adults with Moderately to Severely Active Ulcerative Colitis. Media Center. October 21, 2019. Accessed January 12, 2024. https://www.jnj.com/janssen-announces-u-s-fda-approval-of-stelara-ustekinumab-for-the-treatment-of-adults-with-moderately-to-severely-active-ulcerative
3. Colquhoun M, Kemp AK. Ustekinumab. StatPearls. March 27, 2023. Accessed January 12, 2024. https://www.ncbi.nlm.nih.gov/books/NBK570645/
4. Abreu MT, Rowbotham DS, Danese S, et al. Efficacy and Safety of Maintenance Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension. J Crohns Colitis. 2022;16(8):1222-1234. doi:10.1093/ecco-jcc/jjac030