Ustekinumab Maintenance Therapy for Ulcerative Colitis Safe, Effective at 4 Years: UNIFI-LTE

In a cohort of adults with moderately to severely active ulcerative colitis (UC), long-term maintenance therapy with subcutaneous ustekinumab (Stelara, Janssen) every 8 or 12 weeks was associated with durable improvement in clinical and endoscopic outcomes through 4 years, according to final results of the UNIFI long-term extension (LTE) study.1

Among study participants who responded clinically to ustekinumab induction, nearly two-thirds (64.9%) achieved symptomatic remission after 44 weeks of maintenance therapy, investigators wrote in the American Journal of Gastroenterology. At week 200, the proportion of participants in symptomatic remission was 55.2% of whom the majority (96.4%) were no longer receiving corticosteroids. The researchers reported no new safety signals.

“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

"Advances in biologic therapies have allowed a paradigm shift in treatment goals from controlling symptoms to endoscopic healing, thus improving long-term outcomes.”

Ustekinumab was first granted US Food and Drug Administration (FDA) approval in 2009 for the treatment of psoriasis.2 The human interleukin (IL)-12 and IL-23 antagonist 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.3 Ustekinumab has subsequently been approved for the treatment of psoriatic arthritis and plaque psoriasis in adults and children aged 6 years and older,3 for moderate to severe Crohn disease in adults and,3 in 2019, for moderate to severe UC in adults.2

UNIFI-LTE1

UNIFI is a phase 3 clinical trial program that included an 8-week induction study (single dose of ustekinumab via IV infusion) followed by a 44-week maintenance study (ustekinumab 90 mg via subcutaneous injection every 8 weeks) to assess the efficacy and safety of ustekinumab in persons with moderately to severely UC unresponsive to previous treatments. Results from the induction and maintenance studies were used to support ustekinumab’s FDA approval for UC in 2019.

The current LTE study began after week 44 of maintenance and followed participants through the final safety visit at week 220. All ustekinumab induction responders who completed the 44-week maintenance phase were eligible to continue treatment in the LTE continuing dosing at either 8 or 12 weeks. The maintenance study was unblinded after analysis of the week 44 endpoints.

Investigators assessed C-reactive protein (CRP) and fecal calprotectin every 3 months through week 200, according to the study. The team evaluated participants’ health related quality of life every 6 months using the Inflammatory Bowel Disease Questionnaire (IBDQ) and looking specifically at scores across 4 dimensions: bowel, systemic, social, and emotional.

Using the standard Mayo score to assess efficacy at week 200, Afif and colleagues evaluated full Mayo clinical remission, full Mayo clinical response, modified Mayo response, and endoscopic improvement. All adverse events were assessed from week 44 through the final safety visit.

FINDINGS1

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, according to the study. Afif et al reported that a greater proportion of participants who had been naïve to biologic therapy (67.2%; n = 117) achieved symptomatic remission than those with a history of previous unsuccessful treatment with a biologic agent (41.6%; n = 67). Importantly, they also reported that essentially all of these participants (96.4%) no longer required corticosteroid treatment.1

LTE participants evaluated at 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, the investigators reported. 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.

Further positive results showed that absolute stool numbers remained low, with no change in the proportion of participants with ≤3/day through week 200. The proportion of patients with Mayo stool frequency subscores of 0 or 1, or no rectal bleeding also were maintained through week 200. Afif and colleagues also reported that concentrations of median serum CRP, fecal calprotectin, and IBDQ remission were maintained from weeks 44 to 200.

Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events, according to the study. From week 156 to the final safety visit at week 220, investigators reported no deaths, major adverse cardiovascular events, or tuberculosis in Ustekinumab-treated participants.

“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,” 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. Stewart J. Stelara FDA approval history. Drugs.com. January 28, 2021. Accessed January 15, 2024. https://www.drugs.com/history/stelara.html 3. Janssen Announces U.S. FDA approval of Stelara (ustekinumab) for the treatment of adults with moderately to severely active ulcerative colitis. News release. Johnson & Johnson. October 21, 2019. Accessed January 15, 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