Long-Term Efficacy and Safety of Ustekinumab for Ulcerative Colitis: 4-Year Data from the UNIFI Long-Term Maintenance Study
Rahul Dalal, MD, MPH
Instructor, Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
This summary reviews 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 2024;119(5):910-921.
Access the article for free through The American Journal of Gastroenterology
Correspondence to Rahul Dalal, MD, MPH, Associate Editor. Email: EBGI@gi.org
Keywords: Ustekinumab, ulcerative colitis
STRUCTURED ABSTRACT
Question: What is the long-term (4-year) efficacy and safety of ustekinumab for ulcerative colitis (UC)?
Design: This was a long-term extension of the UNIFI randomized controlled trial comparing ustekinumab to placebo for induction of remission and maintenance of remission of ulcerative colitis. Those who responded to ustekinumab induction and completed 44 weeks of ustekinumab maintenance therapy were eligible for the long-term extension. Patients were followed through week 200, at which time endoscopic assessment was performed.
Setting: The original UNIFI trial enrolled patients from 24 countries.1
Patients: Three hundred and forty-eight UC patients were randomized to ustekinumab, 90mg subcutaneous (subq) every 8 weeks (q8wks) or 90mg subq every 12 weeks (q12wks), during the UNIFI maintenance of remission stage and completed 44 weeks of maintenance therapy were included.
Interventions: Ustekinumab 90 mg subq q12wks (n=172) or 90 mg subq q8wks (n=176). Beginning at week 56 (after 12 week of induction therapy and 44 weeks of maintenance of remission therapy), patients in the q12wks group could undergo dose optimization to receive ustekinumab 90 mg q8wks.
Outcomes: Multiple outcomes were assessed including symptomatic remission (Mayo stool frequency score 0 or 1 and rectal bleeding score of 0), corticosteroid-free symptomatic remission, full Mayo clinical remission (Mayo score <2), full Mayo clinical response (decrease in score by >30% or >3 points), modified Mayo score response (no physician global assessment subscore), and endoscopic improvement, among others. Adverse events and immunogenicity were also assessed.
Data Analysis: Symptomatic remission was evaluated using non-responder imputation for missing data and treatment failure, observed cases analysis, and modified observed case analysis. Safety events were evaluated using event rates per 100 person-years.
Funding: The study was funded by Janssen Research & Development, LLC.
Results: Of 348 study patients, 55.2% achieved symptomatic remission at week 200. Among these, 96.4% were in corticosteroid-free symptomatic remission. Of 171 patients who completed endoscopic evaluations at week 200, approximately 70% in both groups had clinical remission and approximately 80% in both groups had endoscopic improvement (Figure 1). The full Mayo score outcomes at week 200 are presented in Figure 1.
The most frequently observed adverse events included nasopharyngitis, worsening of ulcerative colitis, and upper respiratory tract infections. No deaths, major cardiovascular events, or tuberculosis infection were observed. Four patients did develop opportunistic infections with cytomegalovirus (n=2), oral herpes, (n=1) and Listeria monocytogenes (n = 1). Approximately 5.5% of patients developed anti-drug antibodies, but this did not appear to affect treatment efficacy.
Figure 1. Full Mayo score outcomes at week 200. q8wks, every 8 weeks q12wks; every 12 weeks; SC, subcutaneous.
COMMENTARY
Why Is This Important?
Ustekinumab, which is directed at the p40 subunit shared by interleukin (IL)-12 and IL-23, was the first IL-23 monoclonal antibody approved for the treatment of UC in the US, and is also approved for treatment of adults and pediatric patients with psoriatic arthritis and plaque psoriasis. Data about the long-term durability, efficacy, and safety of this drug class in the UC population was limited, and performance of endoscopy at week 200 enhanced the assessment of efficacy. The UNIFI long-term extension study confirms that ustekinumab is effective in maintaining both steroid-free clinical remission as well as endoscopic response through 4 years of treatment in UC patients.
Importantly, adverse event data over 4 years in the UC population were similar to long-term safety data in the psoriatic arthritis and plaque psoriasis populations. Specifically, minimal opportunistic infections with CMV were observed with no cases of tuberculosis, no major cardiovascular events, and no increase in nonmelanoma skin carcinomas compared to UC patients treated with placebo. Finally, immunogenicity/ development of antibodies to ustekinumab was uncommon (5.5%) and reportedly did not impact treatment efficacy.
Key Study Findings
Outcomes were overall similar between q8wks and q12wks dosing. Long-term safety events were consistent with the known safety profile of ustekinumab in other disease states and immunogenicity was overall uncommon (5%) and inconsequential.
Caution
After 1 year, patients were unblinded and placebo was discontinued. Therefore, the observations of this study do not reflect a comparison to a control group. Additionally, endoscopic assessments were not available for all patients and were not centrally read, so these assessments may suffer from inter-reader variability. The study is also not adequately powered to compare q8w vs q12w dosing regimens, and further dose optimized regimens (every 4 weeks or every 6 weeks) were not assessed.
My Practice
In my practice, I commonly prescribe ustekinumab to both bio-naïve and bio-experienced patients with moderate-to-severe UC. The long-term data presented in this study demonstrate that those who respond to ustekinumab IV induction often maintain clinical remission through 4 years of treatment. These findings allow me to provide reassurance when counseling my patients regarding the efficacy, safety, and durability of this treatment option, particularly for individuals who are hesitant to initiate a biologic therapy. I also commonly dose optimize ustekinumab empirically to every 4 weeks or every 6 weeks after loss of clinical response to q8w dosing, as this has been shown in real-world studies to be effective in recapturing response.2-3
For Future Research
Long-term studies are needed to investigate the efficacy and safety of further dose-optimized regimens of ustekinumab, including every 4 weeks and every 6 weeks regimens. Randomized trials comparing the efficacy of ustekinumab to other advanced therapies for UC are also needed.
Conflict of Interest
Dr. Dalal has research grant support from Janssen and Pfizer and has served as a consultant for Janssen, Takeda, and Centaur Labs.
Waqqas Afif, MD
REFERENCES
- Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2019;381(13):1201-1214.
- Dalal RS, Esckilsen S, Barnes EL, et al. Predictors and outcomes of ustekinumab dose intensification in ulcerative colitis: a multicenter cohort study. Clin Gastroenterol Hepatol 2022;20(10):2399-2401.e4.
- Dalal RS, Pruce JC, Allegretti JR. Long-term outcomes after ustekinumab dose intensification for inflammatory bowel diseases. Inflamm Bowel Dis 2023;29(5):830-833.