The Emergence of Tilisokibart in Ulcerative Colitis Treatment: Exploring Key Insights of the ARTEMIS-UC Trial
Tanmaya Phanda, PharmD
The Emergence of Tilisokibart in Ulcerative Colitis Treatment: Exploring Key Insights of the ARTEMIS-UC Trial
By: Tanmaya Phanda, PharmD
This blog will provide a background of ulcerative colitis, summarize findings from the ARTEMIS-UC trial, and discuss the potential impact of tilisokibart in patients with inflammatory bowel diseases
Introduction
Ulcerative colitis, the most common type of chronic inflammatory bowel disease (IBD), affects about five million people worldwide. The condition is caused by inflammation and ulcer formation, typically beginning in the mucosa and submucosa of the rectum, and extending proximally into the colon. Common symptoms include abdominal cramping, diarrhea, and rectal bleeding. Ulcerative colitis can also lead to serious complications such as toxic megacolon and increases the risk of colorectal cancer to 2% after 10 years, 8% after 20 years, and 18% after 30 years. Since there is no cure for ulcerative colitis, the main treatment goal for patients is to achieve clinical remission (defined as reduced to no symptoms) to improve quality of life and prevent disease progression.
The American Gastroenterological Association (AGA) guidelines recommend oral and rectal* 5-aminosalicylates) 5-ASA class of medications such as sulfasalazine, mesalamine, and diazo-bonded 5-ASA in patients initially diagnosed with ulcerative colitis. However, over 50% of patients with IBD fail to respond or eventually lose response to 5-ASA over time. More effective advanced therapies like biologics and small molecule agents are needed in patients with moderate to severe symptoms:
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Drug Class
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Medications
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|
Anti-tumor necrosis factor (TNF) agents
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Adalimumab (Humira®), golimumab (Simponi®), and infliximab (Remicade®)
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Integrin receptor antagonists
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Vedolizumab (Entyvio®)
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Interleukin inhibitors
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Guselkumab (Tremfya®), mirikizumab (Omvoh®), risankimuab (Skyrizi®), and ustenekimab (Stelara®)
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Janus kinase (JAK) inhibitors
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Filgotinib (Jyseleca®), tofacitinib (Xeljanz®), and upadacitinib (Rinvoq®)
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Sphingosine 1-phosphate receptor (S1PR) modulators
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Etrasimod (Velsipity®) and ozanimod (Zeposia®)
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Despite the efficacy of biologics in inducing and maintaining remission, 12–22% of patients with ulcerative colitis do not initially respond to biologics. Additionally, 49–59% of patients with ulcerative colitis eventually lose their responses, underlining the need for additional novel treatments.
Recent studies have shown that human tumor necrosis factor-like cytokine 1A (TL1A) plays a key role in the pathophysiology mechanisms of IBD. There is an increased expression of TL1A and its receptor, death domain receptor 3 (DR3) during intestinal inflammation. In addition, TNFSF15 and TNFRSF25, genes encoding for TL1A and DR3 respectively, are genetic risk factors for inflammatory bowel diseases.
This breakthrough has led to the potential emergence of tulisokibart, a novel humanized IgG1 kappa monoclonal antibody, that inhibits TL1A binding to DR3, resulting in a decrease in profibrotic pathways of IBD. Animal models have shown murine TL1A antibodies effectively treat colitis, suggesting a promising therapeutic option for humans with ulcerative colitis.
Trial Introduction
ARTEMIS-UC (NCT04996797), a phase 2, multicenter, double-blind, and placebo-controlled trial, evaluated the efficacy and safety of tulisokibart in adults with moderately to severely active ulcerative colitis.
Methods
Key Inclusion criteria:
- Moderately to severely active ulcerative colitis (defined by a three-component modified Mayo score [a rectal-bleeding subscore, a stool frequency subscore, and an endoscopic subscore] of 4 to 9)
- Endoscopic subscore of ≥2
- Rectal-bleeding subscore ≥1,
- Glucocorticoid dependence (inability to successfully taper to <10 mg per day of prednisone equivalent)
- Treatment failure with glucocorticoids, immunosuppressants, or approved advanced therapies (≤ 4 advanced agents from ≤ 3 classes)
All patients also completed a genetic-based diagnostic test that was designed to identify patients with an increased likelihood of response to an anti-TL1A antibody. Based on the results, they were divided into 2 cohorts for the 12-week treatment period:
- Cohort 1: patients regardless of status with respect to the test for likelihood of response
- Cohort 2: patients with a positive test for likelihood response
After a 5-week screening period, 135 and 43 patients in cohorts 1 and 2, respectively, were randomly assigned in a 1:1 ratio to receive intravenous tulisokibart or placebo. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Intravenous 1000 mg tulisokibart was given on day 1, followed by 500 mg at weeks 2, 6, and 10. — Figure 1.
Figure 1. Study Design
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Cohort 1
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Patients with Positive Test for Likelihood of Response
(Cohorts 1 and 2)
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Placebo (N=67)
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Tulisokibart (N=68)
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Placebo (N=37)
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Tulisokibart
(N=38)
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Across both cohorts, 75 patients with positive test for likelihood of response
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The baseline characteristics of the patients were similar in the tulisokibart and placebo groups. — Table 1.
Table 1. Patient Baseline Characteristics
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Characteristic
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Cohort 1
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Patients with Positive Test for Likelihood of Response
(Cohorts 1 and 2)
|
| |
Placebo (N=67)
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Tulisokibart (N=68)
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Placebo (N=37)
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Tulisokibart
(N=38)
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|
Age — yr
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42.2±16.3
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40.4±14.4
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38.6±13.0
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37.3±15.7
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Female — no. (%)
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29 (43)
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34 (50)
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13 (35)
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20 (53)
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Disease duration — yr
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6.3±6.2
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6.7±6.4
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7.9±6.3
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5.9±3.9
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|
Modified Mayo score
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7.1±1.1
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6.9±1.2
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6.8±1.2
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6.8±1.3
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Outcomes
The primary outcome assessed clinical remission at week 12 in cohort 1. Clinical remission was achieved if all of the following criteria were met:
- A modified Mayo endoscopic subscore of 0 or 1
- A rectal-bleeding subscore of 0
- A stool-frequency subscore of 0 or 1 and not greater than the baseline value
Key secondary outcomes, such as the percentage of patients with endoscopic improvement, clinical response, and symptomatic remission, were assessed in Cohort 1 and patients with a positive test for likelihood response.
Safety was evaluated by monitoring adverse events across both cohorts in the treatment period.
Results
Tulisokibart yielded a significantly higher percentage of patients achieving clinical remission (26%) compared to placebo (1%). An estimated treatment difference of 25 percentage points (95% confidence interval [CI], 14 to 37; P<0.001) was observed. — Figure 3a. In patients with a positive test for the likelihood of response, a higher percentage of clinical remission was seen in patients treated with tulisokibart (32%) compared to placebo (11%). An estimated treatment difference of 21 percentage points (95% CI, 2 to 38; P=0.02) was observed.— Figure 3b.
Figure 3a. Clinical Remission in Cohort 1
Figure 3b. Clinical Remission in Patients with a Positive Test for Likelihood of Response
Table 2. Key Secondary Outcomes Results
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Key Secondary Outcome
|
Cohort 1
|
Patients with Positive Test for Likelihood of Response
(Cohorts 1 and 2)
|
|
Placebo (N=67)
|
Tulisokibart (N=68)
|
Treatment Difference
(95% CI)
|
Placebo (N=37)
|
Tulisokibart
(N=37)
|
Treatment Difference
(95% CI)
|
|
Endoscopic Improvement (% of patients)
|
6
|
37
|
31
(17 to 43) P<0.001
|
19
|
37
|
8
(−2 to 36)
P=0.06
|
|
Clinical Response
(% of patients)
|
22
|
66
|
44
(27 to 57)
P<0.001
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32
|
55
|
23
(0 to 42)
|
|
Symptomatic Response
(% of patients)
|
6
|
19
|
13
(2 to 25)
P=0.02
|
11
|
21
|
10 (−7 to 27)
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Table 3. Adverse Events in Cohorts 1 and 2
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Event
|
Placebo (N = 88)
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Tulisokibart (N=90)
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|
Adverse event — no. (%)
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38 (43)
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41 (46)
|
|
Treatment-related adverse event*
|
1 (1)
|
4 (4)
|
|
Serious adverse event
|
7 (8)
|
1 (1)
|
|
Treatment-related serious adverse event
|
0
|
1 (1)
|
|
Discontinuations due to adverse events
|
3 (3)
|
1 (1)
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The percentage of adverse events was similar in the placebo and tulisokibart groups (43% vs 46% respectively). In the tulisokibart group, there was one treatment-related serious adverse event reported due to Bowen’s disease. No deaths or acute infusion reactions were reported in either trial group.
Study Conclusions
Tulisokibart was more effective than placebo in inducing clinical remission in adults with moderately to severely active ulcerative colitis. Tulisokibart demonstrated safety, and tolerability, along with positive outcomes in secondary endpoints including endoscopic improvement, clinical response, and symptomatic remission.
Despite the treatment benefits observed, the trial presented key limitations due to the sample size and short treatment period. The analysis of patients with a positive test for the likelihood of response (derived from pooled data of cohorts 1 and 2) is limited because of the small study population and potential selection bias due to cohort differences. Additional trials with larger sample sizes and longer treatment durations are needed to evaluate tulisokibart’s therapeutic index (long-term safety and efficacy) and the clinical usefulness of TL1A genetic diagnostic testing in identifying predictive biomarkers of ulcerative colitis disease progression and effective treatment options.
Clinical Impact and Future Direction
Despite available conventional and advanced therapies for ulcerative colitis, many patients fail to respond to current treatment options, increasing their disease and economic burden. Previous treatment failure pattern studies (N = 6745 patients) demonstrated that 75% experienced treatment failure within the first 12 months (median 5.1 months) and 92% by the 36-month mark. Treatment failure cohorts had higher mean costs than persistent cohort (all-cause, $74 995 vs $56 169; UC-related, $57,096 vs $47,347;(P < .001). Dose escalation/interval shortening contributed to the highest total costs ($101,668 across all treatment failure events. If FDA-approved as the first-in-class treatment, tulisokibart may decrease costs and improve the quality of life for patients who have failed to respond to advanced therapies for ulcerative colitis.
In ARTEMIS-US’s open-label extension period, at week 50, tulisokibart maintained its efficacy and similar safety profile as seen in the 12-week treatment period phase. Merck has initiated the first phase 3 study for an anti-TL1A antibody in inflammatory bowel disease to evaluate the efficacy and safety of tulisokibart in patients with ulcerative colitis (ATLAS-UC; NCT06052059). ATLAS-UC will further determine tulisokibart’s long-term effectiveness and safety in a larger sample size of adults with ulcerative colitis. If FDA-approved, tulisokibart can be the first-in-class treatment option for patients who have failed to respond to current conventional advanced therapies for ulcerative colitis.
References:
- Sands BE, Feagan BG, Peyrin-Biroulet L, et al. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis. N Engl J Med. 2024;391(12):1119-29.
- Walfish AE, Companioni RAC. Ulcerative Colitis. MerckManuals. 2023. https://www.merckmanuals.com/professional/gastrointestinal-disorders/inflammatory-bowel-disease-ibd/ulcerative-colitis
- Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol. 2008;14(25):3937-47.
- Koo HM, Jun YK, Choi Y, et al. 10 years of biologic use patterns in patients with inflammatory bowel disease: treatment persistence, switching and dose intensification - a nationwide population-based study. Therap Adv Gastroenterol. 2023;16:17562848231201728.
- Lee SD, Betts KA, Xiaoyan Du E, Nie X, Gupte-Singh K, Ritter T. Real-World Patterns and Economic Burden Associated With Treatment Failure With Advanced Therapies in Patients With Moderate-to-Severe Ulcerative Colitis. Crohns Colitis 360. 2024;6(2):otae026.
- Singh S, Loftus EV, Limketkai BN, et al. AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2024;167(7):1307-43.
- Mehta RS, Mayers JR, Zhang Y, et al. Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease. Nat Med. 2023;29(3):700-9.
- Merck to Present New Long-Term Data for Tulisokibart (MK-7240), an Investigational Anti-TL1A Monoclonal Antibody, in Inflammatory Bowel Disease at UEG Week 2024. Merck. 2024. https://www.merck.com/news/merck-to-present-new-long-term-data-for-tulisokibart-mk-7240-an-investigational-anti-tl1a-monoclonal-antibody-in-inflammatory-bowel-disease-at-ueg-week-2024/
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