Hope for patients with ulcerative colitis

The drug Tulisokibart, undergoing intensive clinical trials, shows promising results in treating ulcerative colitis. In a study by the ARTEMIS-UC team, published in the New England Journal of Medicine, preliminary results suggest that the therapy could change treatment standards and significantly improve patients' quality of life.

Ulcerative colitis (UC) is a severe chronic disease that affects nearly 0.7% of the population, meaning that 1 in 150 people worldwide suffer from it. It is characterized by recurrent episodes of abdominal pain, chronic diarrhea, and bleeding, leading to a significant deterioration in patients' quality of life. The disease affects individuals and burdens healthcare systems, generating high treatment costs. Current therapies, such as anti-inflammatory, steroidal, and immunosuppressive drugs, help many patients, but their effectiveness is sometimes limited, increasing the need for new solutions.

In the face of these challenges, research into new treatments is becoming crucial. Tulisokibart, a new monoclonal antibody being studied in the ARTEMIS-UC trial, published in the New England Journal of Medicine, may prove to be a breakthrough. The study, led by Prof. Bruce E. Sands and a team of international experts, including Dr. Radoslaw Kempinski of the Department of Gastroenterology, Hepatology, and Internal Medicine, Institute of Internal Medicine at Wroclaw Medical University, was aimed at evaluating both the safety and efficacy of the new therapy.

From laboratory testing to treatment: key phases of drug development

Developing a new drug is rigorous and consists of several key phases. Clinical trials begin with phase zero, where the drug is tested at low doses to obtain preliminary information about its effects and spread in the body. Phase one evaluates the drug's safety and mode of action to establish safe doses and identify potential side effects.

Phase two, which Tulisokibart is currently in, examines the drug's effectiveness and continues to evaluate its safety on a larger group of patients. This is the critical moment that determines the transition to phase three. In this most extensive and costly phase, the efficacy and safety of the drug are finally evaluated on a large group of patients. Once this phase is completed, the registration process can begin. Phase four, the final phase, involves post-market monitoring of the drug to detect rare side effects and interactions with other substances.

Dr. Radoslaw Kempinski, Department of Gastroenterology, Hepatology, and Internal Medicine, Institute of Internal Medicine at Wroclaw Medical University. Fot. T.Walów

As Dr. Kempinski points out, clinical trials such as ARTEMIS-UC represent a significant opportunity for patients: - Patients are often unable to cover the cost of modern drugs, which are sometimes financially inaccessible outside clinical trials. Participation in trials gives them access to therapies beyond their reach.

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Inflammatory process of the intestine

Ulcerative colitis is a disease in which the immune system attacks the intestinal mucosa, causing chronic inflammation. Among its initiators is the TL1A protein. In a healthy body, its production by endothelial cells is not high. In inflammation, it increases significantly. High levels of TL1A lead to excessive activation of the immune response, which intensifies inflammation and can damage tissue.

"This drug acts as an alarm switch. By blocking the TL1A protein, it reduces inflammation," explains Dr. Kempinski. "This is a promising direction, as this mechanism can also inhibit fibrosis in the intestine, one of the most severe sequelae in inflammatory bowel diseases."

Tulisokibart, a monoclonal antibody, blocks the interaction of the TL1A protein with its DR3 receptor, inhibiting harmful immune reactions, increasing T regulatory cell activity, and reducing pro-inflammatory processes and fibrosis.

ARTEMIS-UC clinical trial

The ARTEMIS-UC study was a large-scale, international project involving patients divided into two groups:

Individuals were included in the first group based on clinical presentation and disease severity without consideration of their genetic profile. Patients were included if they were diagnosed with moderate-to-severe ulcerative colitis, steroid dependence, or had experienced treatment failure with other therapies.

The second group included patients who tested positive for a genetic marker associated with an increased likelihood of response to anti-TL1A antibody.

The study aimed to achieve clinical remission after 12 weeks of therapy. In addition, the relief of symptoms, the improvement seen during endoscopic examinations, and the patient's quality of life were assessed using a specialized IBDQ questionnaire.

The Inflammatory Bowel Disease Questionnaire (IBDQ) is a specialized tool for assessing the quality of life of patients with inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease. It consists of questions about physical symptoms, emotional well-being, ability to function in daily life, and social interactions.

Results that surprise

The results of the study proved extremely promising. As many as 26% of patients in the first group showed clinical remission (only 1% in the placebo group). Patients treated with Tulisokibart achieved endoscopic improvement significantly more often (37% compared to 6% in the placebo group). A decrease in the levels of inflammatory markers such as C-reactive protein and fecal calprotectin was observed after just two weeks, indicating the rapid effects of the drug. In the second group, as many as 32% of patients who received the drug achieved clinical remission after 12 weeks of therapy, compared to 11% of patients who received placebo. This difference was statistically significant (P=0.02), confirming the drug's effectiveness in this group. Although secondary endpoints such as endoscopic improvement, clinical response, or histological improvement were also analyzed, no significant differences were found between the groups taking Tulisokibart and placebo in terms of endoscopic improvement. Therefore, the remaining analyses require further study.

The research in the second group, while not having such promising results, is a step towards precise medicine. Wroclaw-based researcher Dr. Kempinski notes the growing importance of this trend, which allows therapies to be selected to meet specific patient needs: - Although standard therapies are available, we often use them by trial and error. He explains that if we can develop precise genetic criteria for patients, we may be able to predict which drug will have the best effect. - In the case of Tulisokibart, we had hoped that a genetic test would identify patients with the best response, but the results for this cohort proved inconclusive.

What's next?

Completion of phase two trials is an important milestone for any new treatment. The drug has shown significant therapeutic potential and can move on to phase three trials, including a larger patient population and lasting longer to confirm its safety and efficacy.

"We always focus on patient safety", says Dr. Kempinski. Our goal is not only to achieve remission but also to maintain it long-term. That's why new drugs such as Tulisokibart are a promising option for us, which we intend to monitor closely in further phases of research.

Despite the promising results, challenges remain. The 12-week study period and the limited number of participants indicate the need for further research to assess the long-term effects and broader use of Tulisokibart. In addition, while the genetic test for response prediction has shown potential, its predictive value requires further study. Phase 3 studies will be vital to answering these questions. Success in this phase could solidify the drug's position as a new treatment option for ulcerative colitis.

The results of the ARTEMIS-UC trial have opened a new chapter in treating ulcerative colitis. It is a scientific achievement and hope for more personalized medical care for patients struggling with limited therapeutic options. The study demonstrates that precise, targeted therapies can transform many people's lives, bringing tangible benefits where traditional methods fail. While further testing is needed, this study is a step forward - a glimpse into a future where ulcerative colitis treatment will be more precise, effective, and patient-centered.

Takeaways

Treatment efficacy

Tulisokibart showed greater efficacy than placebo, leading to remission in patients with moderate to severe UC. The study included patients with steroid dependence or after failed therapies; only 1% of the placebo group achieved remission.

Safety

The safety profile of Tulisokibart was favorable, with a similar incidence of mild and moderate side effects compared to placebo.

Step toward personalized medicine

Although the study did not confirm the test's efficacy, it reflects the growing trend of using genetic information to predict a patient's response to treatment. This approach could lead to more targeted and effective treatment strategies for ulcerative colitis, reducing unnecessary treatment and improving outcomes.

FAQ: Tulisokibart for ulcerative colitis

What is ulcerative colitis, and what treatment options are currently available?

Ulcerative colitis is a chronic inflammatory bowel disease that causes symptoms such as abdominal pain, diarrhea, and rectal bleeding. Current treatments include drugs such as glucocorticoids and immunosuppressants and advanced therapies such as TNF antagonists, vedolizumab, ustekinumab, Janus kinase inhibitors, and S1P receptor modulators. However, many patients fail to achieve clinical remission with these therapies.

What is Tulisokibart, and how does it work?

Tulisokibart is a monoclonal antibody directed against TL1A, a protein involved in inflammatory responses. By binding to TL1A, Tulisokibart prevents its interaction with a receptor (DR3) on immune cells. This action inhibits the inflammatory cascade, ultimately reducing inflammation in the gut.

What is the safety profile of Tulisokibart?

Tulisokibart showed a favorable safety profile in the study. The incidence of adverse events was similar between the tulisokibart and placebo groups, and no new safety risks were identified.

What was the purpose of the ARTEMIS-UC study?

The ARTEMIS-UC study was a phase 2 clinical trial designed to evaluate the efficacy and safety of tulisokibart in patients with moderately to severely active ulcerative colitis who had an inadequate response to conventional or advanced therapies.

The study showed that tulisokibart was significantly more effective than placebo in inducing clinical remission after 12 weeks of treatment. Patients receiving tulisokibart also showed improvements in secondary endpoints such as endoscopic improvement, clinical response, symptomatic remission, histologic improvement, and quality of life.

Did the study use a genetic test?

The study included a genetic diagnostic test to identify patients with a potentially increased likelihood of responding to Tulisokibart. The test was based on the theory that individuals with genetic markers suggestive of TL1A overexpression may benefit more from TL1A blockade.

Although the study observed clinical remission in a higher percentage of positive patients treated with Tulisokibart than placebo, the test's predictive value was not demonstrated. Further studies on larger populations are needed to assess the test's utility.

Ed: D.Sikora

The material is based on the article

Phase 2 trial of anti-TL1A monoclonal antibody tulisokibart for ulcerative colitis
Bruce E. Sands, Brian G. Feagan, Laurent Peyrin-Biroulet, Silvio Danese, David T. Rubin, Olivier Laurent, Allison Luo, Deanna D. Nguyen, Jiandong Lu, Mark Yen, Jaroslaw Leszczyszyn, Radosław Kempiński, Dermot P.B. McGovern, Christopher Ma, Timothy E. Ritter, Stephan Targan.

New England Journal of Medicine

ISSN 0028-4793, e-ISSN 1533-4406
DOI:10.1056/nejmoa2314076