"First, dual-acting IL-23 inhibitor emerges in KOR"

"IBD treatment strategy has been expanded"

Professor Byong Duk Ye from the Department of Gastroenterology at Seoul Asan Medical Center

Increasing number of IBD patients and continuing burden of relapse...the need for an advanced treatment strategy

"Have achieved both endoscopic remission and histological remission…more significance of the introduction of new mechanism drug"

​"Inflammatory Bowel Disease is not a disorder that ends with improved symptoms. The long-term prognosis can be changed only when endoscopic and histological inflammation are also controlled."

Professor Byong Duk Ye, from the Department of Gastroenterology at Seoul Asan Medical Center, stressed the need for new treatment mechanisms, given the high rates of relapse and refractory patients.

The therapeutic goal for Inflammatory Bowel Disease (IBD) is expanding beyond simple symptom relief to 'deep remission,' which includes achieving both endoscopic remission and histological remission. Janssen's Tremfya (guselkumab), with a dual-action mechanism that blocks both the IL-23 signal and its pathway, has recently been approved in South Korea for both Crohn's disease and ulcerative Colitis, emerging as a new therapeutic option.

Professor Byong Duk Ye from the Department of Gastroenterology at Seoul Asan Medical Center

Professor Ye stated, "Given that a significant number of patients experience recurrent relapse and refractoriness despite utilizing all existing drugs, the introduction of a new-mechanism drug aiming for deep remission holds immense significance in clinical practice."

IBD is a chronic inflammatory disorder of the intestines, broadly categorized into ulcerative colitis and Crohn's disease. Ulcerative colitis is confined to the colon, while Crohn's disease can cause inflammation throughout the entire gastrointestinal tract, from the mouth to the anus.

The etiology of both diseases has not been defined. Due to the chronic, relapsing-remitting nature of the inflammation, the bowel can be damaged over several years to decades, leading to various complications.

Given the difficulty of achieving a cure, the fundamental goal of IBD treatment is to effectively suppress inflammation and maintain a stable state of remission to minimize intestinal damage and complications. Although various drugs, including Janus Kinase (JAK) inhibitors and biologics, have been introduced, a complete cure remains challenging.

Analysis suggests the domestic approval of Tremfya contributed to expanding treatment options. Tremfya is the first and only dual-action IL-23 inhibitor approved in Korea for both Crohn's disease and ulcerative colitis.

Professor Ye said, "IBD treatment has continuously advanced, but the patient population continues to grow, and there are patients who don't respond or experience relapse after using all existing drugs," and added, "The introduction of a new-mechanism drug is welcome news for both patients and healthcare providers."

Q. Why is remission still challenging to achieve despite the development of numerous IBD treatments?

The biggest reason is that the disease's etiology has not been fully elucidated. The inflammatory pathways are highly diverse and complex, making it difficult to block all inflammatory routes at the same time with currently available drugs.

Furthermore, blocking a specific inflammatory pathway can sometimes lead to the compensatory activation of other pathways. This is why some patients initially show treatment efficacy but experience disease worsening over time. In such cases, it may become necessary to switch the drug or adjust the treatment dosage.

Ultimately, because the mechanism of inflammation is multilayered and not fully understood, current therapies alone are insufficient to fundamentally cure the disease. Nevertheless, recently developed agents are based on mechanisms that more precisely target inflammatory pathways, leading to a steady increase in the number of patients maintaining long-term remission.

Q. Tremfya's domestic approval has expanded treatment options. Please explain the mechanistic advantages of this drug.

IL-23 is a known cytokine that plays a vital role in the development of inflammation in both Crohn's disease and ulcerative colitis. Consequently, several antibody therapies have been developed to block IL-23 action, all designed to target IL-23 p19 subunit.

​Tremfya is unique for its dual-acting mechanism, which includes an additional mechanism targeting immune cells. Tremfya is the only IL-23 inhibitor that acts directly on CD64+ immune cells that produce IL-23. The Fab region of the Tremfya antibody binds to the IL-23 p19 subunit to block the inflammatory signal, and the Fc region binds to the receptor on CD64+ immune cells, suppressing the activation and function of these immune cells.

Tremfya is a drug with a dual-acting mechanism that both blocks the signal molecule causing inflammation and suppresses the activity of the cells generating that signal. This structural feature is a unique strength of Tremfya, not present in other interleukin-23 p19 blockers.

Q. Tremfya demonstrated superiority over Stelara in Crohn's disease. Could you please explain which clinical endpoint we should focus on?

The Phase 2/3 GALAXI clinical trial in Crohn's disease included endoscopic response as a primary efficacy endpoint. Endoscopic response assesses the degree of improvement in intestinal inflammation via endoscopic scores, while endoscopic remission signifies a more advanced state where the damaged intestinal mucosa has recovered to near-normal.

Deep remission is defined as the simultaneous achievement of clinical remission (symptom resolution) and endoscopic remission (mucosal healing). The GALAXI study assessed these measures as both individual and composite endpoints.

The study results showed that at the one-year maintenance timepoint, Tremfya demonstrated significantly superior results compared to Stelara (ustekinumab) across endoscopic response, endoscopic remission, and various composite indices. Endoscopic metrics are objective indicators reflecting the level of inflammation control more accurately than subjective patient symptoms. This improvement holds critical significance for long-term complication prevention and prognosis enhancement.

Q. What is the practical meaning of achieving deep remission (achieving both clinical and endoscopic remission) for patients?

Deep remission is significant because IBD is a chronic disease requiring lifelong management, and it can prevent long-term complications. When symptoms improve, patients are freed from pain, diarrhea, and bloody stools, finding comfort in daily life and improving their overall Quality of Life (QoL). Achieving endoscopic remission also suppresses bowel inflammation that the patient may not consciously recognize, thereby reducing the risk of relapse or complications from intestinal damage.

In other words, deep remission is a key goal that goes beyond mere symptom alleviation, improving the long-term course of the disease and reducing the likelihood of recurrence. Therefore, in clinical practice, there is continuous emphasis on the need for both symptom improvement and improved endoscopic findings to maintain a good state. Recently, patients are also increasingly aware of the importance of 'deep remission' and actively pursuing it as a treatment goal.

Q. The efficacy of Tremfya has also been proven in ulcerative colitis. How would you evaluate the clinical value of this finding?

The Phase 3 QUASAR clinical trial in ulcerative colitis evaluated not only endoscopic remission but also histological response and histological remission. Histological evaluation is a quantitative assessment of the presence and degree of inflammatory cells in the intestinal mucosa by microscopic observation.

The study results showed that Tremfya demonstrated significantly superior results compared to the placebo group in endoscopic remission, histological improvement, and histological remission rates.

Histological evaluation is becoming important in ulcerative colitis because these indicators are closely associated with long-term QoL improvement and the prevention of relapse and worsening.

Even when inflammation appears almost resolved on endoscopic examination, tissue biopsy results may show residual inflammation. Studies consistently report that these patients have a higher frequency of relapse and a greater risk of emergency room visits during long-term follow-up. While histological remission is not yet an officially established treatment goal, as evidence accumulates, it is likely to be elevated as a new therapeutic goal.

Q. What types of patients in the clinical setting in South Korea can be treated with Tremfya?

Based on pivotal study designs, Tremfya is expected to be effective in patients who have not used both biologic- and small-molecule-agents and those who have previously used these agents. Therefore, it is a drug that can be widely utilized not only as a first-line therapy but also in the second-line and beyond treatment phases.

Furthermore, agents targeting the IL-23 p19 subunit demonstrate a superior safety profile, offering a clinical advantage for patients requiring long-term treatment by reducing concerns about side effects.

The maintenance dosing schedule of once every 8 weeks also enhances patient convenience. Moreover, while some existing oral medications have restrictions requiring discontinuation during pregnancy or childbirth, there is an expert consensus that Tremfya treatment can be continued through pregnancy, birth, and lactation. This positions it as an essential drug that expands treatment options for women of childbearing age and young female patients.

Q. Considering clinical practice, patients, and policy, what are the unmet needs that should be addressed in IBD treatment?

First, considering healthcare providers, there is a need for the broader dissemination of the understanding that the IBD treatment goal has been elevated beyond simple symptom improvement to the fundamental control of inflammation itself. This is a key concept for improving long-term prognosis and preventing complications, but it is not yet applied at the same level across all clinical settings.

Furthermore, improving adherence to long-term therapy remains a significant challenge. Despite IBD being a chronic, lifelong disease, many patients stop taking medication or delay hospital visits once their symptoms improve. Therefore, spreading awareness that consistent treatment and management are necessary, even without symptoms, is essential.

Finally, the hurdles to treatment access need to be lowered. Although Korea's 'Special Case Medical Expense Coverage System' allows eligible CD/UC patients to receive reimbursed biologics or small-molecule drugs with only a 10% co-payment, the initial entry hurdle for these agents remains relatively high. Additionally, the criteria for drug switching are stringent, and improvements are needed to allow for more flexible adjustment of treatment strategies based on the patient's condition.