Comprehensive Report on Tulisokibart (MK-7240/PRA023): An Investigational Anti-TL1A Monoclonal Antibody

1. Executive Summary

Tulisokibart, an investigational humanized IgG1 kappa monoclonal antibody, represents a novel therapeutic approach targeting Tumor Necrosis Factor-like Cytokine 1A (TL1A). Originally developed by Prometheus Biosciences under the designation PRA023 and now advanced by Merck & Co., Inc. as MK-7240, Tulisokibart is in late-stage clinical development primarily for inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD).[1] Phase 2 clinical trials (ARTEMIS-UC for ulcerative colitis and APOLLO-CD for Crohn's disease) have demonstrated statistically significant and clinically meaningful efficacy in inducing clinical remission and endoscopic improvement in patients with moderately to severely active disease, many of whom had failed previous conventional or advanced therapies.[1]

The mechanism of Tulisokibart involves the specific inhibition of TL1A, a cytokine implicated in both pro-inflammatory and pro-fibrotic pathways. This dual action is a key differentiator, suggesting potential benefits beyond symptomatic relief, particularly in conditions characterized by tissue remodeling and fibrosis, such as Crohn's disease and Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD).[1] The therapeutic strategy for Tulisokibart includes the co-development of a companion diagnostic (CDx) aimed at identifying patients with a genetic predisposition to increased TL1A expression, thereby potentially enhancing treatment response through a precision medicine approach.[1] While the CDx has shown some predictive value, its role and optimization are still under evaluation.

The acquisition of Prometheus Biosciences by Merck in June 2023 for approximately $10.8 billion, largely driven by the potential of Tulisokibart, highlights the significant perceived value of this asset.[3] This strategic investment by a major pharmaceutical entity indicates a strong conviction in the drug's scientific rationale and its capacity to address substantial unmet medical needs in IBD and potentially other immune-mediated inflammatory diseases. Merck's subsequent rapid initiation and expansion of large-scale Phase 3 clinical trials for UC (NCT06052059) and CD (NCT06430801), alongside investigations into SSc-ILD (NCT05270668) and Hidradenitis Suppurativa (HS) (NCT06202901), further underscore this commitment and the broad therapeutic potential envisioned for Tulisokibart.[20]

The drug has generally exhibited a favorable safety and tolerability profile in Phase 2 studies, with adverse event rates comparable to placebo and low immunogenicity.[1] If the promising efficacy and safety observed in Phase 2 are confirmed in the ongoing Phase 3 program, Tulisokibart, with its dual anti-inflammatory and anti-fibrotic mechanism, could significantly alter the treatment landscape for IBD. Its potential to directly address fibrosis, a major contributor to complications in Crohn's disease, would be a particularly noteworthy advancement over existing therapies that primarily target inflammation.

2. Introduction to Tulisokibart

Tulisokibart is an investigational therapeutic agent that has garnered significant attention for its potential in treating various immune-mediated inflammatory diseases.

Nomenclature:

The internationally recognized nonproprietary name for this drug is Tulisokibart.1 During its development by Prometheus Biosciences, it was known as PRA023.1 Following the acquisition of Prometheus Biosciences by Merck & Co., Inc., the drug is also referred to by the Merck designation MK-7240.1

Developer:

Tulisokibart was initially developed by Prometheus Biosciences, Inc. In June 2023, Merck & Co., Inc. (Rahway, New Jersey, USA) acquired Prometheus Biosciences, thereby taking over the continued development of Tulisokibart.1

Drug Class:

Tulisokibart is a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody.1 This classification indicates it is a protein-based therapeutic engineered from immune system components to target a specific molecule.

Chemical and Biologic Identifiers:

To ensure precise identification and facilitate information retrieval across various databases and scientific literature, Tulisokibart is associated with several unique identifiers. These are summarized in Table 1.

Table 1: Tulisokibart - Key Identifiers and Properties

Feature	Detail	Reference(s)
International Nonproprietary Name (INN)	Tulisokibart	1
Other Designations	MK-7240, PRA023	1
Developer	Prometheus Biosciences (initially), Merck & Co., Inc. (currently)	1
Drug Class	Humanized IgG1 kappa monoclonal antibody	1
CAS Number	2648504-55-4	4
DrugBank ID	DB18719	6
FDA UNII	ON09TCS5H3	48

3. Mechanism of Action and Pharmacodynamics

Tulisokibart exerts its therapeutic effects by specifically targeting and modulating the activity of Tumor Necrosis Factor-like Cytokine 1A (TL1A).

Target:

The molecular target of Tulisokibart is TL1A, a protein also known as TNF Superfamily Member 15 (TNFSF15) or Vascular Endothelial Growth Inhibitor (VEGI).1 TL1A is a member of the TNF superfamily of cytokines. Under normal physiological conditions, TL1A is primarily expressed by endothelial cells. However, during inflammatory states, its expression is substantially upregulated in various immune cells, including antigen-presenting cells (APCs), macrophages, and dendritic cells.1 TL1A can exist in both a membrane-bound trimeric form and a soluble form, the latter resulting from alternative splicing or enzymatic cleavage by tumor necrosis factor-alpha converting enzyme (TACE).1 Both forms are biologically active.

Molecular Interaction:

Tulisokibart is a humanized IgG1 kappa monoclonal antibody engineered to bind with high affinity and specificity to both the soluble and membrane-associated forms of human TL1A.1 This binding interaction is crucial as it physically blocks TL1A from engaging with its cognate receptor, Death Domain Receptor 3 (DR3), also known as TNFRSF25.1 The interaction between TL1A and DR3 is a key signaling event in the immune system. Activation of DR3 by TL1A typically triggers downstream signaling cascades involving adaptor proteins like TRADD and TRAF2, and kinases such as RIP. These cascades culminate in the activation of transcription factors, notably Nuclear Factor-kappa B (NF-κB) and Mitogen-Activated Protein Kinases (MAPKs). The activation of these transcription factors leads to changes in gene expression that promote cell proliferation, regulate apoptosis, and drive the production of various cytokines, thereby playing a significant role in both innate and adaptive immune responses.1

Pharmacodynamic Effects:

By preventing the TL1A-DR3 interaction, Tulisokibart modulates several key immunological and pathological processes:

• Anti-inflammatory Effects: A primary consequence of TL1A blockade by Tulisokibart is the suppression of pro-inflammatory responses. This includes the downregulation of type 1 helper T-cell (Th1) and type 17 helper T-cell (Th17) responses, which are critical drivers of inflammation in many autoimmune diseases.[1] Furthermore, inhibition of TL1A signaling leads to a reduction in the secretion of key pro-inflammatory cytokines such as interferon-gamma (IFN-γ), interleukin-17 (IL-17), and interleukin-6 (IL-6).[1]
• Immunomodulatory Effects: Beyond direct anti-inflammatory actions, Tulisokibart appears to have broader immunomodulatory effects. Notably, it has been reported to increase the activity of regulatory T-cells (Tregs).[1] Tregs play a crucial role in maintaining immune homeostasis and suppressing excessive immune responses. The restoration of depleted colonic Tregs has been specifically noted as a hallmark of response in a difficult-to-treat subgroup of UC patients, suggesting a mechanism for re-establishing immune balance in the gut.[17]
• Anti-fibrotic Effects: A potentially distinguishing feature of Tulisokibart is its ability to decrease pro-fibrotic pathways.[1] TL1A itself is implicated in promoting fibrosis. By inhibiting TL1A, Tulisokibart may mitigate tissue remodeling and the excessive deposition of extracellular matrix components that lead to scarring and organ dysfunction. This anti-fibrotic action is particularly relevant for conditions such as Crohn's disease, where intestinal strictures are a common and serious complication, and for SSc-ILD, which is characterized by progressive lung fibrosis. The capacity to modulate both inflammation and fibrosis offers a significant advantage over many existing therapies for IBD and other immune-mediated diseases, which primarily target inflammatory pathways.[1] If this dual action is confirmed to be clinically significant in Phase 3 trials, Tulisokibart could offer more comprehensive disease control, potentially altering the long-term course of fibrostenotic conditions by addressing tissue damage, not just controlling inflammatory symptoms.
• Impact on Biomarkers: Clinical studies have shown that treatment with Tulisokibart is associated with a reduction in the levels of key inflammatory biomarkers. Specifically, decreases in high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, and fecal calprotectin, a marker of intestinal inflammation, have been observed.[1] These changes were noted relatively early in the treatment course, with differences in hs-CRP levels observed as early as week 2 and for fecal calprotectin as early as week 6 during induction therapy.[1] The rapid modulation of these objective markers of inflammation suggests efficient target engagement by Tulisokibart and a potentially quick onset of its biological effects. This early biomarker response could be indicative of subsequent clinical and endoscopic improvements and may translate to faster symptom relief for patients compared to therapies with a slower onset of action.

4. Preclinical Development

The progression of Tulisokibart into clinical trials was supported by a foundation of preclinical research that established its mechanism of action and demonstrated its potential efficacy in relevant disease models.

Summary of in vitro and in vivo studies:

In vitro studies confirmed that Tulisokibart (PRA023) binds with high affinity and specificity to both soluble and membrane-associated forms of human TL1A.1 This specific binding is fundamental to its ability to neutralize TL1A activity. Broader preclinical programs targeting TL1A have indicated that such antibodies can effectively reduce intestinal inflammation and fibrosis, providing a strong rationale for this therapeutic approach.5

Efficacy in animal models:

The efficacy of Tulisokibart was evaluated in several animal models of colitis, leveraging humanized mouse models to ensure the relevance of testing a human-specific antibody:

• TNBS-induced colitis model in B-hTL1A mice: In a trinitrobenzene sulfonic acid (TNBS)-induced colitis model, which mimics aspects of Crohn's disease, Tulisokibart (PRA023, administered at 25 mg/kg) demonstrated significant therapeutic effects. Treatment led to improvements in key parameters including body weight, Disease Activity Index (DAI) score, colon index (reflecting changes in colon length and weight), and histological pathological scores. Importantly, Masson staining, used to assess collagen deposition and fibrosis, also showed improvement, indicating an anti-fibrotic effect.[1] These findings established this humanized mouse model as a robust platform for evaluating anti-human TL1A antibodies.
• DSS-induced acute colitis in B-hTL1A mice: Tulisokibart (PRA023, 25 mg/kg) also showed efficacy in a dextran sulfate sodium (DSS)-induced acute colitis model, which is commonly used to study ulcerative colitis. Treatment improved clinical symptoms, further validating the antibody's anti-inflammatory potential in a different colitis paradigm.[50]
• Combined efficacy in TNBS-induced colitis in B-hTL1A/hIL23A/hIL12B mice: In a more complex humanized model expressing human TL1A, IL-23A, and IL-12B, Tulisokibart demonstrated improved outcomes in TNBS-induced colitis. Notably, its efficacy was enhanced when administered in combination with Risankizumab, an anti-human IL-23p19 antibody.[50] This observation points towards potential synergistic effects when targeting multiple inflammatory pathways, an avenue that might be explored in future therapeutic strategies for IBD, especially in severe or refractory cases.

The consistent efficacy of Tulisokibart across these varied colitis models, particularly the improvements in both inflammatory and fibrotic markers in humanized B-hTL1A mice, provided a compelling preclinical basis for its development as a dual-acting therapeutic agent. The utilization of mice humanized for TL1A (B-hTL1A mice developed by Biocytogen) was instrumental, as it allowed for the direct assessment of a human-specific antibody in an in vivo setting, bridging a critical gap in translational research.[1] This preclinical evidence strongly supported the hypothesis that Tulisokibart could offer benefits by addressing both inflammation and fibrosis, key components of its therapeutic proposition.

Pharmacokinetics and Safety (Non-Clinical):

The provided research materials focus predominantly on the clinical pharmacokinetics and safety of Tulisokibart. Detailed non-clinical toxicology studies for Tulisokibart are not extensively described beyond the general positive outcomes in animal efficacy models. However, related research on other antibodies targeting the TL1A/DR3 pathway offers some context. For instance, SL-325, a DR3 blocking antibody, showed no evidence of toxicity or residual agonism in cynomolgus macaques, with a pharmacokinetic profile suggestive of extended dosing intervals.43 Another TL1A-targeting antibody, XmAb942, was estimated to have a half-life of over 71 days in humans, supporting a quarterly (Q12W) maintenance dosing schedule, which is highly desirable for chronic conditions.52 While these data are not directly for Tulisokibart, they suggest that molecules targeting this pathway can achieve favorable pharmacokinetic and safety profiles. The progression of Tulisokibart through Phase 1 and into extensive Phase 2 and 3 trials implies an acceptable preclinical safety margin.

5. Clinical Development Program

The clinical development of Tulisokibart has been extensive, spanning multiple phases and indications, reflecting its potential as a broad-spectrum immunomodulatory agent. Table 2 provides a summary of the key clinical trials.

Table 2: Summary of Key Tulisokibart Clinical Trials

NCT Number	Phase	Indication(s)	Status (Latest Snippet)	Key Design Features	Primary Endpoint(s) (Selected)	Sponsor
NCT04676178	1a	Healthy Volunteers	Completed	Phase 1a, assess safety, PK	Safety, PK	Prometheus/Merck
NCT06829225	1	Healthy Chinese Participants	Completed	Single dose, IV vs SC PK	Safety, PK (AUC, Cmax, etc.)	Merck
NCT06575595	1	Healthy Volunteers	Completed	Single SC dose, Autoinjector vs. Syringe PK	PK (Cmax, AUC)	Merck
NCT04996797	2	Ulcerative Colitis (ARTEMIS-UC / MK-7240-005)	Active, not recruiting	Randomized, Double-Blind, Placebo-Controlled, 12-week induction, CDx stratification	Clinical Remission (mMS) at Week 12	Prometheus/Merck
NCT05013905	2a	Crohn's Disease (APOLLO-CD / MK-7240-006)	Active, not recruiting	Open-Label, 12-week induction, vs. historical placebo	Endoscopic Response (SES-CD ≥50% reduction) at Week 12	Prometheus/Merck
NCT05270668	2	SSc-ILD (ATHENA-SSc-ILD / MK-7240-007 / PR200-104)	Active, not recruiting	Randomized, Double-Blind, Placebo-Controlled, 50-week	Change in FVC (mL) at Week 50	Prometheus/Merck
NCT06202901	2b	Hidradenitis Suppurativa (MK-7240-012)	Not yet recruiting (May 2025)	Randomized, Double-Blind, Placebo-Controlled, 16-week induction + LTE	Proportion achieving HiSCR50 at Week 16	Merck
NCT06052059	3	Ulcerative Colitis (MK-7240-001)	Recruiting	Randomized, Double-Blind, Placebo-Controlled, Induction & Maintenance	Clinical Remission (mMS) at Week 12	Merck
NCT06430801	3	Crohn's Disease (ARES-CD / MK-7240-008)	Recruiting	Randomized, Double-Blind, Placebo-Controlled, Induction & Maintenance	Clinical Remission (CDAI <150 or SF/AP score) & Endoscopic Response at Week 12	Merck
NCT06651281	3	CD and UC (Long-Term Extension / MK-7240-011)	Recruiting	Open-Label Extension	Long-term safety and efficacy	Merck

Sources:.[1]

Phase 1 Clinical Trials:

The initial phase of clinical development focused on establishing the safety, tolerability, and pharmacokinetic profile of Tulisokibart in healthy individuals.

• NCT04676178 (Healthy Volunteers): This was the first-in-human, Phase 1a study for PRA023 (Tulisokibart). Dosing commenced in December 2020, following FDA acceptance of the Investigational New Drug (IND) application.[5] The trial has since been completed.[6] While specific results from this study are not detailed in the provided information, the successful progression to larger Phase 2 and 3 trials implies that no prohibitive safety signals were identified and that the pharmacokinetic profile was deemed acceptable for further development. The long half-life observed with similar TL1A antibodies (e.g., +71 days for XmAb942) hints at the potential for infrequent dosing, a desirable characteristic for chronic therapies.[52]
• NCT06829225 (MK-7240-002, Healthy Chinese Participants): This completed Phase 1 study aimed to evaluate the safety and pharmacokinetics of Tulisokibart when administered intravenously versus subcutaneously in healthy Chinese participants.[51] The study assessed standard pharmacokinetic parameters such as Area Under the Curve (AUC$_{0-last}$, AUC$_{0-inf}$), maximum concentration (C$_{max}$), time to maximum concentration (T$_{max}$), terminal half-life (t$_{1/2}$), apparent clearance (CL/F), and apparent volume of distribution (Vz/F). A secondary objective was to determine the absolute bioavailability of subcutaneously administered Tulisokibart.[51] The trial enrolled 48 participants.[51] Specific findings have not been detailed in the available documents.
• NCT06575595 (MK-7240-010, Healthy Volunteers, SC Autoinjector vs. Syringe): This completed Phase 1 trial focused on characterizing the pharmacokinetics of a single subcutaneous dose of Tulisokibart delivered via an autoinjector compared to different concentrations delivered via a traditional vial and syringe.[47] It enrolled 60 healthy adults aged 18-55 years and assessed similar PK parameters as NCT06829225.[54] Results are not yet publicly available in the provided materials.

Phase 2 Clinical Trials:

Phase 2 studies were designed to evaluate the efficacy and further assess the safety of Tulisokibart in patient populations with specific inflammatory and fibrotic diseases.

• Ulcerative Colitis (UC):
• NCT04996797 (ARTEMIS-UC / MK-7240-005): This pivotal Phase 2, multicenter, randomized, double-blind, placebo-controlled trial evaluated Tulisokibart for a 12-week induction period in adults with moderately to severely active UC who had previously failed conventional or advanced therapies.[1] Patients were stratified by prior biologic exposure and companion diagnostic (CDx) status, then randomized 1:1 to receive either placebo or intravenous Tulisokibart (1000 mg on Day 1, followed by 500 mg at Weeks 2, 6, and 10).[1] The study was structured with Cohort 1 including all-comers and Cohort 2 enrolling only CDx-positive patients.[1]
• Patient Population: Cohort 1 comprised 135 patients (68 Tulisokibart, 67 placebo), and Cohort 2 included 43 patients. Across both cohorts, 75 CDx-positive patients were randomized.[1] The enrolled population was relatively refractory, with approximately half having prior exposure to advanced therapies.[46]
• Efficacy Results (Week 12, Cohort 1 unless stated): The results, detailed in Table 3, demonstrated significant efficacy for Tulisokibart. Table 3: Efficacy Outcomes from Phase 2 ARTEMIS-UC Trial (NCT04996797) in Ulcerative Colitis (Week 12, Cohort 1)

Endpoint	Tulisokibart (N=68) (%)	Placebo (N=67) (%)	Difference (%, 95% CI)	p-value
Clinical Remission (mMS)	26.5 (or 26)	1.5 (or 1)	25.0 (14 to 37)	<0.001
Endoscopic Improvement	36.8 (or 37)	6.0	30.8 (or 31) (17 to 43)	<0.001
Clinical Response (mMS)	66.2 (or 66)	22.4 (or 22)	43.8 (or 44) (27 to 57)	<0.001
Symptomatic Remission	22.1 (Calculated)	9.0 (Calculated)	13 (2 to 25)	0.02
Histologic Improvement	45.6 (Calculated)	16.4 (Calculated)	29 (12 to 43)	<0.001
Histologic-Endoscopic Mucosal Improvement	33.8 (Calculated)	7.5 (Calculated)	27 (14 to 40)	<0.001
Mucosal Healing	33.8 (Calculated)	7.5 (Calculated)	27 (14 to 40)	<0.001
IBDQ Response	63.2 (Calculated)	30.0 (Calculated)	33 (17 to 47)	<0.001

        *Clinical remission (mMS) defined as endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline. Endoscopic improvement defined as endoscopy subscore ≤ 1 with no friability. Clinical response (mMS) defined as reduction from Baseline ≥ 2 points and ≥ 30% in mMS, accompanied by a reduction ≥ 1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤ 1. Symptomatic remission defined as stool frequency subscore of 0 and rectal bleeding subscore of 0. Histologic improvement defined as Geboes score ≤ 3.1. Histologic-endoscopic mucosal improvement defined as Geboes score ≤ 3.1 and endoscopy subscore ≤ 1; mucosal healing defined as Geboes score ≤ 2B.1 and endoscopy subscore ≤ 1. IBDQ response defined as IBDQ score increase of ≥ 16 points from Baseline. Calculated values based on provided differences and placebo rates.*        *Sources:.[1, 7, 8, 9, 10, 11, 12, 13, 14, 44, 45, 46]*    *   **Companion Diagnostic (CDx) Performance:** In the combined CDx-positive patient group (N=75), clinical remission was achieved by 32% (or 31.6%) of those on Tulisokibart versus 11% (or 10.8%) on placebo (Difference 21% or 20.8%; 95% CI 2-38; P=0.02).[1, 7, 10, 11, 12, 13, 14, 46] However, the difference in endoscopic improvement for this CDx-positive subgroup was not statistically significant (37% vs 19%, P=0.06), which led to the termination of the hierarchical testing sequence for subsequent CDx-specific analyses.[1] It was noted that 76% of patients were CDx-negative, and the observed difference in remission rates between the CDx-positive group (32%) and the overall unstratified cohort (26%) was modest.[10]    *   **Safety & Tolerability:** Tulisokibart was generally well-tolerated. The incidence of adverse events (AEs) was similar in the Tulisokibart group (46%) and the placebo group (43%). Most AEs were mild to moderate in severity. Serious adverse events (SAEs) were notably less frequent in the Tulisokibart arm (1%) compared to placebo (8%). No acute infusion reactions were reported, and no new safety signals were identified. Antidrug antibodies (ADAs) developed infrequently, with only three patients showing persistent positivity, and there was no discernible effect of ADAs on clinical remission or endoscopic improvement.[1, 7, 8, 9, 10, 11, 12, 13, 14, 44, 45, 46]    *   **Status:** The trial is listed as active, not recruiting.[6, 40, 53]    *   **Long-Term Extension (OLE) Data (ARTEMIS-UC):** Data presented at DDW2025 indicated that Tulisokibart remained well-tolerated with no new safety signals identified through 50 weeks of treatment in the OLE.[43]    *   **Re-induction Data (ARTEMIS-UC):** Presentations at DDW2025 and ECCOIBD2025 showed that re-induction treatment with Tulisokibart was effective in participants who did not achieve response during the initial induction phase. Up to two Tulisokibart induction regimens, totaling 24 weeks, were well-tolerated without new safety signals.[43]

• Crohn's Disease (CD):
• NCT05013905 (APOLLO-CD / MK-7240-006): This Phase 2a, multi-center, open-label study assessed the efficacy and safety of Tulisokibart as induction treatment in adults with moderately to severely active CD (CDAI score ≥220 and ≤450, with endoscopic evidence of active disease: SES-CD score ≥6, or ≥4 for isolated ileal disease) who had an insufficient response or intolerance to conventional and/or biologic therapies.[5] Patients received intravenous Tulisokibart 1000 mg on Day 1, followed by 500 mg at Weeks 2, 6, and 10. The primary endpoint was endoscopic response (defined as a ≥50% reduction in SES-CD score from baseline) at Week 12, with efficacy benchmarked against historical placebo control rates.[8]
• Patient Population: The study enrolled 55 patients. A high proportion (70.9%) had prior exposure to biologic therapies, and the mean disease duration was 10.3 years, indicating a treatment-experienced population.[8]
• Efficacy Results (Week 12): The results are summarized in Table 4. Table 4: Efficacy Outcomes from Phase 2a APOLLO-CD Trial (NCT05013905) in Crohn's Disease (Week 12)

Endpoint	Tulisokibart (N=55) (%)	Historical Placebo Estimate (%)	Placebo-Adjusted Difference (%)	p-value (vs. historical placebo)
Endoscopic Response (SES-CD ≥50% reduction)	26.0	12	14.0 (in biomarker+ population)	0.002
Clinical Remission (CDAI <150)	49.1	16	33.1 (in all-comers)	<0.001

        *Sources:.[8, 9, 12, 15]*        Efficacy was also observed in patients previously exposed to biologics (33% endoscopic response, 38.5% clinical remission). Significant reductions from baseline in inflammatory markers CRP and fecal calprotectin were noted at all timepoints.[8, 12, 15]    *   **Companion Diagnostic (CDx) Performance:** The pre-specified CDx algorithm showed limited additional benefit for clinical responses. However, an alternative CD-specific algorithm, using the same genetic markers but not derived from clinical trial data, demonstrated enhanced performance, with 57% achieving clinical remission and 45% achieving endoscopic response among this retrospectively identified CDx-positive subgroup.[15]    *   **Safety & Tolerability:** Tulisokibart demonstrated favorable tolerability, with no serious or severe adverse events deemed related to the study drug.[8, 9, 12, 15]    *   **Status:** The trial is listed as active, not recruiting.[6, 40, 56]    *   **Long-Term Extension (OLE) Data (APOLLO-CD):** Similar to the UC trial, the OLE data for APOLLO-CD, presented at DDW2025 and ECCOIBD2025, showed that Tulisokibart was well-tolerated through 50 weeks of treatment with no new safety signals. Infection AEs were mostly non-serious, mild to moderate, resolved, and did not lead to discontinuation.[43]

• Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD):
• NCT05270668 (ATHENA-SSc-ILD / MK-7240-007 / PR200-104): This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Tulisokibart in patients with SSc-ILD.[5] The trial planned to enroll approximately 100 to 152 patients, randomized 1:1 to active treatment or placebo.[22]
• Patient Population: Eligible patients have SSc with onset within the last 5 years, diffuse cutaneous scleroderma (defined by a modified Rodnan skin score between 10 and 35), and SSc-related ILD confirmed by high-resolution computed tomography (HRCT) showing at least 10% lung involvement. Patients must also have a Forced Vital Capacity (FVC) ≥45% of predicted and a Diffusing capacity of the lung for carbon monoxide (DLCO) ≥45% of predicted.[22]
• Endpoints: The primary endpoint is the change from baseline in FVC (in mL) at Week 50. Secondary endpoints include change in quantitative interstitial lung disease (QILD-WL) assessed by HRCT, improvement in the American College of Rheumatology Combined Response Index in Diffuse SSc (ACR-CRISS) score, change in Health Assessment Questionnaire Disability Index (HAQ-DI), and change in Living with Pulmonary Fibrosis (L-PF) Quality of Life (QoL) outcome.[22] The performance of the companion diagnostic will also be assessed.[22]
• Status: The trial is active but not recruiting.[6] Topline results were anticipated in the first half of 2024.[22]
• Regulatory Designation: Tulisokibart (as PRA023) received Fast Track Designation from the FDA for the treatment of SSc-ILD in January 2021.[9]
• Hidradenitis Suppurativa (HS):
• NCT06202901 (MK-7240-012): This is a Phase 2b, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of Tulisokibart in participants with moderate to severe HS.[24] The study includes a 16-week double-blind treatment period followed by a 100-week Long-Term Extension (LTE) period, itself composed of a 40-week Main Extension and a 60-week Optional Extension.[24]
• Patient Population: The trial aims to enroll approximately 147 adults (aged 18-75 years) with a clinical diagnosis of HS for at least 6 months, moderate to severe disease, a history of inadequate response or intolerance to systemic antibiotics, and a draining tunnel count of ≤20 at screening and randomization.[24]
• Endpoints: The primary endpoint is the proportion of participants achieving a 50% reduction in Hidradenitis Suppurativa Clinical Response (HiSCR50) at Week 16. HiSCR50 is defined as at least a 50% reduction in the total abscess and inflammatory nodule (AN) count, with no increase in abscess count and no increase in draining tunnel count. Secondary endpoints include the proportion achieving HiSCR75, change from baseline in the Dermatology Life Quality Index (DLQI), and the incidence of adverse events.[24]
• Status: As of May 2025, the trial was listed as not yet recruiting.[25] The estimated trial completion date is January 2029.[39]

Phase 3 Clinical Trials:

Following the positive Phase 2 results, Merck has rapidly advanced Tulisokibart into large-scale Phase 3 programs for its lead indications.

• Ulcerative Colitis (UC):
• NCT06052059 (MK-7240-001): This is a Phase 3, randomized, double-blind, placebo-controlled program designed to definitively evaluate the efficacy and safety of Tulisokibart in participants with moderately to severely active UC.[20] The program consists of two studies: Study 1, which includes both induction and maintenance treatment phases, and Study 2, which focuses on induction treatment only. The primary hypothesis for both studies is that at least one dose level of Tulisokibart is superior to placebo in achieving clinical remission (as defined by the Modified Mayo Score) at Week 12.[20]
• Patient Population: The program aims to enroll approximately 1020 participants aged 16 to 80 years.[20]
• Status: The trial is actively recruiting participants.[20] It commenced in October 2023, with an estimated primary completion date of November 2026.[20]
• Crohn's Disease (CD):
• NCT06430801 (ARES-CD / MK-7240-008): This Phase 3 program mirrors the structure for UC, comprising a randomized, double-blind, placebo-controlled evaluation of Tulisokibart in participants with moderately to severely active CD.[21] It also includes two studies: Study 1 (induction and maintenance) and Study 2 (induction only), involving both intravenous and subcutaneous formulations of Tulisokibart versus placebo. The primary hypotheses center on achieving clinical remission (defined by CDAI <150 for US/FDA or by stool frequency/abdominal pain score for EU/EMA) and endoscopic response at Week 12 with at least one Tulisokibart dose level being superior to placebo.[21]
• Patient Population: The program aims to enroll approximately 1200 participants (720 in Study 1 and 480 in Study 2) aged 16 to 80 years.[21]
• Status: This trial is actively recruiting.[21] It started in June 2024, with an estimated primary completion date of October 2028.[21]
• Long-Term Extension Study (CD and UC):
• NCT06651281 (MK-7240-011): This Phase 3 open-label extension study is designed to evaluate the long-term safety and efficacy of subcutaneously administered Tulisokibart.[29] Participants who have completed qualifying Phase 2 or Phase 3 parent studies for CD or UC and are deemed by the investigator to derive clinical benefit from continued treatment are eligible to enroll.[29]
• Status: The study is recruiting participants.[29] It initiated in November 2024 and has a very long projected primary completion date of December 2037, underscoring the commitment to understanding the very long-term effects of Tulisokibart.[38]

The rapid advancement of Tulisokibart into large, global Phase 3 programs for both UC and CD shortly after Merck's acquisition of Prometheus Biosciences, coupled with the expansion into other immune-mediated diseases like SSc-ILD and HS, signals a robust development strategy and significant confidence in the therapeutic's potential. This broad and aggressive clinical plan suggests Merck views Tulisokibart as a "pipeline-in-a-product," capable of addressing unmet needs across a spectrum of conditions.[9] The inclusion of a very long-term extension study further highlights the commitment to thoroughly evaluating the durability of response and long-term safety.

Furthermore, the investigation of Tulisokibart in SSc-ILD and HS is particularly noteworthy. SSc-ILD is a severe, progressive fibrotic lung disease and the leading cause of mortality in systemic sclerosis, with limited effective treatments.[22] Hidradenitis suppurativa is a chronic, debilitating, and painful inflammatory skin condition that significantly impacts quality of life and also has few effective therapeutic options.[24] The dual anti-inflammatory and anti-fibrotic mechanism of Tulisokibart is theoretically well-suited to address the underlying pathologies of both these conditions. The FDA's granting of Fast Track Designation for Tulisokibart in SSc-ILD acknowledges the seriousness of this condition and the drug's potential to fill an unmet medical need.[9] Success in these challenging indications would not only provide crucial new treatments but also solidify the therapeutic importance of the TL1A pathway across a wider array of diseases beyond IBD, significantly broadening Tulisokibart's clinical utility and market potential.

6. Companion Diagnostic (CDx)

A key component of the Tulisokibart development program has been the concurrent development of a genetic-based companion diagnostic (CDx) test. This test was designed by Prometheus Biosciences with the aim of identifying patients who have an increased likelihood of responding to Tulisokibart, based on a genetic predisposition to increased TL1A expression.[1]

Performance in Ulcerative Colitis (ARTEMIS-UC, NCT04996797):

In the ARTEMIS-UC Phase 2 trial, the CDx was used to stratify patients. When combining CDx-positive patients from both Cohort 1 (all-comers) and Cohort 2 (CDx-positive only), clinical remission at week 12 was achieved by 32% of patients treated with Tulisokibart compared to 11% of those on placebo (P=0.02).1 In the overall Cohort 1 population (without pre-selection by CDx status), Tulisokibart led to a 26% remission rate versus 1% for placebo (P<0.001).1

While CDx-positive patients demonstrated a numerically higher remission rate on Tulisokibart, the placebo-adjusted benefit (21 percentage points for CDx-positive vs. 25 percentage points for all-comers) was not dramatically different. It was also noted that a significant proportion of patients (76% in one analysis) were CDx-negative, and the absolute difference in remission rates between the CDx-positive group (32%) and the unstratified cohort (26%) was described as small.10 Furthermore, the between-group difference for endoscopic improvement in the CDx-positive subpopulation was not statistically significant (37% vs. 19%, P=0.06), which led to the termination of the hierarchical testing sequence for subsequent analyses in this specific subgroup.1

Performance in Crohn's Disease (APOLLO-CD, NCT05013905):

In the APOLLO-CD Phase 2a trial for Crohn's disease, the pre-specified CDx algorithm reportedly provided only limited additional benefit in predicting clinical responses.15 However, an "alternative CD-specific algorithm," which used the same genetic markers but was not based on the clinical trial data itself, was explored retrospectively and demonstrated enhanced performance. In this exploratory analysis, the alternative algorithm identified a CDx-positive subgroup where 57% achieved clinical remission and 45% achieved endoscopic response.15

Potential Role and Evolving Strategy:

The initial results suggest that while the concept of identifying a TL1A-related genetic signature to predict response is promising, the current companion diagnostic may require further validation and refinement, particularly for Crohn's disease. The exploration of an "alternative CD-specific algorithm" indicates an adaptive approach to the CDx development, suggesting that the specific genetic markers or the way they are weighted might need to be optimized differently depending on the indication (UC vs. CD) or refined as more data becomes available.

The Phase 3 clinical trials for both UC and CD will be crucial in determining the definitive utility and predictive power of the companion diagnostic.13 A significant strategic consideration arises from the observation that a large percentage of patients in the ARTEMIS-UC trial were CDx-negative.10 If Tulisokibart demonstrates substantial efficacy in the broader patient population (CDx-negative individuals included), as suggested by the strong 25% placebo-adjusted remission rate in the all-comers cohort of ARTEMIS-UC 1, a regulatory pathway that does not mandate CDx testing for all patients might be pursued. This would broaden market access. Conversely, if the CDx can reliably identify a subpopulation with exceptionally high response rates, it could still play a vital role in a precision medicine strategy, particularly for guiding treatment choices in refractory patients or in specific clinical scenarios. The ongoing Phase 3 trials will be instrumental in clarifying these aspects and shaping the final regulatory and commercialization strategy for both Tulisokibart and its associated companion diagnostic. The ATHENA-SSc-ILD trial (NCT05270668) is also slated to assess the performance of the companion diagnostic candidate for PRA023.22

7. Aggregated Safety and Tolerability Profile

The safety and tolerability of Tulisokibart have been evaluated across its Phase 1 and Phase 2 clinical trial program.

Overall Summary from Phase 2 (ARTEMIS-UC and APOLLO-CD):

Tulisokibart was generally reported as well-tolerated in both the ARTEMIS-UC (ulcerative colitis) and APOLLO-CD (Crohn's disease) Phase 2 trials.1

In the ARTEMIS-UC study, the overall incidence of adverse events (AEs) was comparable between the Tulisokibart group (46%) and the placebo group (43%). The majority of these AEs were mild to moderate in severity.1 Notably, serious adverse events (SAEs) were less frequent in patients receiving Tulisokibart (1%) compared to those receiving placebo (8%).1 Furthermore, no AEs led to discontinuation of the study drug in the PRA023 (Tulisokibart) arm of ARTEMIS-UC.14

In the open-label APOLLO-CD study, no serious or severe AEs were considered by investigators to be related to the study drug.8

Specific Adverse Events:

The most common AEs reported in more than 5% of patients in any group during the ARTEMIS-UC trial were COVID-19 (which occurred with similar frequency in both Tulisokibart and placebo groups) and worsening of ulcerative colitis (which was, as expected, more frequent in the placebo group).1

Regarding infections, these were reported in 18% of patients in both the Tulisokibart and placebo groups in the ARTEMIS-UC study.1 Long-term extension data from the APOLLO-CD trial, extending up to 50 weeks, indicated no new safety signals related to infections. Most infection AEs observed during the extension were non-serious, mild to moderate in severity, resolved, and did not lead to treatment discontinuation.43

No acute infusion reactions were observed in either group during the ARTEMIS-UC trial.1

Immunogenicity:

The development of antidrug antibodies (ADAs) to Tulisokibart was infrequent during the ARTEMIS-UC trial. Only three patients were reported to have persistent ADA positivity. Importantly, there was no evidence to suggest that the presence of these ADAs had an impact on clinical remission or endoscopic improvement.1 This low immunogenicity profile is an encouraging sign for a biologic therapy intended for chronic administration, as high rates of ADA formation can sometimes lead to a loss of efficacy or hypersensitivity reactions over time.

Long-Term Safety:

Open-label extension (OLE) data from both the ARTEMIS-UC and APOLLO-CD trials, covering up to 50 weeks of treatment, consistently showed that Tulisokibart was well-tolerated, with no new safety signals emerging during the extended treatment period.43 Similarly, re-induction treatment regimens with Tulisokibart, totaling up to 24 weeks, were also reported to be well-tolerated without the identification of new safety concerns.43

Phase 1 Safety (Healthy Volunteers):

While specific AE details from the initial Phase 1a study in healthy volunteers (NCT04676178) are not extensively provided in the available documents, the successful and rapid progression of Tulisokibart into a broad Phase 2 and subsequently Phase 3 program suggests an acceptable safety profile was established in healthy subjects. The primary outcomes for the Phase 1 study in healthy Chinese participants (NCT06829225) explicitly included the number of participants experiencing AEs and the number of participants discontinuing the study due to AEs, underscoring the focus on safety in these early trials.51

The overall safety profile emerging from the Phase 2 program appears favorable, particularly when considering the often complex safety considerations for IBD therapies. The lower rate of SAEs with Tulisokibart compared to placebo in the randomized ARTEMIS-UC study, and the absence of new safety signals during long-term extensions, are positive indicators.[1] This profile may offer advantages over some existing IBD drug classes which can be associated with more significant safety concerns.[8]

8. Pharmacokinetics

The pharmacokinetic (PK) profile of Tulisokibart, which describes how the drug is absorbed, distributed, metabolized, and excreted by the body, has been investigated in Phase 1 clinical trials involving healthy volunteers.

• Phase 1 Data (Healthy Volunteers):
• NCT04676178: This initial first-in-human study would have provided the foundational PK data for Tulisokibart. While specific PK parameters from this trial are not detailed in the provided snippets, its successful completion allowed for progression to later-phase trials.[5]
• NCT06829225 (MK-7240-002, Healthy Chinese Participants): This study specifically aimed to evaluate the PK of Tulisokibart following single intravenous (IV) versus subcutaneous (SC) administration in healthy Chinese participants. Key PK parameters assessed included AUC$_{0-last}$, AUC$_{0-inf}$, C$_{max}$, T$_{max}$, t$_{1/2}$, CL/F, and Vz/F. A secondary objective was to determine the absolute bioavailability of SC Tulisokibart.[51]
• NCT06575595 (MK-7240-010, Healthy Volunteers, SC Autoinjector vs. Syringe): This trial was designed to characterize the PK of a single SC dose of Tulisokibart when administered via an autoinjector compared to administration with a traditional vial and syringe, including evaluation of different concentrations. The PK parameters of interest were similar to those in NCT06829225.[47]
• Key Pharmacokinetic Parameters: The primary objectives of these Phase 1 studies consistently included the determination of:
• Area Under the Concentration-Time Curve (AUC): AUC$_{0-last}$ (to the last quantifiable concentration) and AUC$_{0-inf}$ (extrapolated to infinity) are measures of total drug exposure.[51]
• Maximum Concentration (C$_{max}$): The peak plasma concentration achieved after drug administration.[51]
• Time to Maximum Concentration (T$_{max}$): The time taken to reach C$_{max}$.[51]
• Apparent Terminal Half-life (t$_{1/2}$): The time taken for the plasma concentration of the drug to decrease by half during the terminal elimination phase.[51] A long half-life is often desirable for monoclonal antibodies, allowing for less frequent dosing. For context, a similar anti-TL1A antibody, XmAb942, was reported to have an estimated half-life of over 71 days in humans, supporting potential Q12W (every 12 weeks) maintenance dosing.[52]
• Apparent Clearance (CL/F): The rate at which the drug is cleared from the body, adjusted for bioavailability if administered non-intravenously.[51]
• Apparent Volume of Distribution (Vz/F): A measure of the extent to which a drug distributes into body tissues rather than remaining in the plasma, adjusted for bioavailability.[51]
• Absolute Bioavailability (F%): For SC administration, this measures the fraction of the administered dose that reaches systemic circulation compared to IV administration.[51]

While the specific values for these parameters for Tulisokibart are not available in the provided documents, the design of the Phase 1 trials indicates a thorough characterization of its PK profile. The dosing regimens used in Phase 2 and planned for Phase 3 (e.g., IV induction followed by SC maintenance) would have been informed by these Phase 1 PK findings, aiming to achieve and maintain therapeutic drug concentrations with an acceptable dosing frequency.

9. Regulatory Status and Designations

Tulisokibart has received certain regulatory designations aimed at facilitating its development, but it has not yet received marketing approval from any regulatory agency.

• FDA (United States):
• Fast Track Designation: Tulisokibart (as PRA023) was granted Fast Track Designation by the FDA for the treatment of Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD) in January 2021.[9] This designation is intended to expedite the development and review of drugs that treat serious conditions and fill an unmet medical need.
• Breakthrough Therapy Designation: The provided documents do not indicate that Tulisokibart has received Breakthrough Therapy Designation from the FDA for any indication.[17]
• Orphan Drug Designation: There is no specific mention in the provided snippets that Tulisokibart has received Orphan Drug Designation from the FDA for its lead indications of ulcerative colitis or Crohn's disease.[6]
• Current Review Status: Tulisokibart is not currently under review by the FDA for marketing approval. Phase 3 clinical trials are ongoing for ulcerative colitis and Crohn's disease, and Phase 2 trials are active or concluding for SSc-ILD and planned for Hidradenitis Suppurativa.
• EMA (European Union):
• PRIME (PRIority MEdicines) Scheme: The available information does not suggest that Tulisokibart has been granted access to the EMA's PRIME scheme.[19] While one document mentions that V940 (a different Merck product) received PRIME designation [58], this does not apply to Tulisokibart.
• Orphan Drug Designation: The provided snippets do not indicate that Tulisokibart has received Orphan Drug Designation from the EMA for ulcerative colitis or Crohn's disease.[2] One document explicitly states that the IMP (Investigational Medicinal Product) MK-7240/PRA023 (Tulisokibart) has not been designated as an orphan drug in the EU for the indication of SSc-ILD in the context of trial EudraCT 2021-005206-10 (NCT05270668).[32]
• Current Review Status: Tulisokibart is not currently under review by the EMA for marketing approval. Clinical development is ongoing in Europe as part of the global Phase 3 programs. The primary hypotheses for the Phase 3 Crohn's disease trial (NCT06430801) include endpoints defined according to both US/FDA (CDAI <150) and EU/EMA (stool frequency and abdominal pain score) criteria for clinical remission, indicating planning for submissions in both regions.[21]
• Other Regulatory Bodies: No specific information regarding regulatory status or designations from other international health authorities is available in the provided research materials.
• Companion Diagnostic Regulatory Pathway: The genetic-based companion diagnostic (CDx) being developed alongside Tulisokibart will likely follow a regulatory pathway linked to the drug's approval. Its validation and approval will depend on demonstrating its ability to effectively identify patients who are more likely to benefit from Tulisokibart treatment, as shown in the ongoing clinical trials.

10. Discussion and Future Perspectives

Tulisokibart (MK-7240/PRA023) has emerged as a highly promising investigational therapy, particularly for inflammatory bowel diseases, with a unique mechanism of action that distinguishes it from many existing treatments.

Summary of Key Strengths:

The clinical development program for Tulisokibart has yielded several key strengths:

1. Significant Efficacy in Phase 2 IBD Trials: Tulisokibart demonstrated robust efficacy in inducing clinical remission and endoscopic improvement in patients with moderately to severely active ulcerative colitis (ARTEMIS-UC) and Crohn's disease (APOLLO-CD), many of whom were refractory to prior therapies.[1] The magnitude of placebo-adjusted responses, particularly the 25.0% clinical remission rate in the all-comers UC cohort, is noteworthy.
2. Novel Dual Mechanism of Action: Its ability to target TL1A allows Tulisokibart to modulate both pro-inflammatory and pro-fibrotic pathways.[1] This dual action is a significant potential advantage, especially in Crohn's disease where fibrosis and stricture formation are major complications with limited medical treatments, and in inherently fibrotic conditions like SSc-ILD.
3. Favorable Safety and Tolerability Profile: Across Phase 2 studies and their long-term extensions, Tulisokibart has been generally well-tolerated, with adverse event rates often comparable to placebo and no new significant safety signals emerging with extended use.[1] The low immunogenicity observed so far is also a positive attribute for long-term therapy.[1]
4. Precision Medicine Approach: The co-development of a companion diagnostic (CDx) to identify patients more likely to respond based on genetic markers of TL1A pathway activity represents an effort towards personalized medicine in IBD.[1]
5. Potential in Other Immune-Mediated Diseases: Investigations into SSc-ILD [5] and Hidradenitis Suppurativa [24] highlight its broader therapeutic potential. The FDA Fast Track Designation for SSc-ILD underscores this.[9]

Current Challenges and Unanswered Questions:

Despite the promising outlook, several challenges and questions remain:

1. Phase 3 Confirmation: The efficacy and safety observed in Phase 2 trials need to be robustly confirmed in the larger, ongoing Phase 3 programs for UC and CD.
2. Long-Term Efficacy and Safety: While OLE data up to 50 weeks is encouraging, longer-term data from the dedicated extension study (NCT06651281, extending to 2037) will be critical for understanding the durability of response and any late-emerging safety concerns.
3. Optimal Positioning in Treatment Algorithms: If approved, determining Tulisokibart's precise place in the increasingly complex treatment algorithms for IBD, SSc-ILD, and HS will require further comparative data (though not directly available from current trials) and real-world evidence. Its role relative to existing biologics, small molecules, and other emerging therapies targeting different pathways needs clarification.[46]
4. Companion Diagnostic Utility and Validation: The clinical utility of the CDx needs to be definitively established. The modest predictive benefit seen in UC and the need for an alternative algorithm in CD suggest that further validation and refinement are necessary.[1] The balance between a precision approach and broad market access will depend on Phase 3 outcomes in both CDx-positive and CDx-negative populations.
5. Comparative Effectiveness: The current trials are placebo-controlled. Head-to-head comparisons with other active treatments, particularly newer biologics and small molecules, would be valuable but are not part of the current publicly available trial designs.

Future Research Directions:

Future research should focus on:

1. Deepening Understanding of Anti-Fibrotic Effects: Quantifying the clinical impact of Tulisokibart's anti-fibrotic properties, especially in preventing stricture progression in CD and slowing lung function decline in SSc-ILD.
2. Exploring Other TL1A-Mediated Diseases: Given TL1A's role in various immune pathologies, Tulisokibart could be investigated in other conditions like rheumatoid arthritis or psoriasis.[1]
3. Combination Therapies: Building on preclinical findings (e.g., with anti-IL23p19 [50]), exploring Tulisokibart in combination with other agents could be a strategy for patients with highly refractory disease or to achieve deeper remission.
4. Pediatric Development: While current Phase 3 trials include adolescents (≥16 years) [20], dedicated studies in younger pediatric populations may be warranted if adult data are positive.

Potential Impact on Treatment Paradigms:

If the Phase 3 program confirms the Phase 2 findings, Tulisokibart has the potential to significantly impact treatment paradigms:

• For IBD: It could become a key therapeutic option, particularly for patients with a significant fibrotic component in CD, or those who are refractory to or intolerant of existing treatments. Its favorable safety profile, if maintained, would also be an attractive feature. The dual mechanism offers hope for more comprehensive disease modification than purely anti-inflammatory agents.
• For SSc-ILD and HS: Success in these indications would be a major breakthrough, given the high unmet medical need and limited effective therapies. For SSc-ILD, an effective anti-fibrotic and anti-inflammatory agent could alter the disease course. For HS, a novel systemic therapy with a good safety profile would be a welcome addition.

The strategic acquisition by Merck and the aggressive, broad clinical development plan underscore the high expectations for Tulisokibart. Its journey through Phase 3 and potential regulatory review will be closely watched by the medical community.

11. Conclusion

Tulisokibart (MK-7240/PRA023) is an investigational humanized monoclonal antibody targeting TL1A, a cytokine implicated in both inflammation and fibrosis. Its development, spearheaded initially by Prometheus Biosciences and now by Merck & Co., Inc., has shown considerable promise. Phase 2 clinical trials in ulcerative colitis (ARTEMIS-UC) and Crohn's disease (APOLLO-CD) have demonstrated statistically significant and clinically meaningful improvements in clinical remission and endoscopic outcomes, often in treatment-refractory populations, with a generally favorable safety and tolerability profile.[1]

The dual mechanism of action, addressing both inflammatory and fibrotic pathways, positions Tulisokibart uniquely, offering potential advantages over existing therapies, particularly for fibrostenotic Crohn's disease and other fibrotic conditions like SSc-ILD.[1] The co-development of a companion diagnostic aims to introduce a precision medicine approach, although its definitive role and utility are still being refined through ongoing large-scale Phase 3 trials.[1]

Merck's substantial investment and the rapid, broad expansion of the clinical program into Phase 3 trials for UC and CD, as well as Phase 2 investigations for SSc-ILD (with FDA Fast Track Designation) and Hidradenitis Suppurativa, underscore the strong belief in Tulisokibart's therapeutic potential across multiple indications with high unmet medical needs.[3]

While Tulisokibart has not yet received marketing authorization from the FDA or EMA, the ongoing Phase 3 studies are critical for confirming its efficacy and safety. Successful outcomes could lead to a significant advancement in the management of these complex and often debilitating conditions, potentially offering a new standard of care for selected patient populations. The long-term safety and efficacy data, along with the final role of the companion diagnostic, will be key determinants of its ultimate impact on clinical practice.

Works cited

1. bookcafe.yuntsg.com, accessed May 28, 2025, https://bookcafe.yuntsg.com/ueditor/jsp/upload/file/20241012/1728709871182088044.pdf
2. Tulisokibart: A Promising New Treatment for Inflammatory Diseases - Clinical trials, accessed May 28, 2025, https://clinicaltrials.eu/inn/tulisokibart/
3. Tulisokibart by Merck for Crohn's Disease (Regional Enteritis): Likelihood of Approval, accessed May 28, 2025, https://www.pharmaceutical-technology.com/data-insights/tulisokibart-merck-crohn-s-disease-regional-enteritis-likelihood-of-approval/
4. Human TL1A Tulisokibart Biosimilar | CAS #2648504-55-4 | InvivoGen, accessed May 28, 2025, https://www.invivogen.com/anti-human-tl1a-tulisokibart-biosimilar-antibody
5. Tulisokibart Clinical Naked monospecific - YAbS database - The Antibody Society, accessed May 28, 2025, https://db.antibodysociety.org/db0/1129/
6. Tulisokibart: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed May 28, 2025, https://go.drugbank.com/drugs/DB18719
7. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis - PubMed, accessed May 28, 2025, https://pubmed.ncbi.nlm.nih.gov/39321363/
8. s21.q4cdn.com, accessed May 28, 2025, https://s21.q4cdn.com/488056881/files/doc_presentations/2023/04/Acquisition-of-Prometheus-Biosciences-Investor-Event-Slides-FINAL.pdf
9. EX-99 - SEC.gov, accessed May 28, 2025, https://www.sec.gov/Archives/edgar/data/1718852/000095017023005064/rxdx-ex99_1.htm
10. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis | Request PDF - ResearchGate, accessed May 28, 2025, https://www.researchgate.net/publication/384350103_Phase_2_Trial_of_Anti-TL1A_Monoclonal_Antibody_Tulisokibart_for_Ulcerative_Colitis
11. First-in-Class Therapy for Ulcerative Colitis Proves Effective in Clinical Trial - Mount Sinai, accessed May 28, 2025, https://reports.mountsinai.org/article/gastro2025-tulisokibart
12. Up-and-Coming Tulisokibart Succeeds in Inducing Ulcerative Colitis Remission, accessed May 28, 2025, https://www.managedhealthcareexecutive.com/view/up-and-coming-tulisokibart-succeeds-in-inducing-ulcerative-colitis-remission
13. OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results - ResearchGate, accessed May 28, 2025, https://www.researchgate.net/publication/367563786_OP40_PRA023_Demonstrated_Efficacy_and_Favorable_Safety_as_Induction_Therapy_for_Moderately_to_Severely_Active_UC_Phase_2_ARTEMIS-UC_Study_Results
14. OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results - European Crohn's and Colitis Organisation, accessed May 28, 2025, https://www.ecco-ibd.eu/publications/congress-abstracts/item/op40-pra023-demonstrated-efficacy-and-favorable-safety-as-induction-therapy-for-moderately-to-severely-active-uc-phase-2-artemis-uc-study-results.html
15. DOP87 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn's Disease: Phase 2a APOLLO-CD Study Results | Request PDF - ResearchGate, accessed May 28, 2025, https://www.researchgate.net/publication/367547011_DOP87_The_Anti-TL1A_Antibody_PRA023_Demonstrated_Proof-of-Concept_in_Crohn's_Disease_Phase_2a_APOLLO-CD_Study_Results
16. Targeted drug therapy shows promise for ulcerative colitis remission - News-Medical.net, accessed May 28, 2025, https://www.news-medical.net/news/20240926/Targeted-drug-therapy-shows-promise-for-ulcerative-colitis-remission.aspx
17. Top 7 Breakthrough Drugs for Ulcerative Colitis Treatment - DelveInsight, accessed May 28, 2025, https://www.delveinsight.com/blog/emerging-drugs-for-ulcerative-colitis-treatment
18. JP Morgan Healthcare Conference, accessed May 28, 2025, https://s21.q4cdn.com/488056881/files/doc_events/2024/Jan/09/mrk-jp-morgan-healthcare-conference-2024-for-website.pdf
19. Big Pharma's R&D ROI: Merck, Pfizer, J&J, AbbVie strategies, accessed May 28, 2025, https://www.drugdiscoverytrends.com/are-big-pharma-giants-getting-the-right-roi-on-their-rd-investments-a-visual-exploration/
20. A Study to Evaluate Efficacy and Safety of MK-7240 in Participants With Moderately to Severely Active Ulcerative Colitis - MSD Clinical Trials, accessed May 28, 2025, https://www.msdclinicaltrials.com/trial/nct06052059/
21. A Study to Evaluate the Efficacy and Safety of Tulisokibart in Participants With Moderate to Severe Crohn's Disease - Merck Clinical Trials, accessed May 28, 2025, https://www.merckclinicaltrials.com/trial/nct06430801/
22. Prometheus Biosciences Initiates Third Phase 2 Study of PRA023 for Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) - BioSpace, accessed May 28, 2025, https://www.biospace.com/prometheus-biosciences-initiates-third-phase-2-study-of-pra023-for-systemic-sclerosis-associated-interstitial-lung-disease-ssc-ild
23. Phase 2 Safety and Efficacy Study of Tulisokibart (MK-7240/PRA023) in Subjects With Systemic Sclerosis Associated With Interstitial Lung Disease (SSc-ILD) (MK-7240-007) | UCLA Health Clinical Trials and Research Studies, accessed May 28, 2025, https://www.uclahealth.org/clinical-trials/phase-2-safety-and-efficacy-study-tulisokibart-mk-7240pra023
24. Study to Evaluate Tulisokibart for Hidradenitis Suppurativa (MK-7240-012), accessed May 28, 2025, https://ctv.veeva.com/study/study-to-evaluate-tulisokibart-for-hidradenitis-suppurativa-mk7240012
25. A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Tulisokibart in Participants With Moderate to Severe Hidradenitis Suppurativa - AdisInsight, accessed May 28, 2025, https://adisinsight.springer.com/trials/700382435
26. A Study to Evaluate the Efficacy and Safety of Tulisokibart (MK-7240) in Participants With Moderate to Severe Crohn's Disease (MK-7240-008) - Clinical Trials | Stanford Medicine, accessed May 28, 2025, https://clinicaltrials.stanford.edu/trials/a/NCT06430801.html
27. A Study to Evaluate the Efficacy and Safety of Tulisokibart (MK-7240) in Participants With Moderate to Severe Crohn's Disease (MK-7240-008), accessed May 28, 2025, https://stanfordhealthcare.org/trials/a/NCT06430801.html
28. A Study to Evaluate Efficacy and Safety of Tulisokibart (MK-7240) in Participants With Moderately to Severely Active Ulcerative Colitis (MK-7240-001) | Clinical Research Trial Listing - CenterWatch, accessed May 28, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06052059/a-study-to-evaluate-efficacy-and-safety-of-tulisokibart-mk-7240-in-participants-with-moderately-to-severely-active-ulcerative-colitis-mk-7240-001
29. Error | ClinicalTrials.gov, accessed May 28, 2025, https://clinicaltrials.gov/study/NCT04224272?intr=Zanidatamab&rank=7
30. Study of Tulisokibart for Patients with Systemic Sclerosis and Interstitial Lung Disease, accessed May 28, 2025, https://clinicaltrials.eu/trial/study-of-tulisokibart-for-patients-with-systemic-sclerosis-and-interstitial-lung-disease/
31. Phase 2 Safety and Efficacy Study of Tulisokibart (MK-724... - Esperity Clinical Trials, accessed May 28, 2025, https://clinicaltrial.be/en/details/31691?per_page=20&only_recruiting=0&only_eligible=0
32. EU Clinical Trials Register, accessed May 28, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-005206-10/DE
33. Q1 2024 Reflecting Pipeline to Feb 21, 2025 - Merck.com, accessed May 28, 2025, https://www.merck.com/wp-content/uploads/sites/124/2025/02/Public-Pipeline-1Q2025-1.pdf
34. MK-7240 - UF Health, accessed May 28, 2025, https://ufhealth.org/clinical-trials/mk-7240
35. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Program to Evaluate the Efficacy and Safety of MK-7240 in Participants with Moderately to Severely Active Ulcerative Colitis - Froedtert, accessed May 28, 2025, https://www.froedtert.com/clinical-trials/phase-3-randomized-double-blind-placebo-controlled-program-evaluate-efficacy-and
36. A Study to Evaluate the Efficacy and Safety of Tulisokibart (MK-7240) in Participants With Moderate to Severe Crohn's Disease (MK-7240-008) | Clinical Research Trial Listing - CenterWatch, accessed May 28, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06430801/a-study-to-evaluate-the-efficacy-and-safety-of-tulisokibart-mk-7240-in-participants-with-moderate-to-severe-crohns-disease-mk-7240-008
37. Long-term Safety and Efficacy of Tulisokibart in Crohn's Disease or Ulcerative Colitis, accessed May 28, 2025, https://clinicaltrials.cedars-sinai.edu/view/MK-7240-011-00
38. Extension Study of Long-term Safety and Efficacy of Tulisokibart in Participants With Crohn's Disease or Ulcerative Colitis - MSD Clinical Trials, accessed May 28, 2025, https://www.msdclinicaltrials.com/trial/nct06651281/
39. Study to Evaluate Tulisokibart for Hidradenitis Suppurativa (MK-7240-012), accessed May 28, 2025, https://connect.careboxhealth.com/en-US/trial/listing/604955
40. Tulisokibart | MedPath, accessed May 28, 2025, https://trial.medpath.com/drug/5c39e7046114adff
41. A Study to Evaluate the Efficacy and Safety of Tulisokibart in Participants With Moderate to Severe Crohn's Disease - MSD Clinical Trials, accessed May 28, 2025, https://www.msdclinicaltrials.com/trial/nct06430801/
42. UCSD Inflammatory Bowel Disease Trial → Tulisokibart (MK-7240) in Participants With Moderately to Severely Active Ulcerative Colitis (MK-7240-001), accessed May 28, 2025, https://clinicaltrials.ucsd.edu/trial/NCT06052059
43. tulisokibart (MK-7240) News - LARVOL Sigma, accessed May 28, 2025, https://sigma.larvol.com/product.php?e1=884512&tab=newstrac
44. New Biologic Tulisokibart Beats Placebo in Ulcerative Colitis Trial - The Hospitalist, accessed May 28, 2025, https://blogs.the-hospitalist.org/content/new-biologic-tulisokibart-beats-placebo-ulcerative-colitis-trial
45. First-in-Class Therapy for Ulcerative Colitis Proves Effective in Clinical Trial - Physician's Channel - Mount Sinai New York, accessed May 28, 2025, https://physicians.mountsinai.org/news/first-in-class-therapy-for-ulcerative-colitis-proves-effective-in-clinical-trial
46. Tulisokibart: A New Drug for Moderate-to-Severe UC That May Come With Personalized Medicine - American College of Gastroenterology, accessed May 28, 2025, https://gi.org/journals-publications/ebgi/axenfeld_alkazzi_apr2025/
47. Tulisokibart - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 28, 2025, https://synapse.patsnap.com/drug/6ef2707e46594926b55e7db003db94d1
48. TULISOKIBART - GSRS, accessed May 28, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/ON09TCS5H3
49. Crohn's Disease Recruiting Phase 3 Trials for Tulisokibart (DB18719) | DrugBank Online, accessed May 28, 2025, https://go.drugbank.com/indications/DBCOND0028893/clinical_trials/DB18719?phase=3&status=recruiting
50. TL1A Pathway: Embarking on New Frontiers in IBD Therapy with Biocytogen's Humanized Mice, accessed May 28, 2025, https://biocytogen.com/blog-tl1a-tnfsf15-ibd-inflammatory-bowel-disease-humanized-mouse-model
51. Single Dose Study of Tulisokibart (MK-7240) in Healthy Chinese Participants (MK-7240-002) | MedPath, accessed May 28, 2025, https://trial.medpath.com/clinical-trial/5d075f84c059a5ce/nct06829225-mk-7240-safety-pharmacokinetics-chinese
52. Interim Results from First-in-Human Study of XmAb942 & TL1A Pipeline Update | Xencor, accessed May 28, 2025, https://xencor.com/wp-content/uploads/Interim-Results-from-First-in-Human-Study-of-XmAb942-TL1A-Pipeline-Update.pdf
53. Ulcerative Colitis (DBCOND0029012) | DrugBank Online, accessed May 28, 2025, https://go.drugbank.com/conditions/DBCOND0029012
54. Pharmacokinetic (PK) Characterization of Subcutaneous Tul... - Esperity Clinical Trials, accessed May 28, 2025, https://clinicaltrial.be/fr/details/448679?per_page=100&only_recruiting=0&only_eligible=0&only_active=0
55. Pharmacokinetic (PK) Characterization of Subcutaneous Tulisokibart (MK-7240-010), accessed May 28, 2025, https://ctv.veeva.com/study/pharmacokinetic-pk-characterization-of-subcutaneous-tulisokibart-mk7240010
56. Tulisokibart Active Not Recruiting Phase 2 Trials for Crohn's Disease (CD) Treatment, accessed May 28, 2025, https://go.drugbank.com/drugs/DB18719/clinical_trials?conditions=DBCOND0052193&phase=2&purpose=treatment&status=active_not_recruiting
57. A Study to Evaluate the Efficacy and Safety of Tulisokibart (MK-7240) in Participants With Moderate to Severe Crohn's Disease (MK-7240-008) - Vanderbilt Clinical Trials, accessed May 28, 2025, https://vanderbilt.trialstoday.org/trial/NCT06430801
58. mrk-20231231 - SEC.gov, accessed May 28, 2025, https://www.sec.gov/Archives/edgar/data/310158/000162828024006850/mrk-20231231.htm
59. ECCO-IBD - FirstWord Pharma, accessed May 28, 2025, https://firstwordpharma.com/river/tag/fw_conference/ECCO-IBD
60. Research Grade Tulisokibart - Cell Sciences, accessed May 28, 2025, https://www.cellsciences.com/research-grade-tulisokibart
61. Hidradenitis Suppurativa - Dermatologic Disorders - Merck Manual Professional Edition, accessed May 28, 2025, https://www.merckmanuals.com/professional/dermatologic-disorders/acne-and-related-disorders/hidradenitis-suppurativa
62. Pipeline - Merck.com, accessed May 28, 2025, https://www.merck.com/research/product-pipeline/
63. Merck & Co., Inc. - SEC.gov, accessed May 28, 2025, https://www.sec.gov/Archives/edgar/data/310158/000162828025017867/formars202410-k.pdf
64. Afimkibart - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 28, 2025, https://synapse.patsnap.com/drug/d81bcd9e67d246d6bc4ea9204019fe6e
65. EU/3/24/3014 - orphan designation for treatment of acute promyelocytic leukaemia, accessed May 28, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-24-3014
66. Synapse - Global Drug Intelligence Database, accessed May 28, 2025, https://synapse.patsnap.com/drug/d81bcd9e67d246d6bc4ea9204019fe6e?campaign_promotion=news_series
67. TulisokibarT Add to MyFW+ - Pharma Industry News and Analysis, accessed May 28, 2025, https://firstwordpharma.com/river/tag/fw_product/TulisokibarT