Tulisokibart's Phase IIb HS Signal: First-in-Class Promise Meets Phase 3 Attrition Reality

MSD's Tulisokibart Phase IIb Study Meets Primary Endpoint in HS

Merck & Co (MSD) announced positive Phase IIb results for its investigational humanised monoclonal antibody, tulisokibart, in patients with moderate to severe hidradenitis suppurativa (HS). The multi-centre, randomised, double-blind, placebo-controlled MK-7240-012 study achieved its primary endpoint, demonstrating that both high- and medium-dose regimens were superior to placebo at week 16. Specifically, 72% of patients in the high-dose arm (480mg every two weeks) and 64% in the medium-dose arm (480mg every four weeks) achieved a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50), compared to 35% in the placebo arm. This marks the first positive Phase IIb data for the anti-TL1A class in dermatology, with plans to advance tulisokibart to Phase III for HS patients.

• The Phase IIb MK-7240-012 study successfully met its primary endpoint, with tulisokibart showing significant efficacy in moderate to severe hidradenitis suppurativa. At week 16, 72% of patients on the high-dose (480mg every two weeks) and 64% on the medium-dose (480mg every four weeks) achieved HiSCR50, representing substantial improvements of 37% and 29% respectively over the 35% response rate observed in the placebo group.
• Beyond the primary endpoint, tulisokibart also demonstrated numerical improvements in key secondary endpoints. A HiSCR75 response was achieved by 41% of high-dose and 40% of medium-dose participants, compared to 15% for placebo. Additionally, patients in the high- and medium-dose groups experienced mean reductions in the Dermatology Life Quality Index (DLQI) of -5.62 and -3.50, respectively, versus -2.46 for placebo.
• The safety profile of tulisokibart was generally consistent across treatment arms and comparable to placebo. Adverse events occurred in 42.9% of high-dose, 47.6% of medium-dose, and 52.4% of low-dose participants, versus 40.9% for placebo. Serious adverse events were low (2.4% in high/medium-dose, 4.8% in low-dose, 2.3% in placebo), with no serious or opportunistic infections reported.

Tulisokibart's Positive Phase IIb Results in Hidradenitis Suppurativa

Several recent randomised trials have advanced the evidence base for biologic therapies in hidradenitis suppurativa (HS), spanning established agents and investigational molecules. The studies below illustrate the range of efficacy and safety profiles observed across different mechanistic targets.

• PIONEER I and II — Adalimumab: Two similarly designed Phase 3, double-blind, placebo-controlled trials evaluated adalimumab 40 mg weekly in patients with HS. The primary endpoint — at least a 50% reduction from baseline in abscess and inflammatory-nodule count with no increase in abscess or draining-fistula counts at week 12 — was met in both trials. Clinical response rates at week 12 were 41.8% (vs. 26.0% placebo; P=0.003) in PIONEER I and 58.9% (vs. 27.6% placebo; P<0.001) in PIONEER II. Serious adverse events in period 1 occurred in 1.3% of adalimumab patients and 1.3% of placebo patients in PIONEER I, and in 1.8% and 3.7%, respectively, in PIONEER II. In period 2, rates of serious adverse events were 4.6% or less across all groups in both studies, with no significant between-group differences.

• Phase 2 Risankizumab Trial (NCT03926169) — Risankizumab: This Phase 2, multicentre, randomised, double-blind, placebo-controlled trial evaluated risankizumab — a humanized immunoglobulin G1 monoclonal antibody inhibiting interleukin 23 via its p19 subunit — in 243 patients with moderate-to-severe HS. The primary endpoint of HiSCR at week 16 was not met: HiSCR was achieved by 46.8% with risankizumab 180 mg, 43.4% with risankizumab 360 mg, and 41.5% with placebo. The study was terminated early. Incidence of treatment-emergent adverse events (TEAEs), severe TEAEs, TEAEs considered possibly related to study drug, and TEAEs leading to discontinuation were generally low and comparable across treatment groups.

• Network Meta-Analysis of Biologics in HS — Multiple Interventions: A 2024 systematic review with network meta-analysis (NMA) encompassing 13 randomised controlled trials, 14 interventions, and 2,748 participants assessed comparative efficacy in moderate-to-severe HS. Odds of achieving clinical response were significantly superior versus placebo for adalimumab (RR: 0.37, 95% CI = 0.06–0.63), adalimumab QW (RR: 0.63, 95% CI = 0.43–0.87), secukinumab (RR: 0.25, 95% CI = 0.11–0.47), and secukinumab Q2W (RR: 0.24, 95% CI = 0.1–0.46). Data for bimekizumab and CJM112 were characterised as promising, while infliximab showed inconsistent clinical response. The blockade of IL-23 and CD5a pathways — via guselkumab, risankizumab, and vilobelimab — was assessed as insufficient to recommend further Phase 3 investigation.

Addressing Unmet Needs in Moderate to Severe HS

Hidradenitis suppurativa continues to present significant therapeutic challenges, particularly for patients with advanced or refractory disease who have exhausted available biologic options. Emerging research highlights several distinct populations and clinical gaps where current treatment paradigms fall short.

• Patients with draining tunnels (dTs): Among patients with moderate-to-severe HS, 46% have draining tunnels, and this subgroup carries a substantially greater clinical and HR-QoL burden — including significantly higher rates of inflammation/redness (73% vs. 63%), drainage from lesions (62% vs. 40%), pain on sitting (48% vs. 37%), low mood/depression (30% vs. 18%), sleep disturbance (28% vs. 19%), and fatigue (28% vs. 18%) compared to those without tunnels. Despite being significantly more likely to be treated with biologics (41% vs. 27%), many tunnel-eligible patients have not received them, representing a clear access and treatment gap.

• Multi-refractory patients who have failed anti-TNFα and anti-IL-17 therapies: A prospective real-world study evaluated guselkumab, an anti-IL-23 monoclonal antibody, specifically in patients with prior treatment failure or contraindications to anti-TNFα and/or anti-IL-17 therapy. At week 16, 40% achieved HiSCR, rising to 50% by week 48, with mean IHS4 scores falling from 14.3 to 9.3 and an average 10-point reduction in DLQI — supporting guselkumab as a potential option in this underserved population.

• Severe refractory HS unresponsive to single biologics: The limitations of monotherapy are highlighted by a case report in which dual blockade of IL-17A (secukinumab) and IL-36R (recibokibart) was employed in a patient with Hurley stage III refractory HS. HiSCR50 was achieved at week 2 and HiSCR100 by week 10, with pain scores decreasing from 8 to 2 and significant ultrasound-confirmed tunnel size reduction — underscoring the unmet need for combination biologic strategies targeting draining tunnels.

• Patients requiring objective disease monitoring tools: A cross-sectional study demonstrated that HS lesions exhibit epidermal barrier dysfunction — measured by increased transepidermal water loss (TEWL) and erythema — that correlates with inflammatory severity and Hurley stage. A direct association was observed between inflammatory nodule TEWL and IHS4 stage, pointing to an unmet need for validated, objective biomarkers of disease activity to complement clinical scoring.

• Surgical candidates with moderate-to-severe HS: A prospective study of 82 patients (80% Hurley II, 20% Hurley III) who were naïve to systemic biologic treatments demonstrated that wide surgical excision significantly improved DLQI from 11.7 at baseline to 4.7 at six months (p < 0.001), alongside significant reductions in pain (NRS-11) and modified Hidradenitis Suppurativa Score (mHSS). This reinforces surgery as an essential component of multimodal care, particularly for patients not yet on or not responding to biologics.

Expanding Tulisokibart's Potential Beyond Hidradenitis Suppurativa

Tulisokibart, an anti-TL1A monoclonal antibody developed by Prometheus Biosciences (a subsidiary of Merck), is being investigated across multiple inflammatory gastrointestinal indications beyond hidradenitis suppurativa. Evidence from phase 2 trials demonstrates clinical activity in both ulcerative colitis and Crohn's disease, with the intervention model varying by study design.

Tulisokibart's Success Validates Anti-TL1A Pathway in HS

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin condition that significantly impacts patients' quality of life, often leading to persistent pain, scarring, and the need for surgical interventions. Despite available treatments, a substantial unmet need persists, with many patients experiencing treatment failure. The recent announcement of positive Phase IIb results for Merck's investigational anti-TL1A monoclonal antibody, tulisokibart, offers a beacon of hope for this challenging disease.

Tulisokibart demonstrated impressive efficacy, with 72% of patients in the high-dose arm and 64% in the medium-dose arm achieving a HiSCR50 response, significantly outperforming placebo. This robust data not only underscores the potential of tulisokibart as a highly effective therapeutic option but also marks a pivotal moment for the anti-TL1A class. This is the first time an anti-TL1A therapy has shown positive Phase IIb results in dermatology, validating the TL1A/DR3 axis as a critical pathway in HS pathogenesis. Research indicates that TL1A, a novel alarmin cytokine, is involved in various inflammatory conditions and plays a role in both immune cell activity and fibrosis, which is particularly relevant given HS's complex pathology.

For Merck, advancing tulisokibart to Phase III represents a strategic move to solidify its position in the dermatology biologics market with a differentiated, novel mechanism of action. This could diversify its portfolio and offer a unique value proposition by potentially addressing both the inflammatory and fibrotic components of HS. However, several considerations remain as the program progresses:

• Immunogenicity: As with many monoclonal antibodies, the potential for anti-drug antibody development needs careful monitoring in larger trials, as it could theoretically influence drug pharmacokinetics or efficacy.

• Comprehensive Safety Profile: While Phase IIb data is promising, the full long-term safety and tolerability profile in a broader patient population will be crucial for market acceptance and differentiation.

• Competitive Landscape: Tulisokibart will enter a market with existing biologics. Its Phase III results will need to clearly demonstrate sustained superior efficacy, a favorable safety profile, or unique benefits to secure a strong position.

Ultimately, the success of tulisokibart in Phase IIb is a significant step forward, not just for Merck, but for the entire HS community, potentially ushering in a new era of targeted therapies for this underserved patient population.