5 Novel Mechanisms Reshaping Atopic Dermatitis Treatment and the Phase 2-3 Clinical Trials That Support Them

November 6, 2025

Atopic Dermatitis

Novel AD therapies targeting OX40, IL-13, IL-36, IL-22, and IL-2 pathways show promise for disease modification and extended dosing intervals in phase 2-3 trials.

The atopic dermatitis (AD) treatment landscape has undergone a remarkable transformation with the introduction of targeted biologics and JAK inhibitors, offering alternatives to traditional systemic immunosuppressants and corticosteroids. And the pipeline continues to expand with investigational treatments targeting novel pathways in AD pathophysiology.

Understanding these emerging mechanisms helps clinicians anticipate future treatment options, aids in patient selection and therapy sequencing, and illuminates potential advantages beyond symptom control, including disease modification and less frequent dosing schedules that could improve adherence. Here are 5 promising mechanistic approaches currently advancing through clinical development and a note on recent clinical trial findings.

1. OX40 Pathway Inhibition: T-Cell Rebalancing

Key drugs: Rocatinlimab (Amgen/Kyowa Kirin), Amlitelimab (Sanofi)

The Science: OX40 is a co-stimulatory receptor expressed on activated T cells that plays a critical role in sustaining inflammatory responses in AD. Unlike therapies that broadly suppress immune function, OX40 inhibitors work by rebalancing T-cells, modulating immune response more selectively and potentially reducing pathogenic inflammation while preserving protective immune function.

Clinical Evidence: Rocatinlimab has advanced through an extensive phase 3 clinical program called ROCKET. The ROCKET-SHUTTLE trial evaluated the drug in combination with topical therapy in treatment-experienced adults with moderate to severe AD, showing significant improvements in AD signs and symptoms.1 Long-term safety data have been positive, with topline results indicating a favorable safety profile over extended treatment periods.2

Amlitelimab met all primary and secondary endpoints in its phase 3 trial, which evaluated dosing both every 4 weeks and every 12 weeks.3 Both regimens demonstrated superiority to placebo in efficacy and skin clearance measures, with efficacy continuing to increase throughout the treatment period.

What's Notable: OX40 inhibitors are dosed as infrequently as every 8-12 weeks, which could significantly improve treatment adherence and patient satisfaction, all investigators note. Perhaps more importantly, the novel mechanism of T-cell rebalancing raises the possibility that these agents could alter the underlying disease course rather than simply controlling symptoms1-3

2. IL-13 Selective Inhibition: Next-Generation Precision

Key drug: APG777 (Apogee Therapeutics)

The Science: While current therapies like dupilumab block both interleukin (IL)-4 and IL-13 signaling by targeting the shared IL-4 receptor alpha subunit, APG777 uses a more selective approach by specifically inhibiting IL-13 alone. The rationale is based on growing evidence that IL-13 may be the more critical driver of AD pathology, particularly in skin barrier dysfunction and chronic inflammation.4

Clinical Evidence: Apogee Therapeutics reported positive topline results from part A of the APEX phase 2 clinical trial.4 The investigational IL-13 inhibitor demonstrated an Eczema Area and Severity Index-75 response rate of 66.9%, a substantial improvement that compares favorably with existing therapies. The trial protocol also incorporated reduced injection frequency.4

What's Notable: The potential for a "best-in-class" designation the investigators suggest reflects optimism that selective IL-13 inhibition could offer an improved benefit-risk profile. The combination of strong efficacy signals and less frequent dosing could position APG777 as a compelling option in an increasingly crowded treatment space.

3. IL-36 Inhibition: A Topical Innovation

Key drug: GX-03 (Turn Therapeutics)

The Science: IL-36 is a member of the IL-1 cytokine family that contributes to skin inflammation in AD. The delivery method is what makes GX-03 particularly interesting: it's a topical IL-36 inhibitor. Topical delivery could offer localized action at the site of disease, reduced systemic exposure, and potentially fewer systemic adverse effects.5

Clinical Evidence: Turn Therapeutics launched its first clinical trial to assess GX-03 in atopic dermatitis in July this year.5 While the phase 1 trial is underway, preclinical data provided encouraging signals, demonstrating that GX-03 reduced disease severity by more than 50% compared to placebo in animal models.5 Results from the current clinical study are expected by year-end.

What's Notable: The topical formulation sets GX-03 apart from the systemic biologics and JAK inhibitors that have dominated recent AD drug development. If successful, GX-03 could offer a potent treatment option for patients who prefer topical therapy or who have localized disease that doesn't warrant systemic treatment. The IL-36 pathway represents relatively unexplored territory in AD therapeutics.5

4. IL-22 Pathway Antagonism: Targeting Tissue Remodeling

Key drug: Temtokibart (LEO Pharma)

The Science: While IL-22 can have protective functions in certain contexts, dysregulated IL-22 signaling contributes to inflammation and tissue remodeling in chronic skin diseases. In AD, IL-22 has been implicated in epidermal hyperplasia and barrier dysfunction. Temtokibart antagonizes IL-22FA1, a component of IL-22 signaling, differing substantially from the type 2 inflammation-focused approaches of most current AD biologics.6

Clinical Evidence: LEO Pharma announced positive preliminary phase 2b findings for temtokibart in atopic dermatitis in mid-September.6 The IL-22FA1 antagonist achieved positive outcomes for the primary endpoint based on percentage change in EASI from baseline to week 16, with the 3 highest dose levels all meeting this endpoint.6

What's Notable: The IL-22 pathway represents a relatively unexplored target compared to the well-trodden IL-4/IL-13 axis. Success with temtokibart could validate IL-22 antagonism as a viable therapeutic strategy. Given that IL-22 plays a role in tissue remodeling and chronicity, blocking this pathway might be particularly valuable in patients with long-standing, recalcitrant disease where structural skin changes have occurred.

5. IL-2 Pathway Agonism: Boosting Regulatory Control

Key drug: Rezpegaldesleukin (Nektar Therapeutics)

The Science: While most AD therapies work by blocking pro-inflammatory signals, rezpegaldesleukin takes the opposite approach: it's an IL-2 pathway agonist designed to boost regulatory T cells (Tregs). Tregs help maintain immune homeostasis and prevent excessive inflammatory responses. In AD, Treg function is often impaired, contributing to unchecked type 2 inflammation. By selectively activating the IL-2 receptor pathway on Tregs, rezpegaldesleukin aims to restore immune balance from within rather than simply blocking inflammatory mediators.7

Clinical Evidence: The REZOLVE-AD phase 2b trial produced promising results that highlighted rezpegaldesleukin's novel mechanism of action, demonstrating the agent's ability to engage its target and produce clinical improvements in AD signs and symptoms. Results were announced in late September.7

What's Notable: The potential for disease modification is perhaps the most exciting aspect of IL-2 pathway agonism. By restoring Treg function and rebalancing the immune system, rezpegaldesleukin, like other drugs in development, might move beyond symptom supression to modify the underlying immune dysregulation that drives AD. If this proves true in longer-term studies, it could represent a paradigm shift in how we think about AD treatment, moving from chronic suppression to potential immune system normalization.7

The Takeaway for Clinical Practice

The diversity of mechanisms advancing through clinical development signals a maturing treatment landscape for atopic dermatitis. Healthcare providers can anticipate several important shifts:

More Options for Personalized Treatment: With multiple mechanisms targeting different aspects of AD pathophysiology, clinicians will have greater flexibility to match treatments to individual patient characteristics, preferences, and prior treatment responses.

Potential for Disease Modification: Several of these novel mechanisms—particularly OX40 inhibition and IL-2 agonism—suggest the possibility of moving beyond symptom control to actually modifying the disease course.

Improved Convenience: The emergence of therapies with dosing intervals of 8-12 weeks addresses a significant quality-of-life concern for patients on long-term treatment.

Topical Innovation: The development of mechanism-specific topical agents like GX-03 could fill an important niche for patients with localized disease or those who prefer to avoid systemic therapy.

While exact timelines depend on clinical trial results and regulatory review, several of these agents could potentially reach the market within the next 2-3 years. Amlitelimab and rocatinlimab, having completed phase 3 trials, are furthest along in development.

For healthcare providers managing patients with atopic dermatitis, staying informed about these emerging options is increasingly important. As the treatment algorithm grows more complex, understanding the mechanistic rationale behind different therapies will help guide rational treatment selection and sequencing decisions.