Unlocking the Potential of the OX40 Pathway in Atopic Dermatitis Treatment

"I think directing ourselves toward the costimulatory molecules can have a profoundly different effect than our prior set of therapies,” Lawrence Eichenfield, MD, said in this Dermatology Times DermView custom video series.

Titled Exploring the Emerging Role of the OX40 Pathway–Targeted Therapies in Atopic Dermatitis, Raj Chovatiya, MD, PhD, MSCI, and Eichenfield engaged in an expert-level discussion on the evolving understanding of atopic dermatitis (AD) pathophysiology and its therapeutic implications, with a focus on the OX40-OX40L pathway.

The Unmet Needs in Atopic Dermatitis

The conversation begins with a reflection on how far the field has come. While significant systemic advancements have transformed care for moderate-to-severe AD, there remain key unmet needs. Eichenfield, vice chair of the Department of Dermatology at UC San Diego and chief of pediatric and adolescent dermatology at Rady Children’s Hospital, emphasized that even with cutting-edge treatments, many patients continue to experience suboptimal outcomes, including incomplete symptom relief and fluctuating disease control.

“There’s still that core clinical need of doing better for more patients and certainly looking for different agents that might work in a subset of patients that don’t have enough response with our other biologics or advanced systemic therapies,” Eichenfield noted.

Chovatiya, clinical associate professor at the Rosalind Franklin University Chicago Medical School, founder and director of the Center for Medical Dermatology and Immunology Research in Chicago, and a Dermatology Times Editorial Advisory Board member, added that achieving long-term, durable remission remains a challenge and that both the broad efficacy across patients and depth of response still need improvement.

Understanding the Heterogeneity of AD

The discussion shifted toward the heterogeneity of AD, both clinically and immunologically. Eichenfield explained how variable symptom presentation, trigger sensitivity, and treatment responses reflect a complex, multifactorial disease process involving environmental, immunologic, and genetic contributors. Chovatiya noted the importance of T-cell subsets in disease expression, highlighting the central role of adaptive immune dysfunction and calling AD “a fascinating push and pull between intrinsic and extrinsic.”

This sets the stage for exploring the OX40-OX40L pathway, a costimulatory immune checkpoint that plays a critical role in early T-cell activation, differentiation, and memory formation. The clinicians explained that OX40 is expressed on activated T cells, while OX40L is expressed on antigen-presenting cells. Their interaction drives T-cell proliferation and survival—functions not targeted by current cytokine- or receptor-specific therapies.

The Role of the OX40-OX40L Pathway

Chovatiya and Eichenfield argue that upstream modulation of T-cell function through this pathway may offer a more comprehensive and durable therapeutic effect, particularly for patients whose disease involves multiple T-cell subsets. Blocking OX40 or its ligand has the potential to broadly dampen T cell–mediated inflammation while minimizing immune suppression. They emphasize that while this pathway plays a fundamental role in normal T cell activation, its chronic activation in AD and other immune-driven conditions like alopecia areata leads to sustained T cell survival, effector differentiation, and reduced regulatory control, contributing to disease persistence.

The conversation introduces a key clinical concept: OX40 and its ligand are not inherently pathogenic, but their overactivity tips the immune balance. Thus, modulation—not elimination—is the therapeutic goal. Eichenfield also touched on how early-life immunologic “imprinting” may shape T cell responses later in life, likening persistent effector T cells to “bullies” influenced by earlier immune exposures.

Chovatiya and Eichenfield then explored the emerging therapeutic agents targeting this pathway, highlighting front-runners in late-stage clinical development:

• Rocatinlimab (anti-OX40): A T cell–depleting monoclonal antibody (mAb), currently in phase 3 trials. The ROCKET studies demonstrated significant reductions in Eczema Area and Severity Index scores, with a subset of patients maintaining extended disease remission post treatment.
• Amlitelimab (anti-OX40L): A nondepleting mAb targeting antigen-presenting cells. Results from the phase 2 STREAM-AD trial showed promising and durable efficacy, with biomarker reductions in Th2/Th22 axes.

Other pipeline agents include IMG-007, STAR-0310, and APG-990, with varying mechanisms (depleting vs nondepleting) and stages of development.

Long-Term Disease Control

When asked about these up-and-coming therapies, Eichenfield said, “We want to see efficacy over time. We’re looking at what happens long term, and then we’re looking at the safety set to see if there’s a difference because they are immunologically changing different sets of cells.”

Clinically, the clinicians suggested that while response onset may be slower than with IL-13 inhibitors or Janus kinase inhibitors, the trade-off may be longer durability and fewer dosing requirements. This raises the possibility of disease modification—a rare goal in AD therapeutics.

“There are a lot more steps you have to go through to really cause an outcome and an effective change,” Chovatiya noted.

As for future placement in the treatment landscape, both experts agree it’s too early to determine, but they anticipate a role for OX40-pathway inhibitors either early posttopical failure or in patients who haven’t responded to other biologics. Eichenfield and Chovatiya emphasized 2 critical areas for further research: predictive biomarkers to guide treatment selection and long-term safety surveillance.

Encouragingly, no major safety concerns such as serious infections or malignancies have emerged thus far, reinforcing the promise of this novel pathway in reshaping the AD treatment paradigm.