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Explore OX40/OX40L inhibition in atopic dermatitis: phase 3 amlitelimab efficacy, safety signals, and what upstream immune control could mean.
Welcome back to ABCs in Dermatology!
000:00 - Introduction: Why OX40/OX40L Matters in Atopic Dermatitis and Chronic Inflammation
08:37 - Ligand vs Receptor Targeting: Mechanistic Differences and the Role
26:39 - Phase 2/3 Data for Amlitelimab: Efficacy, Dosing Frequency, and Disease Modification Signals
41:58 - Safety Profile, Patient Selection, and Future Directions for OX40L Inhibition
Upstream immune regulation in atopic dermatitis is emerging as a central focus of therapeutic development, with OX40–OX40 ligand signaling offering a potential pathway for more durable disease control beyond downstream cytokine blockade.
In this episode of ABCs in Dermatology, co-hosts Christopher Bunick, MD, PhD, and Lindsay Ackerman, MD, examine the evolving science behind OX40 and OX40 ligand inhibition, with particular focus on how this pathway may alter T-cell activation, memory T-cell formation, and immune homeostasis in chronic inflammatory skin disease.
The episode, which is supported by Sanofi with independently developed content, frames the pathway as one of the most closely watched areas in atopic dermatitis drug development, particularly as phase 3 data begin to clarify both the promise and remaining questions around upstream immune modulation. Bunick explains that OX40 ligand, expressed on antigen-presenting cells and other cell types such as dermal fibroblasts, interacts with OX40 on activated T cells as a costimulatory signal.
By targeting this upstream interaction, investigational agents may reduce multiple downstream inflammatory pathways, including TH1, TH2, TH17, and TH22 signaling, while preserving or restoring regulatory T-cell activity. Ackerman emphasizes that this mechanism raises the possibility of disease modification, though both hosts note that the field still needs clearer definitions around what that term means clinically, whether durable remission, reduced treatment frequency, or true off-drug control.
A major portion of the discussion centers on distinguishing OX40 ligand blockade from OX40 receptor inhibition, particularly the implications of T-cell–depleting versus nondepleting antibody designs. That distinction has become increasingly relevant following Kyowa Kirin’s March 3, 2026, announcement that all ongoing rocatinlimab trials would be discontinued after a planned safety update identified emerging malignancy concerns with possible viral or immune-related links, including 1 new confirmed case and 1 suspected case of Kaposi sarcoma in addition to a previously confirmed case.
Kyowa Kirin noted the overall malignancy rate remained below expected background rates but said the characteristics of the cases raised a plausible biological concern that could not be excluded. Against that backdrop, the hosts review safety considerations in the OX40 pathway more broadly, including pyrexia, chills, headache, and malignancy surveillance. In Sanofi’s phase 3 amlitelimab program, the company reported no Kaposi sarcoma events across COAST 1, COAST 2, or SHORE, with malignancy rates low, below 1%, and generally similar between amlitelimab and placebo groups.
Sanofi also reported 2 cumulative Kaposi sarcoma cases among 3778 patients exposed to amlitelimab across all indications, both in patients with known risk factors, and no additional cases across an estimated 4630 patients in the full development program, including blinded studies.
The episode also reviews phase 3 data for amlitelimab, a fully human, non–T-cell-depleting monoclonal antibody targeting OX40 ligand, across COAST 1, COAST 2, and SHORE. The studies enrolled patients aged 12 years and older with moderate-to-severe atopic dermatitis and evaluated amlitelimab given every 4 weeks or every 12 weeks, with both regimens following a loading dose. COAST 1 and COAST 2 evaluated amlitelimab as monotherapy in 601 and 589 participants, respectively, while SHORE evaluated amlitelimab with topical corticosteroids, with or without topical calcineurin inhibitors, in 643 participants.
Bunick and Ackerman highlight that the amlitelimab data showed progressively increasing efficacy through Week 24, with Sanofi reporting no evidence of plateau across endpoints. In COAST 1, vIGA-AD 0/1 responses were 21.1% with every-4-week dosing and 22.5% with every-12-week dosing, compared with 9.2% for placebo; EASI-75 responses were 35.9% and 39.1%, respectively, compared with 19.1% for placebo.
In SHORE, where amlitelimab was studied with topical therapy, vIGA-AD 0/1 responses reached 28.7% and 32.3% with every-4-week and every-12-week dosing, compared with 16.8% for placebo, while EASI-75 responses were 48.1% and 46.8%, compared with 32.3%.
The hosts note that these later-improving response curves are particularly relevant when considering the potential for extended dosing intervals and long-term immune recalibration. They also emphasize the clinical importance of less frequent dosing, given Sanofi’s statement that the data reinforce the potential for every-12-week dosing from the start, while underscoring that amlitelimab remains investigational and has not been evaluated by any regulatory authority.
Relevant disclosures for Bunick include AbbVie, South Beach Symposium, Almirall, Apogee Therapeutics, Arcutis Biotherapeutics, Daiichi Sankyo, Eli Lilly, LEO Pharma, US, Novan, Novartis, Ortho Dermatologics, Palvella Therapeutics, Pfizer Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Timber Pharmaceuticals, and UCB. Relevant disclosures for Ackerman include AbbVie, Alumis, Amgen, Arcutis, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Galderma, L'Oréal, Novartis, Sun Pharmaceutical, and UCB.
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