OX40 Targeting in Atopic Dermatitis: A Pathway Under Scrutiny

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Atopic dermatitis is a heterogeneous inflammatory skin disease driven by immune dysregulation across multiple T cell axes — Th2, Th17, Th22, and others — with clinical presentation that varies considerably by patient age, race, and comorbidity profile. The current therapeutic framework largely targets these pathways downstream, blocking individual cytokines such as IL-4, IL-13, or IL-31, or interrupting intracellular JAK-STAT signaling. These approaches are effective, but disease recurrence upon treatment discontinuation remains a persistent limitation for a meaningful proportion of patients.

Over the past several years, 2 agents targeting the OX40 pathway — an upstream regulator of T cell activation operating at the interface between antigen-presenting cells and T cells — advanced into late-phase clinical development for moderate-to-severe atopic dermatitis. The first, rocatinlimab (Kyowa Kirin/Amgen), an anti-OX40 receptor monoclonal antibody, accumulated a substantial Phase 3 efficacy dataset before its clinical program was discontinued in March 2026 following identification of Kaposi's sarcoma cases across the program.² The second, amlitelimab (Sanofi), an anti-OX40 ligand monoclonal antibody, has a distinct mechanism and a regulatory submission on track for the second half of 2026; Sanofi presented topline Phase 3 data at the 2026 American Academy of Dermatology Annual Meeting.³⁻⁵

The mechanistic differences between the 2 drugs — and whether those differences are sufficient to separate their safety profiles — are a matter of active debate among dermatologists. HCPLive spoke with Eingun James Song, MD, FAAD, Co-Chief Medical Officer and Director of Clinical Research at Frontier Dermatology; April W. Armstrong, MD, MPH, Professor and Chief of Dermatology at the University of California, Los Angeles; and Jennifer Soung, MD, FAAD, Director of Clinical Research at Southern California Dermatology and Clinical Professor at Harbor-UCLA Medical Center, to explore the clinical and scientific questions surrounding both drugs and what the current evidence means for patients and the field.

The Case for Upstream Intervention

Current approved biologics and small molecules in atopic dermatitis target the downstream consequences of T cell activation. The rationale for OX40 pathway intervention lies one step further back in the immunological cascade, at the point where T cell priming and expansion begin.

"Everything that we have right now in atopic dermatitis is working on more downstream cytokines that are being released by these Th2 cells by and large," said Song. "A newer approach is to go one step upstream and interact or intervene at where the antigen-presenting cells interact with the T cells. The thought is that if you could block it at that stage, then we may be able to get more of a durable remission even when you stop the treatment. It's almost like you're turning off the faucet rather than trying to mop up the mess."

The OX40 pathway is involved in the expansion of effector T cells and, notably, effector memory T cells — the latter widely understood to underpin disease persistence and recurrence after treatment withdrawal. "Effector memory T cells are interesting because that is a reason why disease persists," Song said. "So even after you get someone clearer, if you stop the drug, it comes back. But if you wipe out or block the resident memory T cells, we do believe that these patients will stay in durable remission even longer off treatment. You could call that disease modification."

The pathway also operates across Th1, Th17, and Th22 effector T cell subsets, not only Th2 — a feature that may offer more consistent coverage across the endotypic heterogeneity of atopic dermatitis. "The thought is that it might have more consistent efficacy across these different endotypes of atopic dermatitis, opposed to your classic Th2 patient," Dr. Song noted.

Two Drugs, Distinct Mechanisms

Both rocatinlimab and amlitelimab target the OX40 pathway, but at different molecular points and with meaningfully different downstream consequences. Rocatinlimab bound the OX40 receptor on activated T cells and, in addition to blocking signaling, depleted those T cells via antibody-dependent cellular cytotoxicity. Amlitelimab targets the OX40 ligand expressed on antigen-presenting cells and blocks the pathway through steric hindrance, without T cell depletion.

"There are two drugs that work on this pathway," Song said. "One is rocatinlimab, which is an OX40 receptor blocker, but it's also a depleter — it depletes those T cells. That could maybe explain some of the adverse events that we've seen with rocatinlimab, which include pyrexia, chills, and ulcerations in the GI. As opposed to amlitelimab, which is an OX40 ligand inhibitor — it works primarily on antigen-presenting cells, but it's not a depleter. It just blocks by steric hindrance, and we don't see the same adverse events."

Armstrong similarly emphasizes this distinction as the basis for anticipating a different safety profile with amlitelimab. "These 2 are different molecules that inhibit different targets of that OX40 pathway," she said. "Rocatinlimab inhibits the OX40 receptor on the activated T cells. Amlitelimab, in contrast, inhibits the OX40 ligand on the dendritic cells. Inhibiting the OX40 ligand on the APC cells actually gives you a different profile in terms of safety compared to rocatinlimab, and I think we are seeing that in the clinical trial results."

Rocatinlimab: Phase 3 Efficacy and Program Discontinuation

Rocatinlimab demonstrated clinically meaningful efficacy in the pivotal ROCKET-IGNITE and ROCKET-HORIZON Phase 3 trials, published in The Lancet in November 2025.¹ In IGNITE, which enrolled 769 adults with moderate-to-severe atopic dermatitis including patients previously treated with a biologic or JAK inhibitor, EASI-75 was achieved by 42% of patients receiving the 300 mg dose and 36% receiving 150 mg, compared with 13% on placebo (P < .001 for both). vIGA-AD 0/1 was achieved by 24% and 19% of the respective dose groups versus 9% on placebo (P < .001 and P = .002, respectively). In the HORIZON monotherapy trial, 33% of patients on rocatinlimab 300 mg achieved EASI-75 versus 14% on placebo (difference 19.1%; 95% CI, 12.4–25.2), with vIGA-AD 0/1 reached by 19% versus 7%.¹ The drug was also associated with adverse events including pyrexia, chills, and aphthous ulcers, and did not demonstrate superiority to dupilumab in head-to-head data.

In March 2026, Kyowa Kirin and Amgen announced the discontinuation of all rocatinlimab clinical trials following a safety review that identified one newly confirmed and one suspected case of Kaposi's sarcoma, in addition to a previously confirmed case, across the program — findings interpreted as suggesting a potential mechanistic link to OX40 modulation.² The program spanned atopic dermatitis, prurigo nodularis, and asthma.

"There were 2 cases of Kaposi's sarcoma with rocatinlimab and maybe a third suspected case," Song said. "Because of that, the company believed it wasn't in their best interest to continue moving on with the development of that drug."

The Kaposi's Sarcoma Signal: Class Effect or Drug-Specific Risk?

Sanofi has disclosed 1 case of Kaposi's sarcoma within the amlitelimab program, occurring in a patient with known risk factors, and has proceeded with its regulatory timeline.⁴ The central question for the field is whether the Kaposi's sarcoma signal observed across the OX40 space is attributable to rocatinlimab's depleting mechanism specifically, or reflects a broader class risk associated with OX40 pathway modulation.

Song notes that the case observed in the amlitelimab program has not been followed by additional confirmed cases, and points to the broader safety profile as reassuring. "In their studies, they did not report a second case of Kaposi's sarcoma. The good news is that when these emerge from some of these medications that are immunomodulators, when you stop the medication, it tends to slowly go away on its own and tends to be limited just to the skin. And we do seem to see these, although rare, in patients who are at higher risk — older men who have sex with men." He adds that the overall adverse event (AE) profile in the amlitelimab trials was favorable: "We're talking AEs that are similar to placebo in some ways, actually numerically lower."

Soung takes a more skeptical view, one that extends to the OX40 class rather than rocatinlimab alone. "There are some serious safety signals that we're seeing with OX40," she said. "Kaposi's sarcoma is a weird, rare cancer. Yes, it happens in our older patients and immunosuppressed, but now you have a safety signal. It's going to be a warning — the FDA is going to put a warning because it's unusual and unexpected. So then that makes it harder to offer that treatment to patients." On the mechanistic distinction between the 2 agents, she is direct: "I don't think there's a difference. It's a class effect, and I was always worried about targeting T cells in immunology, so I'm not sure it's the best target."

Amlitelimab Phase 3 Data

Amlitelimab was evaluated at dosing intervals of every 4 weeks (Q4W) and every 12 weeks (Q12W) across three Phase 3 trials, with data presented as late-breaking research at AAD 2026 approximately 3 to 4 weeks after the rocatinlimab discontinuation announcement.³⁻⁵ In COAST 1 (n = 601), vIGA-AD 0/1 was achieved by 21.1% (Q4W) and 22.5% (Q12W) versus 9.2% on placebo (P ≤ .01 for both), with EASI-75 rates of 35.9% and 39.1% versus 19.1% (P < .001 for both).³ In COAST 2, vIGA-AD 0/1 rates of 25.3% (Q4W) and 25.7% (Q12W) were observed versus 14.8% on placebo (P ≤ .025 for both), though more stringent co-primary estimand endpoints for European regulatory purposes were not met.⁴ The combination therapy SHORE trial produced the highest response rates, with vIGA-AD 0/1 achieved by 28.7% (Q4W) and 32.3% (Q12W) versus 16.8% on placebo, and EASI-75 rates approaching 47–48% in treated arms versus 32.3%.⁵ In the ATLANTIS long-term safety analysis, vIGA-AD 0/1 increased from 35.4% at week 24 to 50.3% at week 52, with EASI-75 rising from 62.9% to 76.5%.⁴

A notable feature across the datasets was a progressive efficacy curve with no plateau at week 24. "We saw very steady and consistent improvement over the first 24 weeks for the Phase 3 studies, both in the monotherapy trials as well as the combination study with topical corticosteroid," Armstrong said. "What we're seeing is a medication that steadily improved in its performance from baseline over 24 weeks, and we're hoping perhaps we can see in the more stringent endpoints potentially even continued improvement over time."

Song echoed this observation. "What's really fascinating about this drug is that the curves — the inflection point is not just at the primary endpoint, which is 24 weeks; it continues to climb. And one can believe that even up to a year, these patients will continue to get better." On durability of response following treatment discontinuation, Phase 2 data offered an early signal: "Based on the Phase 2 data, it was quite a long time — six months, sometimes plus, before those patients had a flare."

Patient Selection and Clinical Positioning

Amlitelimab's coverage of non-Th2 immune axes is a point of clinical interest, particularly for patients whose disease presentation does not fit the canonical Th2 profile. "Because the mechanism of action is being an OX40 ligand inhibitor, it can decrease the abnormally elevated signaling of a number of different pathways — not just Th2, but also Th17, Th22, and other pathways that contribute to atopic dermatitis pathogenesis in different patient populations," Armstrong said. "The proposition here is likely having an additional therapeutic option where it can address a number of these different pathways, thereby addressing the heterogeneous presentation of atopic dermatitis."

Both Armstrong and Song suggest the more moderate end of the moderate-to-severe spectrum as a likely patient population for amlitelimab, with the extended dosing intervals — particularly Q12W maintenance — representing a practical consideration in treatment planning. Armstrong also raised the possibility of eventually evaluating temporary treatment discontinuation in well-controlled patients. Soung, however, questions whether the clinical differentiation from existing agents is sufficient to justify the risk profile, particularly given that extended dosing is already being pursued for dupilumab. "They're really trying to aim for less frequent dosing," she said. "However, I think dupilumab is going to be able to achieve that without having to maybe even do further studies — there are already studies showing that you can dose every 8 weeks." More broadly, she argues the bar for a new entrant in this space is high: "Your new drug not only has to have the cleanest safety profile, as good as dupilumab, but to offer something different, you need better efficacy."

On the question of treatment sequencing, Armstrong is measured. "How it actually shakes out as far as treatment sequencing, I think it remains to be seen, but I am cautiously optimistic that this will be beneficial for the right patient. A lot of it will just depend on the right patient selection."

A Fractured Outlook

Rocatinlimab's discontinuation has raised questions about the OX40 space that will not be resolved by mechanistic argument alone. Amlitelimab's Phase 3 program has produced a consistent efficacy signal and a safety profile that does not replicate rocatinlimab's pattern of adverse events, but regulatory submissions are pending, additional Phase 3 data are expected, and longer-term safety surveillance will be required. How the field ultimately positions amlitelimab — if it reaches approval — will depend on those data, the FDA's assessment of the Kaposi's sarcoma question, and clinician comfort with the drug's profile relative to well-established alternatives.

"Atopic dermatitis is a much more heterogeneous disease than something like psoriasis, which for the most part is pretty homogenous," Song said. "We should always welcome not just new therapies, but therapies that have unique mechanisms of action that get to the underlying issue of the disease that you're trying to treat. I am optimistic that amlitelimab will have a role for us as dermatologists."

Armstrong’s disclosures include AbbVie, Almirall, Arcutis, ASLAN, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, EPI, Incyte, Janssen, LEO Pharma, Eli Lilly, Nimbus, Novartis, Ortho Dermatologics, Parexel, Pfizer, Regeneron, Sanofi, Sun, and UCB. Soung’s disclosures include AbbVie, Amgen, Arcutis, Aslan, Bristol Myers Squibb, Coval Biopharma, Dermavant, Eli Lilly, Johnson & Johnson, KoBio Labs, National Psoriasis Foundation, Novartis, Ortho Dermatologic, Oruka, Pfizer, Regeneron/Sanofi, and UCB. Song’s disclosures include AbbVie, Alphyn Biologics, Amgen, Apogee, Arcutis, Bristol Myers Squibb, Boehringer Ingelheim, Dermavant, DermBiont, Galderma, Incyte, Janssen, LEO Pharma, MoonLake, Novartis, Ortho, Pfizer, Regeneron, Sanofi, Sun Pharmaceutical Industries, Timber Pharmaceuticals, and UCB.

References

1. Guttman-Yassky E, et al. Efficacy and safety of rocatinlimab for the treatment of moderate-to-severe atopic dermatitis in ROCKET-IGNITE and ROCKET-HORIZON: two global, double-blind, placebo-controlled, randomised phase 3 clinical trials. Lancet. 2025;406(10510):1424-1442. doi:10.1016/S0140-6736(25)01865-3

2. Kyowa Kirin Co., Ltd. Kyowa Kirin announces discontinuation of rocatinlimab clinical trials. GlobeNewswire. Published March 3, 2026. https://www.globenewswire.com/news-release/2026/03/03/3248303/0/en/Kyowa-Kirin-Announces-Discontinuation-of-Rocatinlimab-Clinical-Trials.html

3. Sanofi. Sanofi's amlitelimab met all primary and key secondary endpoints in the COAST 1 phase 3 study in adults and adolescents with atopic dermatitis. Press release. Published September 4, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-09-04-05-00-00-3144170

4. Sanofi. Sanofi's amlitelimab confirms its potential in atopic dermatitis. Press release. Published January 23, 2026. https://www.sanofi.com/en/media-room/press-releases/2026/2026-01-23-06-00-00-3224400

5. Sanofi. AAD: new results from Sanofi's amlitelimab phase 3 studies in atopic dermatitis presented in late-breaking research session. Press release. Published March 28, 2026. https://www.sanofi.com/en/media-room/press-releases/2026/2026-03-28-15-00-00-3264184