Highlights
– Rocatinlimab (anti‑OX40) met coprimary endpoints (EASI‑75 and vIGA‑AD 0/1) at week 24 in two independent global phase 3 trials (ROCKET‑IGNITE and ROCKET‑HORIZON).
– Efficacy signals were dose‑dependent and statistically significant versus placebo: EASI‑75 rates for 300 mg rocatinlimab were 42% (IGNITE) and 33% (HORIZON) at week 24; vIGA‑AD 0/1 rates were 24% and 19%, respectively.
– Safety profile was generally acceptable; most common treatment‑emergent events were pyrexia, chills, and aphthous ulcers, predominantly mild or moderate and concentrated around the first dose.
Background and disease burden
Atopic dermatitis (AD) is a chronic, inflammatory, relapsing skin disease that can substantially impair quality of life through intense pruritus, disrupted sleep, and psychosocial sequelae. For patients with moderate‑to‑severe disease who do not achieve control with topical measures, systemic targeted therapies including monoclonal antibodies and Janus kinase (JAK) inhibitors have transformed management. Nonetheless, treatment gaps remain: some patients have suboptimal responses, lose response over time, or experience adverse events that limit therapy. New mechanisms of action that modify the pathogenic immune cell milieu may expand therapeutic options and provide durable benefit.
OX40 (CD134) is a co‑stimulatory receptor expressed on activated T cells that supports survival and function of pro‑inflammatory T‑cell subsets. Rocatinlimab is a monoclonal antibody that binds OX40, inhibiting OX40‑OX40L interactions and reducing numbers of pathogenic T cells, an approach described as T‑cell rebalancing. The ROCKET programme evaluated whether OX40 blockade with rocatinlimab improves clinical outcomes in adults with moderate‑to‑severe AD.
Study design
ROCKET‑IGNITE (IGNITE) and ROCKET‑HORIZON (HORIZON) were two global, randomised, double‑blind, placebo‑controlled phase 3 trials with 24‑week double‑blind treatment periods conducted in 19 countries each. Eligible adults (≥18 years) had a confirmed diagnosis of AD for ≥1 year and moderate‑to‑severe disease defined by baseline EASI ≥16, vIGA‑AD 3 or 4, and body surface area involvement ≥10%.
IGNITE randomized patients 3:2:2 to subcutaneous rocatinlimab 300 mg, rocatinlimab 150 mg, or placebo. HORIZON randomized patients 3:1 to rocatinlimab 300 mg or placebo. Dosing schedule in both trials was weeks 0, 2, and 4, followed by every 4 weeks with the last dose at week 20. Randomisation was stratified by baseline vIGA‑AD (3 versus 4) and geographic region (Japan; other Asian countries; rest of world).
Coprimary endpoints for both trials were the proportion of patients achieving EASI‑75 (≥75% improvement from baseline) and the proportion achieving vIGA‑AD 0 or 1 (clear/almost clear with ≥2‑point improvement) at week 24. Rescue therapy (topical agents, phototherapy, systemic therapy) was permitted from day 1; patients who received rescue were imputed as nonresponders for subsequent visits. Efficacy analyses included all randomised patients (intention‑to‑treat); safety analyses included all patients who received ≥1 dose and were grouped by actual treatment received.
Key findings
Enrollment and baseline
IGNITE enrolled 769 patients (after protocol revision two early enrollees were excluded from analysis); analysis populations included 328 in the 300 mg rocatinlimab group, 217 in the 150 mg group, and 222 placebo. HORIZON randomized 726 patients (543 rocatinlimab 300 mg; 183 placebo). Baseline disease severity and geographic distribution were balanced across groups by stratified randomisation.
Efficacy outcomes
Both trials met their coprimary endpoints.
In IGNITE at week 24:
- EASI‑75: 138/326 (42%) for rocatinlimab 300 mg, 78/215 (36%) for rocatinlimab 150 mg, and 28/219 (13%) for placebo. Percentage differences versus placebo were 29.5% (95% CI 22.3–36.1) for 300 mg and 23.4% (95% CI 15.4–30.9) for 150 mg (both p<0.001).
- vIGA‑AD 0 or 1: 77/326 (24%) for 300 mg, 41/215 (19%) for 150 mg, and 19/219 (9%) for placebo. Percentage differences versus placebo were 14.9% (95% CI 8.8–20.6) for 300 mg (p<0.001) and 10.3% (95% CI 3.8–16.6) for 150 mg (p=0.002).
In HORIZON at week 24:
- EASI‑75: 178/543 (33%) for rocatinlimab 300 mg versus 25/183 (14%) for placebo (percentage difference 19.1%, 95% CI 12.4–25.2; p<0.001).
- vIGA‑AD 0 or 1: 105/543 (19%) for rocatinlimab 300 mg versus 12/183 (7%) for placebo (percentage difference 12.8%, 95% CI 7.6–17.3; p<0.001).
These results indicate a clear and statistically significant benefit of rocatinlimab over placebo for both global measures of disease activity at 24 weeks, with a dose response observed in IGNITE.
Safety
Treatment‑emergent adverse events (TEAEs) were similar in overall incidence between rocatinlimab and placebo groups. The most commonly reported adverse events that met the prespecified threshold (≥4% incidence in any rocatinlimab group and at least twice the rate of placebo) included:
- Pyrexia: 105/870 (12%) in 300 mg rocatinlimab; 26/214 (12%) in 150 mg rocatinlimab.
- Chills: 48/870 (6%) in 300 mg; 5/214 (2%) in 150 mg.
- Aphthous ulcers: 38/870 (4%) in 300 mg; 6/214 (3%) in 150 mg.
Pyrexia and chills were frequently characterized as injection‑related reactions, typically mild or moderate in severity and occurring after the first dose. Serious adverse event rates were 2%–5% in rocatinlimab groups and 4%–6% in placebo groups. No deaths were reported. Overall, the safety profile was described as clinically acceptable for the 24‑week treatment window.
Expert commentary and interpretation
Rocatinlimab demonstrated statistically significant and clinically meaningful improvements in two large, well‑conducted phase 3 trials across geographically diverse populations. The coprimary endpoints (EASI‑75 and vIGA‑AD 0/1) are widely used and relevant to clinicians and regulators. Strengths of the programme include randomized, double‑blind design, large sample sizes, and concordant outcomes in two independent trials.
Mechanistically, OX40 blockade represents a biologically plausible approach. By targeting a co‑stimulatory receptor on activated T cells, rocatinlimab aims to reduce pathogenic T‑cell persistence and restore immune balance, which might complement or provide an alternative to therapies that target type 2 cytokines or intracellular signalling pathways.
However, several considerations should temper interpretation. Cross‑trial comparisons are inherently limited because of differences in inclusion criteria, background therapy, rescue policies, timing of primary endpoints, and patient populations. Although rocatinlimab produced meaningful responses, absolute responder rates (EASI‑75 at 24 weeks of ~33–42% for 300 mg) may be lower than the highest response rates reported in some trials of other systemic agents for AD; direct head‑to‑head comparisons are required to define relative effectiveness. Importantly, the trials allowed rescue therapy from day 1 and treated rescue‑receiving patients as nonresponders thereafter, which is a conservative analytic approach but can complicate interpretation of treatment durability.
Safety signals were manageable in the 24‑week period. Injection‑related systemic reactions (fever, chills) concentrated around the first dose are notable and may affect early tolerability. Aphthous ulcers and other mucosal effects warrant monitoring. Longer‑term extension data and real‑world experience will be needed to assess durability of benefit, risk of infections, immune‑mediated events, and the effects of chronic OX40 modulation on immune surveillance.
Populations not addressed in these trials include adolescents and children (pediatric AD), pregnant or breastfeeding individuals, and patients with certain comorbidities. Subgroup analyses (for example, baseline disease severity, atopic comorbidities, and prior systemic therapy exposure) that may be reported in full publications or subsequent manuscripts will be important to inform patient selection.
Limitations and research gaps
- Duration: 24 weeks provides short‑to‑mid‑term efficacy and safety data; longer follow‑up is required.
- Comparative effectiveness: no active comparator arms were included; head‑to‑head trials versus established biologics or JAK inhibitors are necessary to position rocatinlimab in treatment algorithms.
- Generalisability: although global, trial populations may underrepresent certain demographic or comorbidity subgroups; pediatric data are absent.
- Mechanistic correlates: translational biomarkers (e.g., changes in T‑cell subsets, cytokine profiles) will help understand responders versus nonresponders and inform combination strategies, but such data were not the primary focus of the reported results.
Clinical implications and conclusion
ROCKET‑IGNITE and ROCKET‑HORIZON provide robust phase 3 evidence that rocatinlimab, an anti‑OX40 monoclonal antibody, improves disease activity in adults with moderate‑to‑severe atopic dermatitis at 24 weeks compared with placebo, with an acceptable safety profile in the trial setting. If confirmed in longer‑term follow‑up and post‑marketing experience, OX40 blockade may become a valuable addition to the therapeutic armamentarium for AD, offering an alternative mechanism of action for patients who have inadequate responses or intolerances to existing therapies.
Clinicians should weigh efficacy, early injection‑related reactions, and the absence of head‑to‑head data when considering rocatinlimab’s potential future role. Pending regulatory approvals and availability of additional data (long‑term safety, real‑world effectiveness, pediatric use), rocatinlimab represents a promising biologic option grounded in T‑cell modulation.
Funding and trial registration
The trials were funded by Amgen and Kyowa Kirin. The studies were registered at ClinicalTrials.gov: ROCKET‑IGNITE (NCT05398445) and ROCKET‑HORIZON (NCT05651711). The primary manuscript: Guttman‑Yassky E, et al. Lancet. 2025; DOI:10.1016/S0140‑6736(25)01865‑3.
References
1) Guttman‑Yassky E, Kabashima K, Worm M, 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 Nov 25:S0140‑6736(25)01865‑3. doi:10.1016/S0140‑6736(25)01865‑3.
2) Simpson EL, Bieber T, Guttman‑Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348. doi:10.1056/NEJMoa1610020.
Note: This article synthesizes and interprets the primary phase 3 trial report. Clinicians should consult full trial publications, regulatory labelling, and guidelines as they become available for prescribing decisions.
