OX40 Inhibition Delivers Significant Response in Treatment-Experienced AD

The pathogenesis of atopic dermatitis (AD) is intricately linked to T-cell-mediated immune responses, with the OX40 receptor on activated T cells playing a pivotal role in driving the inflammatory cascade and the persistence of disease flares.¹ Rocatinlimab (Amgen, Kyowa Kirin), a humanized monoclonal antibody, is a first-in-class T-cell rebalancing therapy designed to block this key co-stimulatory molecule. This targeted mechanism of action aims to mitigate inflammation and potentially modify the course of AD. The ROCKET-SHUTTLE trial, presented as a late-breaking abstract at EADV 2025, investigates the efficacy and safety of rocatinlimab as an add-on therapy for adults with moderate to severe AD.²

The rationale for this study stems from the clinical reality that many patients, even those on advanced systemic therapies, continue to use topical agents for maintenance or to manage breakthrough flares. This trial was designed to evaluate the clinical utility of combining a systemic T-cell rebalancing agent with standard topical care in a patient population reflecting a significant clinical challenge.

Study Design and Patient Population

ROCKET-SHUTTLE was a global, randomized, placebo-controlled, double-blind, phase 3 trial. The study enrolled a total of 746 adult patients with moderate to severe AD who had a history of inadequate response to topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI). A key characteristic of the study cohort was the high percentage of patients with extensive treatment experience, with 59.1% having previously received systemic therapies for AD. Notably, 25.3% of the cohort had prior exposure to biologics or Janus kinase (JAK) inhibitors, underscoring that the trial was conducted in a difficult-to-treat patient population.

Patients were randomized in a 5:4:4 ratio to receive either rocatinlimab 300 mg administered every 4 weeks (Q4W), rocatinlimab 150 mg Q4W, or placebo. All participants were permitted to use low to medium potency TCS or TCI as concomitant therapy from day 1. The study's co-primary endpoints were the proportion of patients achieving an Eczema Area and Severity Index (EASI) score of at least 75% improvement from baseline (EASI 75) and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear) with a ≥2-point reduction from baseline, both assessed at week 24. Key secondary endpoints included EASI 90 and EASI 75 at week 16, and reductions in pruritus.

Efficacy and Safety Data

The trial successfully met both co-primary endpoints, demonstrating the efficacy of rocatinlimab with concomitant topical therapy. At week 24, researchers found the EASI 75 response rates were significantly higher in the rocatinlimab groups compared to placebo. Specifically, 52.3% of patients in the 300 mg group and 54.1% of patients in the 150 mg group achieved EASI 75, compared to 23.5% in the placebo group (P<0.001 for both rocatinlimab arms vs. placebo).

Similarly, the vIGA-AD 0/1 response rates at week 24 were 26.1% and 25.8% for the 300 mg and 150 mg rocatinlimab groups, respectively, versus 12.2% for the placebo group (P<0.001 for both). These results indicate a clinically meaningful improvement in both the extent and severity of the disease. A progressive improvement in efficacy was observed throughout the 24-week period, with no evidence of a plateau in response, suggesting a potential for deeper and more sustained clinical benefit with longer-term use.

The safety profile of rocatinlimab in this trial was consistent with previous studies. The overall rate of treatment-emergent adverse events (TEAEs) was balanced across all groups. Serious adverse events (SAEs) occurred at a slightly higher rate in the rocatinlimab arms (3.1% in the 300 mg group and 4.4% in the 150 mg group) compared to the placebo group (0.9%). Discontinuations due to TEAEs were low and balanced across all treatment arms, suggesting a manageable safety profile in this patient population.

Clinical Implications

The ROCKET-SHUTTLE trial provides crucial evidence supporting the use of rocatinlimab as an effective systemic therapy in the management of moderate to severe AD. The study's design, which incorporates concomitant topical therapy, reflects the reality of clinical practice and validates this combination approach. The trial's success in a heavily pre-treated population is particularly significant, as it suggests that rocatinlimab offers a valuable new option for patients who have exhausted or failed to respond adequately to other systemic treatments, including newer biologics and JAK inhibitors. The observed progressive efficacy over the 24-week period is a promising finding, suggesting that rocatinlimab may provide sustained and deepening therapeutic benefits. Further research, particularly on the long-term durability of response and safety, will be essential to fully integrate rocatinlimab into the AD treatment paradigm.

References

1. Marfil-Cantón M, Prados-Carmona A, Cebolla-Verdugo M, Husein-ElAhmed H, Campos F, Ruiz-Villaverde R. Anti-OX40 biological therapies in the treatment of atopic dermatitis: a comprehensive review. J Clin Med. 2024;13(22):6925. Published 2024 Nov 17. doi:10.3390/jcm13226925
2. Simpson E. Rocatinlimab with concomitant topical therapy significantly improved clinical signs and symptoms of atopic dermatitis in adults: Results from the phase 3 ROCKET-SHUTTLE trial. Presented at: 2025 European Academy of Dermatology and Venerology Congress; September 17-20; Paris, France.