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Kyowa Kirin and Amgen terminate rocatinlimab trials over malignancy signal in atopic dermatitis

Japan-based Kyowa Kirin Co., Ltd. and partner Amgen have discontinued all ongoing clinical trials for rocatinlimab, an anti-OX40 monoclonal antibody that...

Edited by Robert McTiernan··5 min read

Kyowa Kirin and Amgen Terminate All Rocatinlimab Clinical Trials Over Emerging Malignancy Signal

Japan-based Kyowa Kirin Co., Ltd. and partner Amgen have discontinued all ongoing clinical trials for rocatinlimab, an anti-OX40 monoclonal antibody that had been in late-stage development for moderate-to-severe atopic dermatitis, prurigo nodularis, and moderate-to-severe asthma. The decision, announced via press release, follows a planned safety review that identified emerging cases of malignancies with possible viral or immune-related links, including Kaposi's sarcoma. The companies concluded that potential risks may outweigh benefits for the studied patient populations.

The rocatinlimab discontinuation marks the end of a decade-long development program for a molecule once positioned as a first-in-class T-cell rebalancing therapy. Rocatinlimab (previously designated AMG 451 by Amgen and KHK4083 by Kyowa Kirin) is a fully human, non-fucosylated IgG1 antibody that targets the OX40 receptor on activated T cells. Its non-fucosylated Fc region was engineered to enhance antibody-dependent cellular cytotoxicity, enabling not only blockade of OX40 co-stimulatory signaling but active depletion of OX40-expressing pathogenic T cells. The therapeutic hypothesis was that reducing these cell populations could rebalance immune function in Th2-driven diseases, potentially offering durable disease modification rather than cytokine suppression alone.

The ROCKET Program and Efficacy That Preceded the Safety Signal

The global Phase III ROCKET program comprised eight studies spanning six continents, evaluating rocatinlimab as monotherapy and in combination with topical corticosteroids in adults and adolescents with moderate-to-severe atopic dermatitis. Two pivotal trials had already reported positive results before the program was halted. ROCKET HORIZON (NCT05651711) delivered top-line data in September 2024 showing that the 300 mg subcutaneous dose met both co-primary endpoints — vIGA-AD 0/1 with at least a 2-point reduction and EASI-75 at Week 24 — along with all key secondary endpoints. ROCKET IGNITE (NCT05398445) similarly met its co-primary endpoints.

Additional Phase III studies were underway, including ROCKET BOOST (NCT05724199), evaluating combination therapy with topical corticosteroids; ROCKET LAUNCH (NCT05899816), assessing additional dosing regimens; an open-label adolescent study (NCT05633355); and a long-term open-label extension (NCT05882877). A Phase II dose-ranging study in prurigo nodularis (NCT06376045) and early clinical work in asthma were also active. All have now been discontinued.

The Safety Signal That Ended the Program

The safety review identified emerging concerns around malignancies with possible viral or immune-related etiology. According to the press release, this included one new confirmed case and one suspected case of Kaposi's sarcoma, in addition to a previously confirmed case. The companies stated that while the overall number of malignancy cases across the program remained below expected background rates, the characteristics of these cases raised what they described as a plausible biological concern that could not be excluded.

The signal carries a degree of mechanistic coherence. Kaposi's sarcoma is caused by human herpesvirus 8 (HHV-8), and immune surveillance against HHV-8 depends in part on functional T-cell responses. A therapy designed to deplete activated T cells through enhanced ADCC could, in principle, compromise immune vigilance against viral-associated malignancies. The companies have not disclosed detailed rocatinlimab safety data beyond the malignancy cases described in the announcement. Both companies stated they are notifying investigators and regulatory authorities and will conduct a comprehensive analysis of the full dataset.

A Long Development Arc Cut Short

Kyowa Kirin rocatinlimab development began with a Phase I open-label dose-escalation study in Japanese adults with atopic dermatitis (NCT02528357), initiated around 2015, with results published in 2018. A Phase II dose-ranging study in ulcerative colitis was also conducted but that indication was deprioritized. The Phase IIb study in atopic dermatitis (NCT03703102), initiated in October 2018, met its primary endpoint, and data presented at the EADV Congress in October 2021 drew attention for showing sustained clinical improvement even after drug discontinuation — a finding interpreted as possible evidence of disease modification through T-cell depletion.

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In June 2021, Amgen and Kyowa Kirin formalized a joint development and commercialization agreement, with Amgen taking on the sponsor role for the global Phase III program. Kyowa Kirin stated in the termination announcement that it would retain control of the global rocatinlimab program, including regulatory filings and future commercialization decisions, though there is no indication of any path forward for the molecule.

Atopic Dermatitis Treatment Landscape and the OX40 Pathway

The atopic dermatitis treatment landscape has grown increasingly crowded. Dupilumab (Sanofi/Regeneron), targeting IL-4 and IL-13, remains the market leader among biologics. Tralokinumab (LEO Pharma), targeting IL-13, and the JAK inhibitors abrocitinib (Pfizer) and upadacitinib (AbbVie) are approved. Lebrikizumab (Eli Lilly), another IL-13 antibody, and nemolizumab (Galderma), targeting IL-31, have received recent approvals or are in late-stage review. Rocatinlimab was differentiated from all of these by its upstream mechanism — targeting the T cells that produce inflammatory cytokines rather than the cytokines themselves.

The OX40 pathway itself has not yielded an approved therapy in any disease. In inflammatory indications, GBR 830 (GSK), a humanized anti-OX40 antibody, completed Phase II in atopic dermatitis but has shown no Phase III activity. KY1005, an anti-OX40 ligand antibody, completed Phase IIa in atopic dermatitis with an unclear development trajectory. The rocatinlimab safety signal may further dampen enthusiasm for OX40 antagonism in inflammatory disease, though the relevance of these findings to other molecules with different antibody formats and effector functions remains uncertain.

In oncology, OX40 agonists — designed to stimulate rather than suppress T-cell activity — continue in early-phase development. These include INBRX-106 (Inhibrx), PF-04518600 (Pfizer), and HLX51 (Shanghai Henlius), all in Phase I or Phase II studies for solid tumors. The mechanistic concerns raised by rocatinlimab's antagonist approach do not directly apply to agonist programs.

The termination leaves no OX40-targeted therapy in late-stage development for any indication. For atopic dermatitis, the field's remaining pipeline is concentrated around cytokine-targeted biologics and small molecules, with disease modification through T-cell depletion now lacking a clinical-stage candidate.

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