What OX40 inhibitors are in clinical trials currently?

Introduction to OX40 and its Role in Immunotherapy

Overview of OX40 Function
OX40, also known as CD134, is a costimulatory receptor belonging to the tumor necrosis factor (TNF) receptor superfamily. It is expressed predominantly on activated T cells—both CD4+ helper and CD8+ cytotoxic subsets—after antigen engagement. The primary biological function of OX40 is to amplify T cell activation, drive their proliferation, and enhance their survival. Once expressed on the T cell surface after engagement of the T-cell receptor (TCR) with antigen major histocompatibility complex (MHC) molecules presented by antigen-presenting cells (APCs), OX40 binds to its ligand OX40L (CD252), which is expressed on APCs such as dendritic cells. This interaction is critical not only for the expansion of effector T cells but also for the generation and maintenance of long-lasting immunological memory. In some contexts, the OX40-OX40L interaction can also modulate regulatory T cell (Treg) function, thereby fine-tuning immune responses to avoid overactivity.

Importance in Cancer Immunotherapy
The modulation of the OX40 pathway has been increasingly recognized as a promising strategy in cancer immunotherapy. In the tumor microenvironment, where multiple immune inhibitory mechanisms operate to block the classical antitumor immune response, OX40 signaling is one of the key activators that can potentially “step on the gas” to drive T cell effector functions. In several preclinical models, engagement of OX40 not only enhances effector T cell responses but can also reduce the suppressive activity of Tregs at the tumor site. Because of these dual actions, altering OX40 signaling can tilt the balance within the tumor microenvironment towards effective antitumor immunity. Although many of the early clinical studies have focused on OX40 agonists to stimulate immune responses against cancer, there is growing interest in targeting the OX40-OX40L axis in diverse clinical settings, including autoimmune and inflammatory diseases, where the objective shifts from stimulation of immunity to its attenuation. This duality makes OX40 a particularly interesting target across a spectrum of conditions.

Current OX40 Inhibitors in Clinical Trials

List of OX40 Inhibitors
Based on the structured and reliable data from synapse, several OX40 pathway–targeting agents are currently under clinical investigation. They generally target either the OX40 receptor itself or its ligand, OX40L, and are being evaluated primarily in the context of inflammatory diseases such as atopic dermatitis (AD) and, in some cases, cancer. The main agents include:

• Telazorlimab – A humanized antibody directed against OX40. In clinical settings, particularly in atopic dermatitis, Telazorlimab has been used to suppress the inflammatory cascade by reducing the number of OX40+ T cells and OX40L+ dendritic cells. Its Phase II studies have reported that patients in the treatment arm achieved primary endpoints such as significant reductions in EASI (Eczema Area and Severity Index) scores compared to placebo.

• Rocatinlimab – Another humanized OX40 receptor antibody currently being evaluated in multiple clinical trials. Rocatinlimab has been administered in Phase II studies in patients with moderate-to-severe AD, where it demonstrated statistically significant improvement in EASI scores over placebo, with responses maintained even following a drug-free follow-up period. Additional Phase III clinical studies targeting inflammatory skin conditions, including prurigo nodularis, are also underway to assess its long-term efficacy and safety.

• IMG-007 – An OX40 receptor (OX40R) antibody that is in earlier stages of clinical investigation (proof-of-concept studies and Phase 1b/2a trials) in adult populations with atopic dermatitis. IMG-007 is being evaluated for its safety, pharmacokinetics, and potentially its early efficacy signals in modulating the immunologic response by interfering with OX40 signaling.

• Amlitelimab – Although slightly distinct in its mechanism by targeting the OX40 ligand (OX40L) rather than the receptor, Amlitelimab is a competitive antibody that disrupts the OX40-OX40L interaction. According to the recent Astria Therapeutics 2023 Annual Report, Amlitelimab has initiated Phase III clinical trials. Its development is focused on indications like atopic dermatitis, and its advancement into later-stage trials underscores the expectation that blockade of the OX40-OX40L interaction may yield clinical benefits.

• KY1005 – An anti-OX40L antibody, KY1005 has been evaluated in Phase II clinical settings as part of the broader effort to target the OX40 pathway. Preliminary data indicate that KY1005 is capable of achieving significant improvements in EASI scores among patients with AD compared to placebo groups. While the final results remain to be posted, this candidate represents another therapeutic strategy where inhibition of the ligand side of the pathway is being explored.

Phases of Clinical Trials
A comprehensive view on the development stages is crucial:

• Phase I: Early trials are primarily designed to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics (PK/PD) in healthy participants, as well as in patients with early indications. For instance, IMG-007’s Phase I data, involving single-dose or ascending-dose studies in healthy volunteers, are used to confirm safe dosing ranges before advancing to patient populations.

• Phase 1b/2a: Early proof-of-concept studies, which for agents like IMG-007 in atopic dermatitis provide additional data on both therapeutic activity and safety in the target patient population. These studies help in refining optimal dosing schedules and initial efficacy signals.

• Phase II: In this stage, agents such as Telazorlimab and Rocatinlimab are subjected to larger, randomized controlled trials to gauge clinical efficacy. In Phase II studies, endpoints like EASI-75 (75% improvement in Eczema Area and Severity Index) are put forward to determine whether the drug reaches predefined clinical benefits. Telazorlimab demonstrated that AD patients achieved higher rates of EASI improvement versus placebo, reinforcing its efficacy in modulating pathogenic immune responses.

• Phase III: Late-stage, larger-scale trials are underway or planned for agents such as Amlitelimab and Rocatinlimab. These pivotal trials are intended to provide robust evidence of clinical benefit and safety, ideally leading to regulatory approval. For example, Amlitelimab is currently in Phase III trials to determine its efficacy in conditions like AD, while Rocatinlimab is simultaneously undergoing Phase III evaluation in prurigo nodularis and other indications.

Mechanism of Action of OX40 Inhibitors

Biological Mechanism
The OX40 pathway modulates T cell responses and comprises the receptor OX40 on T cells and its binding partner OX40L on APCs. By inhibiting either component, these agents can disrupt the downstream costimulatory signals that normally intensify T cell responses. Telazorlimab, Rocatinlimab, and IMG-007 bind directly to the OX40 receptor, effectively blocking the interaction between OX40 and OX40L. This blockade dampens the exaggerated T cell activation, proliferation, and cytokine production that are implicated in disease pathogenesis, such as the Th2-, Th1-, and Th17-driven pathways observed in atopic dermatitis. By contrast, Amlitelimab and KY1005, which target OX40L, act by preventing ligand binding to OX40, thereby reducing downstream activation signals. The overall biologic effect of these inhibitory interactions involves decreased activation of inflammatory cytokine cascades, reduction in T cell proliferation and inflammatory infiltrates, and in many settings, modulation of Treg function.

Effects on Tumor Microenvironment
While the primary focus for many of these agents is on allergic and autoimmune diseases (e.g., atopic dermatitis), the principles extend to the tumor microenvironment in cancer immunotherapy as well. In tumors, OX40 signaling can enhance T cell effector functions; hence, the selective inhibition of this pathway in situations of hyper-activation might help restore a balanced immune homeostasis. In cancers characterized by an immunosuppressive tumor microenvironment, the careful titration of OX40 pathway modulation can potentiate the antitumor response by reducing the suppressive function of Tregs and potentially altering the cytokine milieu to favor a more immunogenic setting. Preclinical studies have shown that altering OX40-mediated costimulation may lead to a reduction in immunosuppressive cytokines and foster better tumor infiltration by activated T cells, indirectly enhancing the effects of other therapies like checkpoint inhibitors. However, it is crucial to note that in cancer therapy the prevailing strategy has often been to use OX40 agonists to boost antitumor immunity, whereas in inflammatory conditions the strategy shifts toward inhibition. The current inhibitors being developed for AD and other autoimmune indications serve as proof-of-concept for safely manipulating this pathway, with future directions potentially adapting similar concepts for selective use in cancer.

Clinical Trial Outcomes and Data

Efficacy Results
The clinical outcomes reported so far vary by agent and the target indication. In Phase II atopic dermatitis studies, Telazorlimab has demonstrated promising efficacy; AD patients experienced significant reduction in cytokine levels (including Th2, Th1, and Th17/Th22 cytokines), and the achievement of endpoints such as EASI-75 was markedly superior in treatment arms compared to placebo groups. Similarly, Rocatinlimab, in its Phase II trials, has shown statistically significant improvements in clinical scores—EASI and related measures—with benefits that persisted during drug-free follow-ups. IMG-007, though still in the proof-of-concept stage, is being assessed for its pharmacokinetics and immunomodulatory effects. Early data suggest that there is a dose-proportional increase in drug exposure, full target engagement in peripheral blood, and acceptable safety outcomes in healthy participants, which lays the groundwork for its future efficacy assessments once moved to patient studies. Additionally, early-phase data of KY1005 have shown potential promise, with preliminary improvements in EASI scores, although results have not been fully posted.

When looking from a broader perspective, the improvement in clinical endpoints (such as the EASI-75 response in AD) can be hierarchically linked to the degree of suppression in pathogenic T cell populations and the modulation of key inflammatory pathways. This link is supported by the reduction in OX40+ T cells and OX40L+ dendritic cells in lesional skin and peripheral blood of treated patients. These efficacy signals provide the translational rationale for continuing to advanced clinical trial phases.

Safety and Adverse Effects
The safety profiles of OX40 inhibitors in clinical trials have been carefully monitored, given that any intervention affecting T cell co-stimulation carries the theoretical risk for systemic immunosuppression or dysregulation. In early Phase I studies, such as those conducted for IMG-007, adverse events have generally been reported as mild to moderate (grade 1–2), with no dose-limiting toxicities noted. Telazorlimab, in its Phase II trial, demonstrated a manageable safety profile in patients with AD, with incidences of treatment-related adverse events being within acceptable limits. Rocatinlimab’s clinical data likewise suggest that the agent is generally well tolerated, with most adverse events being mild and no serious safety signals observed so far in controlled studies.

Safety evaluations also extend into the realm of long-term follow-up, where the durability of efficacy is measured alongside monitoring for any unexpected immunological or systemic adverse effects. Given the intrinsic role of OX40 in regulating immune function, ongoing vigilance is necessary to ensure that prolonged inhibition does not inadvertently predispose patients to infections or other immune-related complications. The data published so far from studies focusing on AD indicate that these agents have an acceptable short-term safety profile, and that careful dose selection along with biomarker monitoring can further optimize the therapeutic index.

Future Directions and Challenges

Potential Combinatorial Therapies
While single-agent trials provide critical insight into the efficacy and safety of OX40 inhibitors, the future of immunomodulatory therapies is likely to consist of combination strategies. For cancer immunotherapy, where the restoration of immune function is highly complex, OX40 agonism (or its inhibition in certain contexts) could be combined with checkpoint inhibitors such as anti-PD-1/PD-L1 agents. Preclinical studies have suggested that simultaneous targeting of different immune regulatory pathways can lead to synergistic antitumor effects, with data indicating improved tumor growth inhibition when OX40 pathway modulators are combined with radiotherapy or chemotherapy. In the context of inflammatory diseases like AD, combinations with topical agents, PDE4 inhibitors, or other cytokine modulators could optimize overall disease control. Future trials will need to explore these combination regimens in a rational, biomarker-driven manner in order to maximize benefit while mitigating cumulative toxicities.

Regulatory and Development Challenges
Despite the promise, several challenges remain for the continued clinical development of OX40 inhibitors. First, the dynamic expression of OX40 on T cells means that the timing of drug administration—as well as dosing strategies—must be carefully optimized to account for interpatient variability and the transient nature of OX40 expression after antigen encounter. This necessitates the development of robust biomarkers that can predict which patients are most likely to benefit from therapy. In this regard, patents describe methods and biomarkers for predicting efficacy and evaluating pharmacodynamic activity after OX40 agonist treatment, which will be vital in tailoring therapy to individual patient profiles.

Moreover, the careful balance between sufficient immunomodulation in diseases like AD and maintaining a protective immune response against infections or malignancy remains a critical regulatory challenge. Ongoing discussions with regulatory agencies will be paramount in ensuring that the risk–benefit profile of these agents is thoroughly understood. Issues such as long-term safety, immunogenicity, and potential adverse outcomes in the context of immune suppression will continue to influence clinical development strategies.

Conclusion
In summary, the current landscape of OX40 inhibitors in clinical trials is marked by a diverse pipeline targeting either the OX40 receptor or its ligand, OX40L, with the goal of modulating T cell–mediated immune responses. From the synapse‐sourced data, we know that Telazorlimab, Rocatinlimab, IMG-007, Amlitelimab, and KY1005 are the key candidates currently under clinical evaluation. Telazorlimab and Rocatinlimab have already demonstrated promising efficacy and manageable safety profiles in Phase II trials for atopic dermatitis, as evidenced by significant improvements in clinical endpoints such as EASI scores and a reduction in pathogenic immune cell populations. IMG-007 is progressing through early-phase trials with encouraging pharmacokinetic and pharmacodynamic signals, while Amlitelimab and KY1005 are advancing through later stages or are being evaluated for their effect by targeting the ligand component of the pathway.

The mechanisms underpinning these agents involve the disruption of OX40-OX40L interactions, thereby limiting the costimulatory signals required for excessive T cell activation. This disruption not only helps in reducing the overactive immune responses seen in autoimmune diseases like AD but also has implications for improving the tumor microenvironment in cancer therapy by modulating the balance between effector T cells and Tregs. Although the primary focus of many current clinical studies has been in dermatological conditions, the insights gained in these trials could pave the way for future application in oncology—either as monotherapies or in combination with other immunotherapeutic agents, such as checkpoint inhibitors or even radiotherapy.

Going forward, the key challenges in this space include defining appropriate dosing regimens, optimizing patient selection via predictive biomarkers, and integrating combination strategies that may further enhance therapeutic efficacy while controlling adverse effects. The regulatory hurdles associated with modifying an immune checkpoint pathway in a context-dependent manner remain significant. However, the current evidence strongly supports the potential of these agents to modulate pathogenic immune responses safely and effectively, which could result in better-tailored therapies for both autoimmune conditions and possibly for cancer treatment in the future.

In conclusion, the current clinical trial portfolio for OX40 inhibitors—as represented by Telazorlimab, Rocatinlimab, IMG-007, Amlitelimab, and KY1005—demonstrates both the promise and the complexity of targeting the OX40-OX40L axis. These agents are advancing through various phases of clinical evaluation with encouraging early data that support their efficacy in reducing pathological T cell activation and modulating inflammatory signals. Future directions will likely focus on combinatorial approaches and the integration of biomarker-driven patient selection strategies to fully realize the therapeutic potential of OX40 pathway modulation. Continued translational research and rigorous clinical evaluation will be essential in overcoming challenges related to dosing, safety, and long-term efficacy so that these agents can become a transformative part of the therapeutic armamentarium in both oncology and immunology.