What diseases does Odronextamab treat?

Introduction to Odronextamab
Odronextamab is a novel bispecific antibody designed with a fully human IgG4‐based framework that specifically binds to both CD20 on malignant B cells and CD3 on T cells. This dual targeting facilitates T‐cell engagement and activation, resulting in potent cytotoxic activity against B cells, independent of the native T‐cell receptor recognition. This mechanism of action has positioned odronextamab as a promising therapeutic agent in the field of hematological malignancies.

Mechanism of Action
At its core, odronextamab leverages a bispecific design to bridge two key cellular components: the malignant B cells that express CD20 and the cytotoxic T cells that express CD3. By binding to these antigens simultaneously, odronextamab redirects T cells to form an immunological synapse with the target B cells, thereby triggering T‐cell activation, cytokine release, and eventual tumor cell lysis. Studies have demonstrated that this T cell–redirecting approach leads to effective killing even in cases where patients have relapsed or are refractory to conventional CD20‐targeted therapies. The antibody’s design minimizes unwanted binding due to its IgG4 backbone, contributing to reduced immunogenicity and favorable pharmacokinetic properties.

Development and Approval
Developed by Regeneron Pharmaceuticals, odronextamab has undergone extensive preclinical research and early-phase clinical trials. The translational efforts have enabled dose-escalation strategies using data derived from in vitro cytokine release and in vivo tumor regression models, informing the dosing regimens in first‐in‐human (FIH) studies. As part of its development pathway, odronextamab has been tested in multiple Phase 1 and Phase 2 trials across various B‐cell malignancies. Regulatory milestones have been achieved in several regions, with early approvals and acceptances noted in jurisdictions such as the European Union and Iceland for specific indications. The integration of step-up dosing regimens has contributed to mitigating known safety concerns, such as cytokine release syndrome (CRS), while maintaining robust antitumor efficacy across heavily pretreated patient populations.

Diseases Treated by Odronextamab
Odronextamab is primarily developed to treat hematological malignancies, especially those cancers in which malignant B‐cells play a crucial role in disease pathology. Its mechanism of action, targeting CD20 on B cells and engaging T cells via CD3, makes it particularly effective for treating relapsed or refractory B‐cell non‐Hodgkin lymphomas.

Hematological Malignancies
The predominant therapeutic indications for odronextamab focus on B‐cell non‐Hodgkin lymphomas (B‐NHL). Specifically, odronextamab has been approved or is being investigated for:

• Relapsed or Refractory Diffuse Large B-cell Lymphoma (r/r DLBCL)
Diffuse large B-cell lymphoma represents an aggressive subtype of B-NHL. In clinical trials such as the Phase 1 ELM-1 and the subsequent pivotal Phase 2 ELM-2 studies, odronextamab demonstrated promising results in patients with r/r DLBCL who were either naïve to or had prior exposure to CAR T cell therapies. The objective response rates (ORR) and complete response (CR) rates observed in these heavily pretreated populations echo the potential of this bispecific antibody to fill unmet challenges in managing aggressive lymphomas.

• Relapsed or Refractory Follicular Lymphoma (r/r FL)
Follicular lymphoma (FL) is characterized by its indolent nature with multiple relapses over time. However, as disease progresses, many patients become refractory to standard treatments. Odronextamab has shown notable efficacy in this setting. For instance, in patients with r/r FL who received doses higher than 5 mg, the ORR reached up to 92.9% with a complete response rate of 75%, marking it as one of the most effective treatment modalities available for heavily pretreated patients. Detailed data from pivotal Phase 2 trials provide robust evidence for durable responses in follicular lymphoma, supporting odronextamab’s role as an alternative to, or in combination with, existing therapies.

• B-cell Malignancies in General
In a broader sense, odronextamab is indicated for CD20+ B-cell malignancies. This category encompasses not only DLBCL and FL but also other subtypes of non-Hodgkin lymphomas that express the CD20 antigen. Its mechanism of action—involving T-cell redirection—is particularly valuable in settings where conventional CD20 monoclonal antibodies, such as rituximab, have failed to achieve durable responses. The ability of odronextamab to overcome resistance mechanisms seen in these cancers has been extensively studied in early-phase clinical trials, thus solidifying its potential to treat a wide spectrum of B-cell malignancies.

Other Potential Applications
Although the primary focus of odronextamab is on hematological malignancies, there is ongoing research and interest in exploring its utility beyond traditional B-NHL settings.

• Combination Therapies in Hematologic Diseases
Odronextamab’s therapeutic potential may be further enhanced when combined with other novel antibodies or immunomodulatory agents. Preliminary investigations have explored combinations with agents that target additional surface markers or provide costimulatory signals—such as novel CD28×CD22 bispecific antibodies—to amplify the antitumor response. These combination strategies could potentially extend the benefits of odronextamab to patients with complex disease profiles or those with coexisting resistant clones.

• Exploratory Investigations in Solid Tumors
While the current data predominantly support odronextamab’s efficacy in B-cell malignancies, preclinical models are beginning to explore the applicability of T-cell-engaging bispecific antibodies in the solid tumor setting. This area remains an active field of research, and although the structural focus of odronextamab is optimized for CD20+ B cells, lessons learned from its development could pave the way for designing similar bispecific agents for solid tumors. The challenges in solid tumor immunotherapy—such as identifying specific tumor-associated antigens and overcoming the immunosuppressive tumor microenvironment—are being addressed in parallel research initiatives. However, as of now, odronextamab’s clinical application remains concentrated on hematologic indications.

Clinical Efficacy and Trials
The clinical evaluation of odronextamab has been extensive, with multiple trials detailing its impressive efficacy in relapsed/refractory B-cell malignancies. The design of these trials has included step-up dosing regimens, in-depth pharmacokinetic analyses, and robust endpoints that capture both objective response rates and durability of responses.

Summary of Clinical Trials
Several key clinical trials have shaped our understanding of odronextamab’s efficacy and safety profile:

• Phase 1 FIH Studies (ELM-1 Trial)
The first-in-human study of odronextamab involved patients with relapsed/refractory B-cell non-Hodgkin lymphoma. In these early trials, the bispecific antibody induced T-cell-mediated lysis of malignant B cells, and its pharmacodynamic properties were thoroughly assessed. The data from in vitro cytokine release assays and xenograft tumor models were used to set the parameters for human dosing, thereby establishing a solid foundation for subsequent clinical investigations.

• Pivotal Phase 2 Trials (ELM-2, and Subsequent Trials)
Following promising Phase 1 results, the pivotal Phase 2 ELM-2 trial enrolled patients with relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. These studies demonstrated high objective response rates and complete response rates among both CAR-T naïve and CAR-T exposed populations. The trial design incorporated step-up dosing with careful monitoring of cytokine release syndrome and other adverse events, ensuring that efficacy was not achieved at the expense of safety. At the interim analysis, durable responses were also noted, with median durations of response extending to over a year in some cases.

• Combination Studies and Ongoing Trials
Beyond monotherapy, odronextamab is currently being evaluated in combination regimens. Trials such as ATHENA-1, where odronextamab is combined with other bispecific antibodies like REGN5837, are investigating the potential for enhanced T-cell activation and deeper antitumor responses in aggressive B-cell NHL subtypes. Additionally, ongoing Phase 3 trials like OLYMPIA-4 and OLYMPIA-2 are comparing odronextamab-based regimens with standard-of-care treatments, especially in patients with aggressive or previously untreated follicular lymphoma.

Efficacy Results
The efficacy outcomes from these trials have been both encouraging and transformative for the field of lymphoma treatment:

• Relapsed/Refractory Follicular Lymphoma
In heavily pretreated patients with follicular lymphoma, early phase studies reported an objective response rate of up to 92.9% and complete response rates reaching 75% when dosed at 5 mg or higher. Further follow-up data from pivotal Phase 2 studies indicate that these responses are durable—with median durations of complete response and progression-free survival extending into the range of 20 months—thereby providing an effective treatment alternative for patients with limited options.

• Relapsed/Refractory Diffuse Large B-cell Lymphoma
Patients with diffuse large B-cell lymphoma also benefited substantially from odronextamab treatment. In one pivotal trial, an ORR of approximately 52–53% with complete responses in a significant proportion of patients was observed. Notably, the responses were consistent even among patients who had previously received CAR T cell therapy, an indication that highlights odronextamab’s potential in overcoming treatment resistance in high-risk populations.

• Impact on Heavily Pretreated and Refractory Cases
The clinical trials have consistently shown that odronextamab offers meaningful objective and complete responses in populations that have exhausted other treatment options. This includes patients with multiple prior lines of therapy and those with relapsed or refractory disease after standard-of-care treatments. The rapid and effective T-cell engagement mechanism is often reflected in speedy tumor reduction and sustained remissions, as confirmed by independent central review and long-term follow-up data.

Safety and Side Effects
Balancing potent efficacy with tolerability is central to the success of any immunotherapy. Odronextamab has been extensively evaluated in this regard, with clinical trials paying particular attention to its safety profile, including immediate and longer-term adverse events.

Common Side Effects
The most commonly reported side effect across odronextamab trials is cytokine release syndrome (CRS), a known risk with most T-cell-engaging therapies. Key findings indicate:

• CRS Characteristics
During early cycles of treatment, especially during the step-up dosing phase, a significant percentage of patients experience CRS. The incidence rate varies—for instance, in certain cohorts, around 56% of patients experienced CRS, though most cases were of low grade (Grade 1 or 2) and of short duration (median duration of 2 days).
• Other Adverse Events
In addition to CRS, common adverse effects include neutropenia, pyrexia (fever), anemia, and infusion-related reactions. These events are generally manageable with supportive care, and dose modifications or premedication strategies have been effective in mitigating their severity.
• Management Strategies
The implementation of step-up dosing regimens has been crucial in reducing the severity of CRS and other toxicities, ensuring that patients can safely reach therapeutic doses. The side effect profile, though noteworthy, is considered acceptable in view of the profound clinical responses observed in refractory and relapsed patients.

Long-term Safety Data
Long-term safety data for odronextamab are still accumulating; however, the available evidence from extended follow-ups in clinical trials suggests the following:
• Durability of Response Without Cumulative Toxicity
Patients who achieve complete responses often maintain these responses over extended periods without significant additional toxicities. The long-term data suggest that, beyond the initial treatment cycles, odronextamab is generally well tolerated.
• Monitoring Through Extended Follow-up
Ongoing studies continue to monitor patients for potential delayed adverse effects, including late-onset toxicities or secondary malignancies, although such events have not emerged as significant issues in the available follow-up periods. Thus, odronextamab’s safety profile remains favorable relative to its efficacy, giving confidence for its use in heavily pretreated populations.

Future Research and Developments
As the field of immunotherapy continues to evolve, odronextamab is at the forefront of clinical research aimed not only at reinforcing its established indications but also at expanding its potential role in other therapeutic areas.

Ongoing Clinical Trials
Several trials are currently in progress that will further define odronextamab’s position in the treatment paradigm for B-cell malignancies:
• Phase 3 Trials (OLYMPIA-4 and OLYMPIA-2)
Large-scale Phase 3 trials are underway to evaluate odronextamab as either a monotherapy or in combination with other treatment modalities against standard-of-care approaches. For instance, the OLYMPIA-4 trial is a randomized, open-label study comparing odronextamab with standard salvage therapies in relapsed/refractory aggressive B-cell lymphoma. These trials stratify patients based on the timing of relapse from first-line therapy, ensuring that the most challenging patient populations are included.
• Combination Studies with Other Bispecific Antibodies
As mentioned earlier, combination approaches (e.g., odronextamab with REGN5837 in the ATHENA-1 study) are also being pursued. These combinations are designed to deliver dual immunomodulatory signals—one via T-cell redirection and another through costimulatory pathways—which may deepen and extend response durability, especially in aggressive lymphomas.
• Dose Optimization and Administration Routes
Ongoing research is also focused on alternative administration routes, such as subcutaneous formulations, which might enhance patient convenience while maintaining efficacy. These studies are evaluating pharmacokinetic profiles, bioavailability, and the overall safety of redesigned dosing regimens, further broadening the practical implications of odronextamab therapy.

Potential for New Indications
Beyond its established role in treating hematologic malignancies, emerging research is exploring potential new applications for odronextamab:
• Expanded Use in Other B-cell Malignancies
While current indications center on DLBCL and FL, further studies may extend its use to additional B-cell malignancies such as mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) where CD20 is expressed. The ability of odronextamab to generate robust antitumor responses in resistant patient populations supports its evaluation in these settings as well.
• Exploration in Compromised Immunotherapy Settings
Given its mechanism of action, investigators are assessing the role of odronextamab in patients who are refractory to other immunotherapies, including those who have failed CAR T-cell therapy. Ongoing research in subgroups of relapsed/refractory patients not only refines its current indications but also opens the door to its application as a second-line or salvage therapy.
• Potential Applications in Solid Tumors – A Future Perspective
Although there are significant challenges in applying T-cell-engaging bispecific antibodies in solid tumors, the fundamental principles of targeted immunotherapy have spurred interest in adapting odronextamab’s technology to new targets. Research into tumor-specific antigens and overcoming the barriers set by the immunosuppressive tumor microenvironment could eventually allow bispecific antibody formats like odronextamab to be re-engineered and evaluated in selected solid tumor contexts. While such applications are not yet clinically established, they represent an exciting frontier in translational cancer research.

Detailed Conclusion
In general, odronextamab represents a significant advancement in the treatment of CD20+ B-cell malignancies. As a bispecific T-cell engager, its unique mechanism of simultaneously binding to CD20 on cancerous B cells and CD3 on T cells facilitates direct T-cell-mediated cytotoxicity. This mechanism has been validated in both preclinical models and in early-phase clinical trials, producing high objective and complete response rates especially in difficult-to-treat populations with relapsed or refractory disease.

From a specific perspective, odronextamab has demonstrated efficacy in the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) and follicular lymphoma (r/r FL). The drug is primarily targeted towards these hematological malignancies, where it has been applied successfully in patients who have previously failed conventional and even advanced immunotherapies such as CAR T-cell therapy. Detailed studies from both Phase 1 and Phase 2 clinical trials have established its capacity to induce durable responses that rival and even surpass those seen with other immune-based therapies. The clinical trials underscore not only the therapeutic effectiveness of odronextamab in eliciting response but also emphasize its favorable safety profile, with manageable adverse effects such as cytokine release syndrome and neutropenia that are mitigated through step-up dosing strategies.

From a general outlook, future research will likely extend odronextamab’s potential beyond its current indications. The integration of odronextamab in combination regimens, as well as its evaluation in Phase 3 trials (e.g., OLYMPIA-4 and OLYMPIA-2), marks an important step towards possibly incorporating it into earlier lines of therapy. Moreover, exploratory studies and the development of subcutaneous formulations may broaden its applicability and enhance patient quality of life by reducing the frequency of hospital visits and the severity of adverse effects. In parallel, there exists a potential for odronextamab’s underlying technology to be adapted for targeting other malignancies, including potentially solid tumors, through innovations that overcome the immunosuppressive microenvironment characteristic of these cancers.

In conclusion, the current body of evidence strongly supports odronextamab as a transformative therapeutic agent in the treatment of CD20+ B-cell malignancies—particularly in relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma. Its ongoing clinical investigations, combined with promising efficacy results and manageable safety profiles, reaffirm its role in filling critical gaps in current treatment paradigms. Furthermore, the versatility of its design offers promise for future indications and combination strategies, ultimately broadening its impact on patient outcomes across diverse oncological settings.