What IL-5 inhibitors are in clinical trials currently?

Introduction to IL-5 and Its Role
Interleukin‐5 (IL-5) is a key cytokine that plays an essential role in the differentiation, maturation, recruitment, activation, and survival of eosinophils. As a hematopoietic cytokine produced predominantly by type 2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2), IL-5 orchestrates immune responses involved in allergic inflammation and other eosinophil-associated disorders. Over the last decade, understanding of IL-5 biology has advanced substantially, providing the rationale for targeting IL-5 or its receptor in inflammatory conditions (for example, severe eosinophilic asthma).

Biological Function of IL-5
At the molecular level, IL-5 functions by binding to its specific IL-5 receptor α (IL-5Rα) subunit, which then pairs with a common β chain shared with IL-3 and GM-CSF receptors. This receptor engagement activates several intracellular signal transduction pathways such as the JAK/STAT, MAPK, and PI3K cascades, resulting in multiple effector functions of eosinophils—including proliferation, chemotaxis, degranulation, and prolonged survival. From a general perspective, the precise regulation of eosinophil numbers and activity is critical in both host defense mechanisms and in the development of allergic inflammation. Specific studies have highlighted that dysregulated IL-5 secretion leads to excessive eosinophil production; when maintained in a chronic state, this can contribute to tissue remodeling and airway hyperresponsiveness seen in diseases like asthma.

IL-5 and Its Role in Disease
In the context of disease, IL-5 is strongly implicated in the pathogenesis of conditions driven by eosinophilic inflammation such as severe eosinophilic asthma, nasal polyposis, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndromes, and even certain skin conditions. The persistence of eosinophils in affected tissues results in the release of cytotoxic granule proteins (like major basic protein, eosinophil cationic protein) and other mediators that cause tissue damage and clinical exacerbations. As a result, IL-5 represents a highly attractive target for anti-inflammatory biologic therapies that aim to reduce eosinophil-mediated damage. Particularly in asthma, anti-IL-5 strategies have been instrumental in reducing exacerbation rates and the dependency on systemic corticosteroids in patients with a high eosinophil burden.

IL-5 Inhibitors Overview
The identification of IL-5 as a master regulator of eosinophil function has led to the development of a variety of IL-5 inhibitors. These agents are designed to either neutralize IL-5 directly or inhibit its receptor function, thereby suppressing the downstream effects of eosinophil activation and survival.

Mechanism of Action of IL-5 Inhibitors
IL-5 inhibitors are predominantly monoclonal antibodies that target either the cytokine itself or its receptor on eosinophils. By binding directly to IL-5 (as in the case of drugs like mepolizumab and reslizumab) or by blocking IL-5Rα (as with benralizumab), these inhibitors prevent the cytokine–receptor interaction. This blockade interrupts the downstream signaling pathways essential for eosinophil activation, leading to decreased eosinophil counts and reduced inflammatory responses. Detailed structural studies have provided insights into how these antibodies bind to IL-5 or its receptor, disrupting specific charge complementary regions that are pivotal for receptor engagement. This mechanistic understanding has contributed to the design of new molecules and peptidomimetics with enhanced potency and selectivity.

Clinical Applications of IL-5 Inhibitors
Originally developed for the treatment of eosinophilic asthma, IL-5 inhibitors have now been evaluated in a range of eosinophil-driven disorders. The clinical applications extend to diseases where high eosinophil levels are a hallmark, such as severe asthma phenotypes, chronic rhinosinusitis with nasal polyps, and certain hypereosinophilic syndromes. In clinical practice, the use of such inhibitors has resulted in a decreased rate of exacerbations, reduced systemic corticosteroid exposure, and an improvement—albeit sometimes modest—in lung function and quality of life. As our understanding of the IL-5 pathway develops further, there is growing interest in exploring the potential benefits of these inhibitors in other conditions where eosinophils might play a role in the pathology.

Current IL-5 Inhibitors in Clinical Trials
Following extensive preclinical validation and early clinical successes with established agents such as mepolizumab, additional IL-5 inhibitors have entered clinical trials. Recent clinical trial data from the Synapse database suggest that several emerging IL-5 inhibitors are being evaluated for safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy in various phases of clinical development. These candidates not only include biosimilars of established inhibitors but also novel agents designed to improve upon or complement currently approved therapies.

List of IL-5 Inhibitors in Trials
Based primarily on structured data from synapse, the current IL-5 inhibitors in clinical trials include:

• RC1416 injection – A Phase Ib clinical study is evaluating the safety, tolerability, PK/PD, immunogenicity, and preliminary efficacy of RC1416 injection in patients with moderate to severe asthma. This candidate is being tested as a potential novel IL-5 inhibitor.

• TQC3566 injection – This agent is being evaluated in a Phase I clinical study in healthy volunteers. TQC3566 injection is essentially a mepolizumab injection (or biosimilar) that is being compared with NUCALA® to assess its pharmacokinetic profile and safety, indicating efforts to develop alternative IL-5 neutralizing antibodies.

• 610 – Represented by a series of clinical studies, the agent “610” has been under evaluation in multiple clinical trials. A Phase IIb study assessed its efficacy and safety in adult subjects with severe eosinophilic asthma. Further studies include a Phase III trial in Chinese adult subjects with severe eosinophilic asthma, another Phase IIb study evaluating its use in adult asthma subjects, and a Phase III clinical trial assessing its efficacy and safety in treating adult asthma subjects. These studies collectively emphasize the active development of “610” as a promising anti-IL-5 agent in eosinophilic asthma, with multiple indications in different patient populations and regions.

• SHR-1703 injection – Multiple clinical trials are currently evaluating the long-term safety, pharmacodynamics, and efficacy of SHR-1703 injection in eosinophilic asthma patients. A Phase II study has been initiated to assess long-term safety and efficacy. In addition, a multicenter, randomized, double-blind, placebo-controlled study (Phase III) is evaluating the efficacy and safety of SHR-1703 in eosinophilic asthma. Another Phase III trial is evaluating SHR-1703 injection in a parallel-design study. Furthermore, there is also a study extending the investigation of SHR-1703 in patients with allergic bronchopulmonary aspergillosis in a randomized, double-blind, placebo-controlled clinical study.

These trials demonstrate both the geographic diversity and stage progression of IL-5 inhibitor candidates in the clinical pipeline. The accumulation of data from these studies will not only provide comparative insights into safety and efficacy profiles but also help to identify optimal dosing regimens and patient subpopulations that may benefit most from IL-5 targeted therapy.

Phases and Status of Clinical Trials
The clinical trials for the aforementioned IL-5 inhibitors encompass several phases, highlighting the rigorous evaluation process required for novel biologics:

• RC1416 injection is currently in a Phase Ib trial. In this study, researchers are primarily focusing on evaluating the safety and tolerability in patients with moderate to severe asthma. Early-phase studies like these often assess PK/PD profiles and immunogenicity, which are essential indicators of how the drug will behave in a larger patient population.

• TQC3566 injection has advanced into a Phase I clinical study. Here, healthy Chinese male volunteers are being recruited to compare the agent with an established drug (NUCALA®) regarding its pharmacokinetics and safety profile. Such studies are critical for establishing biosimilarity and many aspects of clinical safety before expanding into patient populations.

• The agent “610” has progressed into later-stage trials, including Phase IIb and Phase III studies. In a Phase IIb trial, researchers focus on demonstrating preliminary efficacy in adult subjects with severe eosinophilic asthma while ensuring safety and tolerability. Subsequent Phase III studies, such as those registered in the CTR and CTGOV databases, are designed to provide confirmatory evidence of efficacy and further monitor adverse events in larger patient populations. Specifically, one Phase III trial is being conducted in Chinese adult subjects, another study further elaborates on its use in adult asthma subjects, and another Phase III trial is assessing its efficacy in a randomized, double-blind, placebo-controlled manner. These trials are sequential steps aiming to combine robust clinical efficacy data with safety profiles to potentially expand regulatory approvals across multiple regions.

• SHR-1703 injection is also being evaluated in multiple trial phases. One trial is a Phase II single-group study to assess the long-term safety and pharmacodynamics. Other trials include multicenter, double-blind, placebo-controlled Phase III studies aiming to establish the efficacy and safety of SHR-1703 in eosinophilic asthma and another similar design trial. Additionally, SHR-1703 is being trialed in a randomized, double-blind, placebo-controlled study in patients with allergic bronchopulmonary aspergillosis, indicating its potential use in multiple eosinophilic conditions beyond asthma. These various trial phases reflect the commitment to rigorously evaluating immunotherapeutics from initial safety assessments to confirmatory effectiveness studies.

Challenges and Future Directions
While the advancement of IL-5 inhibitors through clinical trials is promising, several challenges remain that are driving further research into optimizing these therapies. At the same time, the future prospects for IL-5 inhibition strategies appear robust given evolving clinical needs and the potential for combination therapies.

Current Challenges in IL-5 Inhibitor Development
A number of challenges have been recognized during the clinical development of IL-5 inhibitors:

• Heterogeneity in Patient Response: One major challenge is the variability in patient response to IL-5 inhibitors. Although reductions in blood eosinophil counts and improvement in exacerbation rates have been documented, improvements in other clinical indices (such as lung function and quality-of-life measures) are sometimes modest. This variable response may reflect differences in disease endotypes, the degree of eosinophilic inflammation, dosage regimens, and potential factors such as the presence of residual eosinophils that are less responsive to IL-5 blockade.

• Optimal Dosing and Administration: Determining the optimal dose and administration schedule remains critical. Early-phase studies focus on safety and pharmacokinetics; however, translating these findings into correct dosing in later-phase trials is challenging. For instance, the Phase Ib study for RC1416 injection and the comparison studies involving TQC3566 injection aim to optimize these doses, minimizing side effects while maximizing therapeutic benefit.

• Immunogenicity and Long-Term Safety: As with any biological therapy, the potential for immunogenicity—where the patient’s immune system generates anti-drug antibodies—remains a concern. Long-term safety data are being accumulated through ongoing trials with agents such as SHR-1703, which is being evaluated for effects over extended treatment periods. Monitoring and managing immunogenic responses is essential for maintaining long-term efficacy and safety.

• Comparative Efficacy among IL-5 Inhibitors: With several IL-5 inhibitors in the developmental pipeline, including “610” and SHR-1703 injection, establishing a clear hierarchy in terms of efficacy, safety, cost-effectiveness, and ease of administration poses a significant challenge. In head-to-head comparisons (such as those between TQC3566 and NUCALA®), researchers are actively comparing pharmacokinetic and pharmacodynamic properties to guide future therapeutic decisions.

• Expanding Indications and Combination Therapy: Another challenge is meeting the clinical needs of indications beyond severe eosinophilic asthma. While current focus is on asthma and related airway disorders, IL-5 inhibition may also be beneficial in treating conditions like eosinophilic granulomatosis with polyangiitis, nasal polyposis, and even allergic bronchopulmonary aspergillosis. Defining the boundaries and optimal approaches in these diverse clinical settings requires tailored study designs and potential combination with other therapies.

Future Prospects and Research Directions
Future directions for IL-5 inhibitors are promising in several regards:

• Refining Patient Stratification: Ongoing research aims to better identify patient endotypes that will derive maximal benefit from IL-5 inhibition. Biomarker-driven approaches, including the measurement of blood eosinophil counts and other inflammatory mediators, may enhance patient selection for these therapies and help tailor treatment regimens.

• Development of Novel Agents: The current portfolio, which includes RC1416 injection, TQC3566 injection, “610”, and SHR-1703 injection, is only part of a broader strategy to enhance IL-5 blockade. Structural and mechanistic studies have provided insights that could lead to the design of peptidomimetics or small molecules that are even more potent or have favorable pharmacodynamic properties.

• Combination Therapies: An emerging strategy is to combine IL-5 inhibitors with other biologics or conventional therapies. For example, combining IL-5 blockade with inhibitors targeting other components of the type 2 inflammatory cascade (such as IL-4 or IL-13) may result in more robust suppression of eosinophilic inflammation. Early clinical studies evaluating such combinations could pave the way for more effective regimens.

• Global Development and Regulatory Approvals: The pipeline for IL-5 inhibitors is expanding globally, as evidenced by clinical trials conducted in various geographical areas. Phase III studies in China for “610” and multicenter international trials for SHR-1703 indicate an increasing acceptance and regulatory interest in these agents. Future research will likely include further global trials and real-world studies to assess long-term efficacy and safety across diverse populations.

• Addressing Resistance Mechanisms: Although anti-IL-5 therapy has dramatically improved outcomes for many severe asthmatic patients, there is still the phenomenon of non-response or partial response. Preclinical research is exploring the mechanisms underlying residual eosinophilia and resistance to IL-5 blockade, which may include alternative signaling pathways or compensatory mechanisms by other cytokines. Understanding these pathways will be crucial for developing second- or third-generation inhibitors or rational combination regimens.

• Advanced Delivery Systems and Biosimilars: Improvements in drug formulation and delivery, such as sustained-release injections or inhaled preparations, could improve patient adherence and therapeutic outcomes. Additionally, the development of biosimilars like TQC3566 injection offers the potential to reduce costs and increase accessibility of IL-5 inhibition therapy, particularly in markets where cost is a major barrier to treatment.

Conclusion
In summary, IL-5 is a critical cytokine centrally involved in the regulation of eosinophil biology and the pathogenesis of eosinophilic diseases. The biological function of IL-5—mediated through interactions with its receptor—drives the activation, survival, and degranulation of eosinophils, ultimately contributing to the chronic inflammatory milieu observed in conditions such as severe eosinophilic asthma. IL-5 inhibitors work by neutralizing IL-5 or blocking its receptor interactions, thereby diminishing eosinophil-mediated inflammation.

Currently, a number of IL-5 inhibitors are in various phases of clinical trials. The pipeline includes novel agents such as RC1416 injection (currently in Phase Ib trials for moderate to severe asthma), TQC3566 injection (in Phase I studies as a biosimilar to established therapies like NUCALA®), and the promising candidates designated as “610” and SHR-1703 injection, which are undergoing multiple Phase IIb and Phase III trials in adult patients with severe or eosinophilic asthma, as well as in related conditions such as allergic bronchopulmonary aspergillosis. These candidates are being evaluated across various geographic regions and patient cohorts, with a focus on optimizing efficacy, safety, and dosing regimens.

Despite promising progress, challenges remain including patient heterogeneity, optimal dosing, immunogenicity, and establishing comparative efficacy among the available agents. Future research is expected to focus on refining patient selection through biomarker-driven approaches, developing combination therapies that target multiple points of the inflammatory cascade, and overcoming resistance mechanisms that limit the full clinical benefit of IL-5 inhibition. Additionally, further innovation in drug formulation and the introduction of biosimilars are anticipated to expand accessibility and improve adherence.

The clinical trial landscape for IL-5 inhibitors reflects both a rich history of scientific discovery and a vigorous future direction for translating these findings into safe and effective therapies for eosinophil-driven diseases. With continued investment in research and adaptive clinical trial designs, IL-5 inhibitors have the potential not only to improve outcomes for patients with severe asthma but also to broaden their therapeutic applicability to other eosinophil-mediated disorders.

In conclusion, the current IL-5 inhibitors in clinical trials—RC1416 injection, TQC3566 injection, “610”, and SHR-1703 injection—represent a dynamic and evolving field. The combined efforts to optimize their safety, efficacy, and application will likely shape the future of biologic therapies in respiratory and allergic medicine, ultimately translating into improved patient care and quality of life.