What TSLP inhibitors are in clinical trials currently?

Introduction to TSLP and Its Role in Disease

Definition and Function of TSLP
Thymic stromal lymphopoietin (TSLP) is an epithelial cell–derived cytokine with a pivotal role as an alarmin that is released upon external insults such as allergens, viruses, and other environmental triggers. It acts as a master regulator at the very beginning of inflammatory cascades by activating innate immune cells as well as orchestrating the adaptive immune response. TSLP exerts its biological effects by binding to a heterodimeric receptor composed of the TSLP receptor (TSLPR) and interleukin-7 receptor alpha (IL‑7Rα), thereby triggering downstream signaling events that sometimes include STAT5 phosphorylation, among other pathways. Its action is critical for initiating T helper type 2 (Th2) immunity and modulating inflammatory profiles at barrier surfaces.

Diseases Associated with TSLP
Given its upstream position in the immune response, aberrant TSLP signaling has been implicated in a wide array of diseases. TSLP is strongly associated with allergic conditions such as asthma and atopic dermatitis, where elevated levels correlate with disease severity. In patients with asthma, TSLP not only triggers Th2 cytokines like IL‑4, IL‑5, and IL‑13 but is also linked to corticosteroid-resistant inflammation. In atopic dermatitis, TSLP expression from keratinocytes contributes to the initiation of skin inflammation and pruritus. Beyond allergy, research has suggested that TSLP might contribute to chronic rhinosinusitis with nasal polyposis (CRSwNP) and may even play a role in certain cancers by establishing a pro-tumorigenic microenvironment. This multifaceted role in disease pathogenesis makes TSLP an attractive therapeutic target across conditions driven by inappropriate inflammatory activation.

Overview of TSLP Inhibitors

Mechanism of Action
TSLP inhibitors are designed to interrupt the TSLP signaling cascade at a very early stage. The main mechanisms of action include direct neutralization of TSLP via monoclonal antibodies and targeting the TSLP receptor to block its subsequent interaction with IL‑7Rα. By preventing the formation of the key ternary complex (TSLP, TSLPR, and IL‑7Rα), these inhibitors suppress downstream activation of immune cells, reduce the production of proinflammatory cytokines, and provide therapeutic benefit in diseases driven by TSLP-mediated inflammation. In some instances, inhibitors may also work by binding to TSLP epitopes responsible for receptor activation, thereby selectively preventing the inflammatory isoform from eliciting a full immune response while leaving homeostatic functions intact.

Types of TSLP Inhibitors
There are several types of therapies under investigation that target TSLP or its receptor. The most common formats are:

• Monoclonal antibodies directed against TSLP (e.g., Tezepelumab) have been the most advanced agents and are designed to bind the cytokine directly, neutralizing its activity.
• Monoclonal antibodies directed toward TSLPR serve to prevent the cytokine from initiating receptor-mediated signaling cascades.
• Novel recombinant fusion proteins that incorporate extracellular portions of TSLPR and IL‑7Rα to act as decoy receptors, sequestering TSLP and blocking its interaction with cell-bound receptors – an approach highlighted in several patent disclosures.
• Small-molecule inhibitors and peptides that disrupt the TSLP:TSLPR complex formation have also been explored through both virtual screening and in vitro evaluations.

These various strategies enable a multi-angled approach to dampening TSLP-driven inflammation by either neutralizing the cytokine itself or by blocking downstream signaling events.

Current Clinical Trials of TSLP Inhibitors

Active Clinical Trials
There is a robust pipeline of TSLP inhibitors currently being evaluated in clinical trials across multiple indications primarily involving allergic and inflammatory diseases. Among the notable candidates are:

• Tezepelumab:
Tezepelumab is the most well-known TSLP inhibitor and has been evaluated in several advanced clinical trials. It is being tested in adult patients with asthma – including emergency room indications and chronic severe asthma – as well as in the context of chronic rhinosinusitis with nasal polyposis (CRSwNP). For instance, one Phase 4 double-blind, randomized controlled trial – referred to as the TEPAA trial – is evaluating its efficacy in the treatment of emergency room asthma in adults, indicating its potential to rapidly suppress acute inflammatory exacerbations. Other trials have measured its impact on symptom reduction in CRSwNP and its ability to improve airflow and reduce exacerbation rates in severe asthma. The use of Tezepelumab highlights the trend wherein blocking the TSLP pathway has led to improvements across a broad spectrum of allergic diseases.

• UPB-101:
UPB-101 is a novel recombinant fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically targets the TSLP receptor (TSLPR) to inhibit downstream signaling. It has completed a first-in-human Phase 1 randomized, placebo-controlled, single dose-escalation study in healthy volunteers—which demonstrated safety and tolerability—and is now advancing to a Phase 1b multiple ascending dose study in patients with asthma. This candidate is particularly promising due to its potential to address both Th2–mediated and innate inflammatory processes, as supported by preclinical models.

• TQC2731:
TQC2731 is another TSLP inhibitor currently under clinical investigation. It is being evaluated in several trials for respiratory indications: one multicenter, randomized, double-blind, placebo-controlled Phase III trial in patients with poorly controlled severe asthma and another study in patients with moderate to severe chronic obstructive pulmonary disease (COPD). The development of TQC2731 is focused on its ability to improve lung function and reduce the exacerbation frequency in patients who are not adequately managed on standard therapies, emphasizing its relevance in severe inflammatory airway disease.

• Lunsekimig (SAR443765):
Lunsekimig is undergoing evaluation in Phase II studies in high-risk adult subjects with asthma as well as in adult participants with moderate-to-severe atopic dermatitis. The objective for these trials is to assess its efficacy, safety, and tolerability when administered subcutaneously. By targeting the TSLP axis, lunsekimig aims to concurrently reduce Th2 inflammation and improve clinical outcomes in both respiratory and dermatological allergic conditions.

• APG333:
APG333 is the subject of a first-in-human study involving healthy participants. Although the specific details of its mechanism have not been fully disclosed in the clinical trial title, the investigational agent is presumed to be a TSLP inhibitor given its inclusion in the TSLP inhibitor pipeline. The trial is designed as a single ascending dose study to evaluate safety, tolerability, and pharmacokinetics in a healthy volunteer population, with an outlook toward subsequent studies in patients.

• Anti-TSLP Antibody GSK5784283:
Evaluated in a multicentre, randomized, double-blind, placebo-controlled, dose-finding, parallel-group Phase II study, GSK5784283 is designed to assess its efficacy in adults with uncontrolled asthma. This candidate is yet another example of the direct neutralization approach whereby the antibody binds to TSLP and prevents it from initiating its signaling cascade.

• SHR-1905:
Though sometimes mentioned in conjunction with other TSLP inhibitor programs, SHR-1905 is undergoing Phase II evaluation in adolescent subjects with asthma, focusing on pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy following subcutaneous administration. This trial reflects the expansion of TSLP inhibitors into pediatric populations where allergic inflammation often plays a central role.

• AIO-001:
Recent news from Aiolos indicates that TSLP inhibition is also under exploration for indications beyond the classic asthma and atopic conditions. AIO-001 is being evaluated in a Phase II trial for immune conditions such as chronic obstructive pulmonary disorder and chronic spontaneous urticaria. This diversified development strategy underlines the broadened scope of TSLP inhibition beyond mainstream allergic diseases.

Phases and Objectives
The current clinical trials of TSLP inhibitors are predominantly focused on respiratory and allergic indications, reflecting the central role of TSLP in these conditions. These trials can be broadly categorized by their phase and primary objectives:

• Phase I – Safety and Dose-Escalation Studies:
For example, the first-in-human studies with APG333 and the initial Phase 1 trials for UPB-101 are designed to establish the safety, tolerability, and pharmacokinetic profiles of these agents in healthy volunteers. These studies typically involve single ascending doses to detect any adverse events and to determine the maximum tolerated dose.

• Phase Ib/II – Proof-of-Concept and Efficacy in Target Populations:
Following safety validation, Phase Ib studies (such as the follow-on trial for UPB-101 in asthma) and Phase II trials (such as those for Tezepelumab, lunsekimig, GSK5784283, and SHR-1905) are conducted in patients with the target diseases. These trials aim to demonstrate preliminary efficacy by assessing endpoints such as reduction in exacerbation rates, improvements in lung function, alleviation of symptoms, and biomarker modulation. Dose-finding is a critical component to optimize the therapeutic index.

• Phase III – Confirmatory Efficacy and Extended Safety:
Larger, multicentre Phase III trials are currently ongoing for candidates like TQC2731 in severe asthma and COPD. These studies are intended to confirm the efficacy observed in earlier trials by comparing the active treatment with placebo in a controlled environment. Endpoints often include reduction in the frequency of exacerbations, improvement in overall lung function, and quality-of-life measures. Trial designs in this phase emphasize patient stratification, long-term safety, and definitive evidence of clinical benefits.

• Special Indication Trials and Phase IV Post-marketing Studies:
Tezepelumab, for example, has advanced to Phase IV studies wherein its utility is being assessed in specific subpopulations such as patients seeking emergency room management for asthma exacerbations. These studies aim to capture real-world effectiveness, long-term safety, and the impact on healthcare resource utilization in routine clinical practice.

Across many of these trials the objectives are similar: to limit the exaggerated inflammatory responses driven by TSLP, ensure that inhibition does not compromise the beneficial aspects of the immune system, and to establish a favorable risk–benefit profile that can be sustained in longer-term treatments. The trials also pay special attention to the potential effects on various biomarkers of type 2 inflammation (e.g., IL‑4, IL‑5, IL‑13, and eosinophil counts) as these are fundamental to understanding the clinical efficacy of TSLP inhibition.

Challenges and Future Directions

Current Challenges in TSLP Inhibitor Development
Despite the promising clinical data emerging from studies on TSLP inhibitors, several challenges remain. One major challenge in the development of these agents is optimizing the balance between therapeutic efficacy and safety. TSLP is involved in both inflammatory and homeostatic processes. As such, completely abrogating its signaling might risk disrupting beneficial immune functions. The need to differentiate between the long and short isoforms of TSLP, each with distinct roles, adds another layer of complexity to designing selective inhibitors.

Furthermore, differences in the patient’s underlying inflammatory phenotype (e.g., levels of blood eosinophils or other biomarkers) can influence the treatment response. Clinical trials have shown that while TSLP inhibition can offer benefits irrespective of baseline biomarkers, the magnitude of effect can differ, potentially necessitating stratified or precision medicine approaches in trial designs. Another significant challenge is the consistency of dosing regimens. Achieving the adequate therapeutic window – wherein the drug exhibits significant efficacy without adverse effects – is a critical focus across dose-finding studies such as those with GSK5784283 and TQC2731.

Moreover, since TSLP inhibitors are relatively new entrants compared with other biologics in asthma and atopic dermatitis, long-term safety, immunogenicity, and durability of clinical responses need further corroboration. There is also the challenge of designing trials that can capture diverse clinical outcomes, particularly when targeting multiple indications that include asthma, COPD, CRSwNP, and atopic dermatitis simultaneously. The translation of controlled clinical trial data into real-world outcomes remains a key area of future investigation.

Future Research Directions
Looking ahead, several research directions are expected to help overcome current limitations in TSLP inhibitor development. First, further molecular understanding of TSLP isoforms could allow for more selective targeting. Dissecting the distinct roles of the long and short isoforms of TSLP may enable the development of inhibitors that selectively neutralize the pathogenic isoform while preserving baseline immune function.

Next, as more data become available from ongoing Phase III and Phase IV studies (for instance, the extensive work underway for Tezepelumab and TQC2731), researchers will be better positioned to refine patient selection criteria and stratification approaches. Such precision medicine strategies would ensure that patients with the greatest likelihood of benefit are adequately targeted, thereby increasing the cost–effectiveness of treatments.

Another promising direction is the investigation of combination therapies. Given that TSLP is an upstream mediator, it may be advantageous to combine TSLP inhibition with other targeted therapies—such as IL‑4Rα blockers or even novel small molecules—in order to achieve synergistic effects. This approach could potentially reduce the required doses of each agent, thereby blunting adverse effects while maximizing clinical benefits, particularly in refractory diseases such as corticosteroid-resistant severe asthma.

Furthermore, advancements in drug delivery systems, particularly for inhaled formulations, might broaden the scope of TSLP inhibitors. For example, while most studies have relied on subcutaneous routes, inhaled administration might offer more rapid local effects in airway diseases and reduce systemic exposure.

Overall, innovation in trial design is also essential. Adapting innovative clinical trial designs that incorporate adaptive endpoints or real-time biomarker assessments could expedite the drug development process and provide richer data sets that better mirror clinical practice. Finally, given the high global burden of diseases like asthma and atopic dermatitis, it is crucial to conduct studies within diverse populations and in real-world settings to capture the broader efficacy and safety profiles of these new agents.

In summary, TSLP inhibitors represent one of the most exciting new frontiers in the management of allergic and inflammatory diseases. The clinical candidates such as Tezepelumab, UPB-101, TQC2731, lunsekimig (SAR443765), APG333, GSK5784283, SHR-1905, and AIO-001 are currently under rigorous evaluation in multiple clinical trial phases aimed at establishing safety, optimal dosing, and efficacy across a range of conditions including severe asthma, COPD, atopic dermatitis, and CRSwNP. These studies are designed in phases ranging from first-in-human dose-escalation studies in healthy volunteers to large multicenter Phase III trials in patient populations with complex, treatment-resistant forms of inflammation. Their objectives vary from determining pharmacokinetic and pharmacodynamic profiles to assessing improvements in clinical endpoints such as exacerbation rates, lung function, quality of life, and reduction of inflammatory biomarkers.

The clinical evaluation of these agents faces challenges, notably in achieving a balance between efficacy and maintaining necessary immune homeostasis, navigating dose optimization issues, and ensuring long-term safety, particularly given the dual roles of TSLP in pathogenic and homeostatic processes. Future research will likely target more refined approaches including selective inhibition of specific isoforms, combination therapies, and innovative trial designs to robustly assess the clinical benefits while mitigating risks. These efforts underscore the promise of TSLP inhibitors to provide transformative treatment options for patients with allergic and inflammatory diseases on a global scale.

Conclusively, the landscape of TSLP inhibitor development is both promising and complex. Ongoing clinical trials across various phases testify to the commitment of the research community to harness the therapeutic potential of TSLP blockade. With candidates like Tezepelumab leading the way in advanced trials and a diverse array of next-generation agents (such as UPB‑101, TQC2731, lunsekimig, APG333, GSK5784283, SHR‑1905, and AIO‑001) expanding the pipeline, the future of TSLP-targeted therapy appears robust. However, success will depend on a careful balance between suppressing pathological inflammation and preserving essential immune functions; a challenge that future research must meet head on through innovative scientific and clinical strategies. These cumulative efforts should ultimately enhance patient outcomes in conditions historically refractory to treatment and validate TSLP inhibition as a cornerstone of precision immunotherapy in allergic diseases.