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The asthma market is huge, and there are already many drugs acting on different targets, such as Dupilumab targeting IL-13 monoclonal antibody Roche & Sanofi, Roche & Novartis' Omalizumab targeting IgE monoclonal antibody, Relizumab targeting IL-5 monoclonal antibody UCB & Teva\ Mepolizumab of GSK, Benralizumab of AstraZeneca, etc., in addition to Relizumab, Dupilumab, Omalizumab, Mepolizumab, and Benralizumab all surpass or approach blockbuster levels, with global sales of $3.907 billion, $3.239 billion, $1.228 billion and $949 million in 2020, respectively.
Asthma is difficult to treat due to the heterogeneity of airway inflammation, and there is an urgent need for new treatments to treat patients with severe, uncontrolled asthma.
Thymic stromal lymphopoietin (TSLP) is a cytokine expressed primarily by the airway epithelium that is released during environmental damage, triggering a series of downstream inflammatory processes. Increased expression of TSLP in the airways of patients with asthma compared to healthy people is associated with disease severity and lung function, i.e., TSLP gene polymorphisms are associated with asthma.
TSLP is a key mediator in asthma pathophysiology, driving eosinophilic (allergic and non-allergic) inflammation of the airways, non-eosinophilic inflammation, and structural changes by acting on a variety of adaptive and congenital immune cells and structural cells. Clinical trials of TSLP blockade through the systemic approach have produced positive results in a wide range of asthma patients: reduced exacerbations and multiple inflammatory biomarkers, while improving lung function.
However, with the exception of Amgen & AstraZeneca's tezepelumab, which filed a marketing application with the FDA on July 8, 2021, the TSLP-targeting drugs have not even entered the third phase of the clinic, and tezepelumab is quite lonely, predicting that tezepelumab's annual sales will reach $1 billion in 2026 if approved for listing.
1. The role of TSLP in asthma
Thymic stromal lymphopoietin (TSLP) is a short-chain four-α spiral bundle type I interleukin-2 (IL-2) family cytokine, homologous to IL-7, first discovered in 1994 and initially identified as cytokines produced by thymic stromal cells. TSLP is divided into short and long subtypes, consisting of 60 amino acids and 159 amino acids, respectively. They are controlled by different gene promoters, which are subject to different stimuli from the outside. The short subtype is expressed in a variety of tissues and is associated with the homeostatic function of TSLP, but its role has not been clearly studied. The expression of the long subtype is inducible, exerts an inflammatory effect, and appears to be related to pathologies such as asthma, atopic dermatitis, or psoriasis.
Toll-like receptor ligands, pro-inflammatory cytokines (IFN-γ, tumor necrosis factor [TNF] and IL-1β), and specific cytokine environments (TNF-α + IL-4 + IL-13) or TNF-α alone can upregulate the long type rather than the short type. It has been documented that long types contribute to dust mite-induced airway epithelial barrier dysfunction, and synthetic short types can prevent these effects.
Similar to IL-25 and IL-33, TSLP is secreted primarily by epithelial cells, airway smooth muscle cells, keratinocytes, stromal cells, fibroblasts, mast cells, macrophages/monocytes, granulocytes, and dendritic cells (dc). There is ample evidence that it is capable of differentiating naïve CD4+ T lymphocytes in type 2 cells, producing IL-4, IL-5, IL-13, and reducing the expression of γ interferons (IFN-γ) associated with type 1 cells, affecting a variety of cells.
TSLP expression in the airways of patients with asthma increases and is associated with the expression of type 2 chemokinesis and the severity of the disease. Cultured primary bronchial epithelial cells spontaneously release TSLP. Suggests that TSLP is involved in the pathogenesis of asthma. However, the literature suggests that abnormal TSLP signaling is strongly associated with other inflammatory allergic diseases, including atopic dermatitis, eosinophilic esophagitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis. In addition, its expression is also triggered by infection of viral, bacterial and parasitic pathogens. Interestingly, the literature has shown that respiratory epithelial cells in asthmatic patients have a strong response to viral double-stranded RNA, with higher TSLP levels than in healthy controls.
TSLP initiates intracellular type 2 signaling by binding to its high-affinity heterodimer receptor complex, which consists of its specific receptor TSLPR (encoded by CRLF2 located on chromosome 5q22.1), which has 24% homology with the co-receptor γ chains in IL-2, IL-4, IL-9 and IL-15, and does not contain the δ-common chain IL-2 family, and the IL-7Rα subunit (CD127) in cells that co-express TSLPR and IL-7Rα. TSLP was initially combined with TSLPR, followed by the recruitment of IL-7Rα chains. TSLP itself has no apparent affinity for IL-7Rα.
TSLP forms a triplex of TSLP/TSLPR/IL-7Rα, activating Janus kinase 1 (JAK1) and JAK2, resulting in lower phosphorylation of signal transducers and major transcriptional activators 5A (STAT5A) and STAT5B, as well as STAT1, STAT3 and other STAT proteins, mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-κB) depending on cell type.
The production and release of airway epithelial cell TSLP is usually activated by various red flags, such as mechanical damage, infection-related factors, and allergens, which support its function as a warning signal for impaired epithelial integrity.
TSLP acts directly on T cells, mast cells and natural killer cells, indirectly activating CD11c+ DC located in the lungs or skin epithelium, and then transferring to lymph nodes, activating the differentiation of CD4+ T cells into type 2 cells, thereby promoting type 2 immune response. Type 2 cell differentiation is mediated by TSLP-induced DC expression of the TNF superfamily protein OX40 ligand (OX40L; CD252). OX40L expressed by DC interacts with OX40 on primitive T cells, generating type 2 lineage commitments by initiating signaling events. These events lead to the production of a large number of pro-inflammatory cytokines, such as IL-4, IL-5, and IL-13, which enhance the production of immunoglobulin (Ig)E, mast cells, and mucus, and increase airway hyperreactivity, but not the IL-10 and IFN-γ of a variety of native immune cells.
In particular, the interaction between TSLP and CD34+ cells promotes a pro-inflammatory phenotype characterized by cytokines 2 (IL-5 and IL-13), as well as a proliferative phenotype in which eosinophil/basophil lines are involved. In addition, it increases the migration of eosinophils, possibly binding to IL-33 through the IL-13-dependent axis, thereby enhancing the production of IL-5 and IL-13.
There is evidence that, through the action of allergic proteases and biological components, TSLP released by bronchial epithelial cells drives eosinophilia in situ. Therefore, it can be considered a vital factor in coordinating, perpetuating and expanding the inflammatory response to asthma. In animal models, overexpression of TSLP in the lungs develops into an asthma-like disorder. In addition, topical application of anti-TSLPR antibodies (Ab) and anti-TSLP antibodies prevents type 2-mediated inflammation of the airways.
The importance of TSLP in asthma has been proven repeatedly. There is evidence that inhaled allergen provocation in patients with mild allergic asthma induces TSLPR expression of CD127 eosinophil line progenitor cells in peripheral blood and basophils in the blood and airway. In addition, airway TSLP expression directly increases the degree of challenge associated with the allergen associated with increased airway obstruction. In patients with asthma, the number of epithelial and submucosal cells expressing TSLP mRNA is inversely correlated with 1 second forced exhalation (FEV1). There is also an association between airway hyperreactivity, serum IgE levels, and the number of mast cells expressing TSLP. More convincingly, despite high-dose inhaled or oral corticosteroid therapy, there is still an increase in TSLP expression in some patients with severe asthma. In fact, type 2 intrinsic lymphocytes (ILC2s) in asthmatic patients with elevated TSLP levels have a steroid-resistant effect.
Therefore, targeted TSLP and TSLP-mediated signaling are considered an attractive strategy for treating asthma. Anti-TSLP monoclonal antibodies (mAbs) and TSLP cytokine traps may be effective strategies for TSLP-targeted therapy.
2. TSLP target drug development twists
At present, many asthma drugs acting on different targets have been listed, such as Omalizumab targeting IgE, Dupilumab targeting IL-13, Reslizumab targeting IL-5 \ Mepolizumab \ Benralizumab, etc., but drugs targeting TSLP have not yet been listed.
In addition to the fully human IgG2λ monoclonal antibody Tezepelumab developed by AstraZeneca and Amgen, the inhaled dosage form developed by Novartis and MorphoSys, the immunoglobulin G1/λ subtype antibody fragment CSJ-117, has entered the phase II clinical stage, and Connaught Noah's CM326 entered phase I clinical trials in April 2021, and other recombinant humanization IgG1 monoclonal antibodies such as Merck-Benzdon MK-8226, Roche RG7258, and Astellas ASP7266 were discontinued after conducting Phase I clinical trials.
Tezepelumab (AMG 157, MEDI9929) is a true first-in-class TSLP-targeting monoclonal antibody, as a fully human IgG2λ monoclonal antibody that binds to human TSLP and blocks interaction with its receptors, thereby inhibiting multiple downstream inflammatory pathways. Its current ongoing clinical trials are shown in the table below.
Phase I clinical studies aimed to assess initial safety, pharmacokinetics showed that Tzepelumab was well tolerated in adult subjects of healthy and atopic dermatitis, and showed predictable linear pharmacokinetic characteristics and acceptable safety and tolerability.
In a proof-of-concept study, intravenous injection of 700 mg of Tezepelumab every 4 weeks for 12 weeks reduced airway hyperresponsiveness and systemic markers (59% and 21% reduction in circulating eosinophil levels compared to placebo) and airway markers (with the amount of exhaled nitric oxide and sputum as the main score item).
After allergen provocation in patients with mild allergic asthma, eosinophil levels fell from 4.1% at baseline levels to 0.4% after 6 weeks of inflammation. Early and late asthma responses are significantly weaker. Compared to the placebo group, the placebo group had a 27% reduction in asthma response and a 34% reduction in the placebo group.
In one phase IIb, randomized, double-blind, placebo-controlled trial, intradermal injection of Tezepelumab (70 mg every 4 weeks, 210 mg every 4 weeks, or 280 mg per 2 weeks) was administered to asthma patients receiving medium to high doses of inhaled corticosteroids/long-acting beta2-agonists for 52 weeks. At week 52, regardless of baseline blood eosinophil count, FeNO, or serum IgE levels, despite recording a sustained decline in blood eosinophil count and FeNO levels, they resulted in a 61%, 71%, and 66% decrease in annual exacerbations, respectively. Regardless of the dose, FEV1 with bronchodilators was consistently higher than the placebo group > 100 mL before 52 weeks, with improved symptom control in the medium and high dose groups, but only in the high dose group. The overall incidence of adverse events did not differ compared to the placebo group, with 1.1% of patients treated with Tezepelumab and 0.7% of patients treated with Tezepelumab.
Post-analysis of the Phase II clinical study showed that Tezepelumab lowered not only blood eosinophil count and FeNO levels, but also IL-5, IL-13, periostein, thymus and activated regulatory chemokines (TARC), and IgE levels. The study also showed that in patients with severe, uncontrolled asthma, Tezepelumab reduced the frequency of hospitalizations and emergency visits, and reduced the number of days spent in hospital or intensive care.
In any case, exposure-response analysis showed that 210 mg every 4 weeks was the optimal dose for the phase III trial in patients with severe asthma, and the efficacy of Tezepelumab on exacerbations and FeNO reductions was not affected by blood eosinophils or other biomarkers of type 2.
It is because of the results of this Phase II clinical trial that the FDA approved Tezepelumab as a "breakthrough" biological drug for the treatment of severe asthma.
Several studies are underway, primarily to verify the long-term efficacy and safety of Tezepelumab in the control of severe asthma in adults and adolescents in the Caucasus or Asia, as well as to evaluate the function and performance of assisted prefill syringes or auto-injectors for subcutaneous injection of Tezepelumab so that patients can self-administer medication at home.
In November 2020, the Phase III clinical trial NAVIGATOR reached the primary study endpoint showing therapeutic benefits for severe asthma by targeting TSLP: tezepelumab resulted in a statistically significant and clinically significant reduction in asthma exacerbations in a broad population of patients with severe asthma, including in patients with low eosinophil counts.
The data showed that the study achieved the primary endpoint: in the overall patient population, tezepelumab + SoC treatment resulted in a statistically significant and clinically significant reduction in the 52-week asthma exacerbation rate (AAER) compared to placebo + standard care (SoC). In this trial, the SoC was a medium- or high-dose inhaled corticosteroid (ICS) plus an additional controlled drug, with or without oral corticosteroids (OCS).
In addition, in a subgroup of patients with a baseline eosinophil count of < 300 cells/microliter, the trial also achieved a primary endpoint: tezepelumab + SoC treatment resulted in a statistically significant and clinically significant reduction in AARR compared to placebo + SoC. In a subgroup of patients with a baseline eosinophil count < 150 cells/microliter, a similar decrease in AAR was observed.
In terms of safety, tezepelumab has shown good tolerance in patients with severe asthma. Preliminary analysis showed no clinically significant difference in safety outcomes between the tezepelumab treatment group and the placebo group.
In December 2020, AstraZeneca/Amgen announced the results of the High-Level Phase III SOURCE Study. The study assessed the difference in efficacy and safety of adding tezepelumab (210 mg every 4 weeks) vs placebo for 48 weeks in 150 patients with severe asthma who required standard therapy (LABA) plus oral corticosteroid (OCS) maintenance therapy. The primary endpoints of the study were the decrease in OCS usage from baseline at week 48 under sustained asthma control, and secondary endpoints included annualized asthma exacerbations, lung function, asthma control, quality of life, and work efficiency.
The results showed that the SOURCE study failed to reach the primary endpoint, and the tezepelumab treatment group failed to reduce daily OCS doses compared to placebo. Other efficacy measures of Tezepelumab are consistent with previous studies, including the registration phase III NAVIGATOR study. Tezepelumab's safety results are also consistent with previous studies.
3. Dawn of listing
On July 7, 2021, Amgen announced that its application for the listing of tezepelumab, a potential "first-in-class" TSLP-targeted antibody therapy developed in collaboration with AstraZeneca, was accepted and granted by the FDA for priority review for the treatment of asthma, with a PDUFA date of Q1 2022.
The application is based on the key Phase 3 clinical trial NAVIGATOR, on September 5, 2021, Amgen published the results of a new data analysis of NAVIGATOR, in adult patients with severe asthma uncontrolled with nasal polyps, receiving standard treatment and adding tezepelumab, compared with the addition of placebo, reduced the rate of disease exacerbation by 86%.
In NAVIGATOR, Tezepelumab reaches both primary and secondary endpoints.
There was no significant difference in safety from placebo.
4. TSLP is not a monoclonal antibody session
Recently, skullcap has been identified as the first small molecule inhibitor of the human TSLP signaling pathway. In vitro studies have shown that the compound blocks human TSLP interactions with human TSLP in a dose-dependent manner. In addition, in ovalbumin-induced animal models, a monotherapy with skullcap effectively reduced eosinophil-rich lung inflammation. Structure-activity relationship studies have determined that compound 11a is a biphenyl flavanone analogue, a new human TSLP inhibitor used to discover and develop new anti-allergic drugs.
In another study, a new compound, PA, inhibits the expression and production of TSLP mRNA by blocking cysteine protease-1 in mast cells. Caspase-1 is known to be activated by pro-inflammatory stimulants because they increase intracellular calcium levels, which leads to caspase-1 activation.
Linaloster acetate, one of the main components of lavender, inhibits the production of TSLP and the expression of mRNA by blocking the caspase-1/NF-κB pathway. In addition, it lowers intracellular calcium levels.
Catechin is the main active ingredient in green tea, the dose of 75, 150, 300mg/ kg, can alleviate the allergic symptoms of allergic rhinitis mice, reduce the level of IL-5, IL-13, by affecting the NF-κB / TSLP pathway, inhibit the expression of epithelial cells TSLP, restore the balance of T-helper type 2/T helper type 1 cells.
Conversely, 16D10, a chalcone derivative, in addition to directly inhibiting NF-κB and activating the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor-erythrocyte line-2 correlated factor 2 (Nrf2) system, selectively inhibits the expression and production of TSLP in mouse and human keratinocyte lines through unknown mechanisms. Importantly, 16D10 inhibits the expression of TSLP and ovalbumin-specific IgG1 and IgE in vivo.
Afecta Pharmaceuticals has developed the small molecule TSLP inhibitor AFX-2721, which is already in the preclinical phase, among others
TSLP target discovery has been 30 years, Merck, Roche and other multinational pharmaceutical giants have been due to clinical development and setbacks, and AstraZeneca & Amgen's tezepelumab from 2008 to open Phase I clinical trials has been nearly 13 years to come to market, Chinese innovative pharmaceutical companies such as Connoa Biologics if they can give full play to the advantages of latecomers is still promising.
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