Treatment of high-risk asthma by blocking il-13 and tslp

Abstract

The present invention provides compounds for use in the treatment of mild-to-moderate asthma with a high risk of asthma exacerbations, wherein said compounds binds bind the cytokines IL-13 and TSLP. High risk of asthma exacerbations is assessed according to specific biomarkers, in particular elevated levels of fractional exhaled nitric oxide (FeNO) and an elevated eosinophil count in blood.

Description

[0001] Treatment of high-risk asthma by blocking IL-13 and TSLP

[0002] DESCRIPTION

[0003] 1 FIELD OF THE PRESENT INVENTION

[0004] The present invention relates to the treatment of high-risk asthma by administering a compound with binds to IL-13 and TSLP. Blocking those two cytokines has shown remarkable effects such as strongly reducing the level of fractional exhaled nitric oxide (FeNO) and the blood eosinophil count. Accordingly, a compound which blocks IL-13 and TSLP is particularly suited in treating a sub-group of asthma patients which suffers from asthma characterized by elevation of certain biomarkers such as FeNO and blood eosinophil count.

[0005] 2 BACKGROUND

[0006] Asthma is a common chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging leading to symptoms of wheezing, shortness of breath, cough, and chest tightness. Despite advances in asthma therapy, including better guidance on the use of antiinflammatory ICS, as well as targeted biologic therapy for patients with severe asthma, the burden of disease remains high across all asthma severity levels.

[0007] The inflammatory component of asthma is thought to involve many cell types including epithelial cells, T lymphocytes, eosinophils, mast cells, neutrophils, ILC2 and their biological products. Approximately half of asthma patients show evidence of "Type 2-high" inflammation, with elevated Th2 cytokines (IL-5, IL-13, and IL-4) and eosinophilic infiltration, while the substantial remainder show evidence of non-eosinophilic ("Type 2- low") inflammation. The presence of type 2 inflammation is identified across all spectrums of asthma severity and may drive worse disease outcomes regardless of GINA stage (Moore et al., Am J Respir Crit Care Med. 2010; 181(4):315-23). Downstream effects of type 2 inflammation include activation of inflammatory mediators as mast cells, eosinophils, and basophils leading to increased mucus production and airway remodelling. These features manifest clinically as asthma exacerbations and progressive loss of lung function.

[0008] The primary treatment goals for patients with asthma are to reduce symptoms and to prevent risk, including exacerbations. Inhaled corticosteroids (ICSs) are the backbone of therapy and reduce symptoms. Additional therapeutic options include long-and shortacting bronchodilators (BDs), including long-acting beta agonists (LABAs). Treatment guidelines, including Global Strategy for Asthma Management and Prevention (GINA), recommend a stepwise approach for all patients with asthma to manage both symptoms and risk, with gradual increase in maintenance therapy to ensure control. For patients with severe asthma, targeted treatment approaches are recommended, leveraging predictive type 2 inflammatory biomarkers or clinical features.

[0009] Despite advances in therapeutic approaches as well as the advent of add-on biologic therapy for patients with severe asthma, there remains a high unmet need for targeted therapy to address disease progression in "mild-to-moderate" patients who do not meet the current criteria for severe asthma. Up to half of all patients with asthma continue to experience symptoms despite guideline-directed maintenance therapy, and asthma exacerbations remain relatively common even in patients with mild severity (Busse et al., J Asthma. 2022;59(5):1051-62; Ding and Small, AdvTher. 2017;34(5):1109-27; Demoly et al., Eur Respir Rev. 2010;19(116):150-7). Asthma exacerbations are associated with increased mortality, regardless of asthma severity (Gayle et al., Thorax. 2019;74:483-91; Engelkes et al., Respir Med. 2020;165:105919). Across the spectrum of asthma severity, type 2 inflammation is a recognized driver of asthma morbidity. Type 2 inflammation can be identified by the several prognostic risk biomarkers, including FeNO level and blood eosinophil count. However, the use of these biomarkers to direct targeted therapy in "milder" populations has not been fully explored.

[0010] In patients with severe asthma, the presence of type 2 inflammation, as exemplified by FeNO level and blood eosinophil counts, identifies patients with more frequent asthma exacerbations, greater loss of lung function, poor asthma control, as well as worse quality of life. These biomarkers are prognostic across a spectrum of asthma severity. In patients with milder asthma as identified by their symptoms, this same pattern has been described. Blood eosinophil counts predict greater risk for developing obstructive lung disease, asthma exacerbations, and loss of lung function (Park et al., Eur Respir J. 2021;58(4):2003823; Couillard et al., Thorax. 2022;77(2):199-202; Hancox et al., Eur Respir J. 2018;51(4):1702536; Meulmeester et al., Lancet Respir Med. 2025 Jun;13(6):505-516). Independently, FeNO levels may predict accelerated loss of lung function in patients with controlled asthma as well as those with moderate-to-severe asthma (Ulrik et al., Eur Clin Respir J. 2021;8(l):1891725; Matsunaga et al., Allergol Int. 2016;65(3):266-71; Coumou et al., Eur Respir J. 2018;51(2):1701785; Pavord et al., Am J Respir Crit Care Med. 2022;205:A3418). In a study of patients with controlled asthma, patients with elevated FeNO levels above 40 ppb demonstrated a 40 ml / year loss of lung function, compared to 16.7 mL / year among those with normal FeNO levels. The combination of both elevated blood eosinophil counts and FeNO identified patients with severe asthma and loss of lung function over 140 mL / year (Pavord et al., Am J Respir Crit Care Med. 2022;205:A3418).

[0011] The type 2 inflammatory biomarkers are also predictive for the response to some interventional therapies. For patients with moderate-to-severe asthma, FeNO levels and blood eosinophil counts identify patients with a greater magnitude of response to intervention with biologic therapy targeting type 2 inflammation, including the I L4R-a Ipha dupilumab as well as the anti-TSLP Tezepelumab (Corren et al., Am J Respir Crit Care Med. 2023;208(l):13-24). In milder populations, elevated blood eosinophil counts predict response to inhaled corticosteroids (ICSs) (Pavord et al., Lancet Respir Med. 2020;8(7):671- 80). However, for many patients with high type 2 inflammation, maintenance ICS does not bring appropriate control of symptoms, exacerbations, or lung function (Couillard et al., ERJ Open Res. 2021;8(l):00570-2021). There remains high unmet need for earlier intervention in these patients with high-risk asthma, such as patient with increased type 2 inflammation through their FeNO levels or blood eosinophil counts. Targeted therapy in this population has the potential to prevent a predictable disease course, remove the cumulative burden of disease, and increase the likelihood of asthma remission.

[0012] SAR443765 (also known as lunsekimig) is a NANOBODY® molecule directed against both IL- 13 and TSLP. The targeting of both TSLP (an upstream initiator of the airway response to inhaled allergen, irritant, or pathogen) and IL-13 (a downstream mediator and enhancer of airway response to insult) is designed to inhibit the initiation and amplification of the asthmatic response. Anti-TSLP and anti-IL-13 monospecific mAbs have been approved for treatment of asthma (tezepelumab) and atopic dermatitis (tralokinumab), respectively. Anti-IL-13 monoclonal antibodies improved lung function in asthma trials, and reduced exacerbations in the subgroup of patients with well-defined type 2 inflammation (Corren et al., J Allergy Clin Immunol Pract. 2024:52213-2198(24)00163-6.), though their effect on exacerbations was inconsistent in a heterogeneous asthma population (Corren et al., N Engl J Med. 2011;365(12):1088-98; Panettieri et al., Lancet Respir Med. 2018;6(7):511-25; Hanania et al., Lancet Respir Med. 2016;4(10):781-96) and they have not been further developed in asthma.

[0013] The present invention provides a new treatment approach in patients with mild to moderate asthma with evidence of high-risk asthma, e.g. as identified by the type 2 inflammatory risk biomarkers FeNO level and blood eosinophil count. Dual cytokine suppression of TSLP as well as IL-13 leads to suppression of type 2 inflammation and downstream airway remodeling, thus preventing exacerbations and potentially future loss of lung function to a greater extent than standard ICS treatment alone.

[0014] 3 SUMMARY OF THE PRESENT INVENTION

[0015] The current invention provides a specific patient population which particularly benefits from SAR443765 treatment. This was possible by elucidating the pronounced effect of SAR443765 on FeNO levels and developing a clinical study protocol for the identification of patients which show high FeNO levels even under ICS / LABA treatment. Based on the inclusion criteria for the clinical study protocol, all study participants have mild-to-moderate asthma and elevated Type 2 biomarkers, such as elevated FeNO levels and high blood eosinophil counts. Those type 2 inflammatory biomarkers identify a population with high-risk asthma, which may not be classified as 'severe' according to current guidelines, but carry risk for exacerbations, poor asthma control and accelerated loss of lung function. In study PDY16622, targeting TSLP and IL-13 led to robust Type 2 suppression and improvement in lung function and measures of small airways disease. In the current study protocol, Part A of the study period ensures adherence to background medication and, by a FeNO suppression test, identifies an inhaled corticosteroid-resistant population that will experience clinical benefits from intervention with targeted TSLP and IL-13 suppression.

[0016] The studied patient population with mild-to-moderate asthma does not receive treatment according to Step 5 of the GINA treatment scale and is thus usually not eligible for treatment with biologic medication, such as antibodies. By pointing out the advantages of treating this patient with SAR443765, the present invention provides new treatment options which were not available before.

[0017] The present invention provides the following exemplary embodiments:

[0018] A compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject

[0019] I. does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline;

[0020] II. receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale;

[0021] III. receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; and / or

[0022] IV. is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils one or more of the following high-risk criteria: a) a FeNO level of i. at least 20 ppb, ii. at least 25 ppb, iii. at least 35 ppb, or iv. at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; b) Eosinophil count i. in blood of at least 0.15 *109cells / L; ii. in blood of at least 0.3 *109cells / L; c) One or more asthma exacerbation in the past 12 months.

[0023] The compound for use according to the previous embodiment, wherein the subject fulfils at least high-risk criterion a) ii., i.e. a FeNO level of at least 25 ppb.

[0024] The compound for use according to any of the previous claims, wherein the subject fulfils at least high-risk criterion a) iii., i.e. a FeNO level of at least 35 ppb.

[0025] The compound for use according to any of the previous claims, wherein the subject fulfils at least high-risk criterion a) iv., i.e. a FeNO level of at least 50 ppb.

[0026] The compound for use according to any of the previous embodiments, wherein the subject fulfils at least high-risk criterion a) iii., i.e. a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, which is determined by a FeNO suppression test, wherein the FeNO suppression test consists of at least 4 weeks of administration of inhaled corticosteroids in an amount of at least 500 pg per day of fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline. The compound for use according to any of the previous embodiments, wherein the subject fulfils at least high-risk criterion a) iv., i.e. a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, which is determined by a FeNO suppression test, wherein the FeNO suppression test consists of at least 4 weeks of administration of inhaled corticosteroids in an amount of at least 500 pg per day of fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

[0027] The compound for use according to any of the previous embodiments, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, wherein the subject fulfills at least high-risk criterion a) iv. before a FeNO suppression test and fulfills at least high-risk criterion a) iii. after the FeNO suppression test, wherein the FeNO suppression test consists of at least 4 weeks of administration of inhaled corticosteroids in an amount of at least 500 pg per day of fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

[0028] The compound for use according to any of the previous embodiments, wherein the subject fulfills at least mild-to-moderate asthma criterion I.

[0029] The compound for use according to any of the previous embodiments, wherein the subject receives inhaled corticosteroid treatment.

[0030] The compound for use according to any of the previous embodiments, wherein the subject further fulfills high-risk criterion b) i., i.e. an eosinophil count in blood of at least 0.15 *109cells / L.

[0031] The compound for use according to any of the previous embodiments, wherein the subject further fulfills high-risk criterion b) ii., i.e. an eosinophil count in blood of at least 0.3 *109cells / L.

[0032] The compound for use according to any of the previous embodiments, wherein the subject further fulfills high-risk criterion c)., i.e. one or more asthma exacerbation in the past 12 months.

[0033] The compound for use according to any of the previous embodiments, wherein the subject further fulfills one or more of the following high-risk criteria: d) type 2 high phenotype, wherein a type 2 high phenotype is characterized by high expression of type 2 cytokines, such as IL-4, IL-5, IL-6 and IL-13; e) Small airway obstruction, as measured by oscillometry, spirometry, or imaging. f) Asthma Control Questionnaire score >1.5; g) forced expiratory volume in 1 second <80% predicted; h) use of >200 doses of asthma reliever medication / month; i) comorbidities, or history of comorbidities, wherein the comorbidities comprise one or more of chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), allergy, eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), obesity, and psychiatric disease; j) previous intubation or intensive care unit admission for asthma; k) environmental exposures, wherein the environmental exposure comprise one or more of smoking, allergen, and pollution; l) eosinophil count in sputum of at least 3%, of total non-squamous cell count.

[0034] The compound for use according to any of the previous embodiments, wherein the compound that binds IL-13 and TSLP is a polypeptide, such as an antibody or an antibody fragment.

[0035] The compound for use according to the previous embodiment, wherein the polypeptide comprises or consists of at least four ISVDs, wherein two ISVDs specifically bind IL-13 and two ISVDs specifically bind TSLP, wherein each of said at least four ISVDs comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least four ISVDs are optionally linked via one or more peptidic linkers, and wherein: a first ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 7, a CDR2 that is the amino acid sequence of SEQ ID NO: 12 and a CDR3 that is the amino acid sequence of SEQ ID NO: 17, a second ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 8, a CDR2 that is the amino acid sequence of SEQ ID NO: 13 and a CDR3 that is the amino acid sequence of SEQ ID NO: 18, a third ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 9, a CDR2 that is the amino acid sequence of SEQ ID NO: 14 and a CDR3 that is the amino acid sequence of SEQ ID NO: 19, and a fourth ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 11, a CDR2 that is the amino acid sequence of SEQ ID NO: 16 and a CDR3 that is the amino acid sequence of SEQ ID NO: 21.

[0036] The compound for use according to any of the two previous embodiments, wherein the polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0037] 4 BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1: Schedule of the clinical trial of example 1 (PDY16622). The schedule indicates the treatments / measurements which were performed at the indicated time points ("D" for "day") of the clinical trial.

[0039] Figure 2: FeNO measurements of the clinical trial of example 1 (PDY16622). Shown is the change in level of fractional exhaled nitric oxide (in parts per billion, ppb) from baseline of the SAR443765 group (dashed line) and the placebo group (solid line).

[0040] Figure 3: FeNO measurements of the clinical trial of example 1 (PDY16622), analyzed according to eosinophil high / low subgroups and inhaled corticosteroids (ICS) use subgroups. Fig. 3A depicts the results of the eosinophil high / low subgroups. Shown is the change in level of fractional exhaled nitric oxide (in parts per billion, ppb) from baseline of the high eosinophilic SAR443765 group (lower dashed line, dark grey), the low eosinophilic SAR443765 group (lower solid line, dark grey), the high eosinophilic placebo group (upper dashed line, light grey) and the low eosinophilic placebo group (upper solid line, light grey). Fig. 3B depicts the results of the ICS use subgroups. Shown is the change in level of fractional exhaled nitric oxide (in parts per billion, ppb) from baseline of the SAR443765 group without ICS use (lower dashed line, dark grey), the SAR443765 group with ICS use (lower solid line, dark grey), the placebo group without ICS use (upper dashed line, light grey) and the placebo group with ICS use (upper solid line, light grey).

[0041] Figure 4: Eosinophil count of the clinical trial of example 1 (PDY16622). Shown is the median change of eosinophil count compared to baseline at D29 (4 weeks) of the SAR443765 group (right) and the placebo group (left).

[0042] Figure 5: Eosinophil count of clinical trial of example 1 (PDY16622, right bar) compared to three other biologies: lebrikizumab (left bar), tezepelumab (second bar from the left), and dupilumab (second bar from the right) at D29.

[0043] Figure 6: FEV1 measurements of the clinical trial of example 1 (PDY16622). Shown is the change of FEV1 (in liter, compared to baseline) of the SAR443765 group (dashed line) and the placebo group (solid line). All measurements were included.

[0044] Figure 7: FEV1 measurements of the clinical trial of example 1 (PDY16622). Shown is the change of FEV1 (in liter, compared to baseline) of the SAR443765 group (dashed line) and the placebo group (solid line). Only measurements which fulfilled all quality criteria were included.

[0045] Figure 8: FEV1 measurements of the clinical trial of example 1 (PDY16622). Shown is the change of FEV1 (in liter, compared to baseline) as shown in Fig. 7. The SAR443765 group and the placebo group were each divided into two subpopulations, depending on the baseline percent predicted FEV1 (ppFEVl). The subpopulations are: SAR443765, baseline ppFEVl > 80% (dark grey solid line); SAR443765, baseline ppFEVl < 80% (dark grey dashed line); placebo, baseline ppFEVl > 80% (light grey solid line); placebo, baseline ppFEVl < 80% (light grey dashed line). Figure 9: Forced Expiratory Flow 25-75% (FEF25-75) measurements of the clinical trial of example 1 (PDY16622). Shown is the change of FEF25-75 (in liter / s, compared to baseline). The left panel shows the change of FEF25-75 of the SAR443765 group (dashed line) and the placebo group (solid line). In the right panel, the SAR443765 group and the placebo group were each divided into two subpopulations depending on the baseline percent predicted FEV1 (ppFEVl). The subpopulations are: SAR443765, baseline ppFEVl > 80% (dark grey solid line); SAR443765, baseline ppFEVl < 80% (dark grey dashed line); placebo, baseline ppFEVl > 80% (light grey solid line); placebo, baseline ppFEVl < 80% (light grey dashed line).

[0046] Figure 10: Measurements of the difference of respiratory resistances at 5 Hz and 20 Hz (R5- 20) of the clinical trial of example 1 (PDY16622). Shown is the change (in cmH2O*s / L, compared to baseline) in the difference between the respiratory resistance at 5 Hz and the respiratory resistance at 20 Hz. The left panel shows the change of R5-20 of the SAR443765 group (dashed line) and the placebo group (solid line). In the right panel, the SAR443765 group and the placebo group were each divided into two subpopulations depending on the baseline percent predicted FEV1 (ppFEVl). The subpopulations are: SAR443765, baseline ppFEVl > 80% (dark grey solid line); SAR443765, baseline ppFEVl < 80% (dark grey dashed line); placebo, baseline ppFEVl > 80% (light grey solid line); placebo, baseline ppFEVl < 80% (light grey dashed line).

[0047] Figure 11: Measurements of the reactance area (AX) of the clinical trial of example 1 (PDY16622). Shown is the change in the reactance area (in cmH2O / L), compared to baseline). The left panel shows the change of the reactance area of the SAR443765 group (dashed line) and the placebo group (solid line). In the right panel, the SAR443765 group and the placebo group were each divided into two subpopulations depending on the baseline percent predicted FEV1 (ppFEVl). The subpopulations are: SAR443765, baseline ppFEVl > 80% (dark grey solid line); SAR443765, baseline ppFEVl < 80% (dark grey dashed line); placebo, baseline ppFEVl > 80% (light grey solid line); placebo, baseline ppFEVl < 80% (light grey dashed line). Figure 12: Further biomarker measurements of the clinical trial of example 1 (PDY16622). Shown is the change of IL-5 level in serum (upper left panel); CCL26 (eotaxin-3) level in plasma (upper right panel), IgE level in serum (lower left panel), and TARC (CCL17) level in serum (lower right panel) and compared to baseline. Each panel shows the results for placebo (left) and SAR443765 (right).

[0048] Figure 13: FeNO measurements of example 2, showing the pre-screening of the clinical trial of example 1 (PDY16622). Shown is the number of pre-screened participants which displayed a FeNO level within the indicated ranges (in parts per billion, ppb). 769 participants were pre-screened.

[0049] Figure 14: ICS treatment in participant groups with certain FeNO levels. The participants of the pre-screening of example 1 (PDY16622) were grouped according to the FeNO measurements shown in Fig. 13 and categorized according to the ICS maintenance treatment (=controller medication) which they received. The categories for ICS treatments were medium-dose ICS (>250-500 pg of fluticasone propionate or comparable ICS total daily dosage), low-dose ICS (<250 pg of fluticasone propionate or comparable ICS total daily dosage), ICS PRN (no ICS maintenance treatment but occasional ICS administration as reliever treatment), and ICS naive (no ICS treatment at all). 575 of the 769 pre-screened participants could be categorized, for the remaining participants there was no information about ICS dose available.

[0050] Figure 15: Eosinophil count in participant groups with certain FeNO levels. The 62 participants of the screening of example 1 (PDY16622) were grouped according to FeNO levels and categorized according to eosinophil count in blood. The categories for eosinophil count were <150 cells / pL (<0.15*109cells / L), 150-300 cells / pL (0.15*109- 0.3*109cells / L), and >300 cells / pL (0.3*109cells / L).

[0051] Figure 16: Design of the study of example 3. Abbreviations: EOS = end of study; EOT = end of treatment; FeNO = fraction of exhaled nitric oxide; ICS = inhaled corticosteroid IMP = investigational medicinal product; LABA = long-acting beta agonist; V = visit. For ICS / LABA, the investigator may choose 1 of 2 possible maintenance and reliever therapy regimens to allow flexibility to follow guideline-based treatment options, and maintain consistency with a participant's maintenance and reliever therapy prior to screening and / or local practice, including either: 500 pg / day of fluticasone propionate plus LABA maintenance therapy with short-acting beta-agonist used as reliever therapy, or 800 pg / day of budesonide plus formoterol maintenance with low-dose budesonide / formoterol used as reliever therapy.

[0052] Figure 17: Design of the study of example 4. Abbreviations as described for Fig. 16. For ICS / LABA, the investigator may choose 1 of 2 possible maintenance and reliever therapy regimens to allow flexibility to follow guideline-based treatment options, and maintain consistency with a participant's maintenance and relievertherapy priorto screening and / or local practice, including either: 500 pg / day of fluticasone propionate plus LABA maintenance therapy with short-acting beta-agonist used as reliever therapy, or 800 pg / day of budesonide plus formoterol maintenance with low-dose budesonide / formoterol used as reliever therapy. Example 4 (Fig. 17) requires a lower FeNO threshold of >35 ppb at VI, whereas Example 3 (Fig. 16) requires >50 ppb.

[0053] 5 DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0054] Patients with asthma and elevated T2 inflammation, as indicated by biomarkers such as high FeNO level and eosinophil count, are at significantly increased risk for exacerbations and loss of lung function, irrespective of their asthma severity assessment (Couillard et al., Thorax. 2022;77(2):199-202). Due to an assessment of their disease as mild or moderate, a substantial amount of those patients with "high-risk" asthma is currently not eligible for treatments with biologies, such as antibodies. SAR443765 (Lunsekimig) can reduce biomarkers such as FeNO level to a higher extent than other known medications. Therefore, it may significantly improve outcomes in patients with high-risk asthma and become a biologic medicament for which high-risk asthma patients are eligible independently of their asthma severity assessment. Accordingly, the present invention provides a novel therapeutic option for patients with high-risk asthma.

[0055] In particular, eligibility for SAR443765 treatment before an asthma patient reaches GINA treatment Step 5 may be highly beneficial since early intervention with potent reduction of type-2 inflammation could prevent dangerous asthma exacerbations and a potentially permanent loss of lung function, and may even increase the likelihood of achieving disease remission from asthma.

[0056] In the clinical trial PDY16622, it was shown that the combined inhibition of IL-13 and TSLP reduces the FeNO level stronger than other known biologies and that said combined inhibition also reduces the eosinophil number and improves the FEVl. Results of PDY16622 are disclosed below in example 1. In particular, it was shown that the inhibition of IL-13 and TSLP reduces FeNO level in patients with and without inhaled corticosteroid (ICS) use (see Fig. 3B and Tab. 3B). Building on those results, we developed a clinical trial to identify and treat a population with high-risk asthma (example 3) which will particularly benefit from the combined inhibition of IL-13 and TSLP.

[0057] 5.1 DEFINITIONS

[0058] Unless otherwise stated below, all terms used in this application, including the specification and claims, have the meaning usually given to them in the respective scientific field.

[0059] As used in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly dictates otherwise.

[0060] Asthma, as used herein, is a pulmonary disease which is characterized by long-term airway inflammation. Asthma comprises airflow obstruction and triggered bronchospasms. Symptoms often include episodes of wheezing, coughing, chest tightness, and shortness of breath. Asthma includes allergic, non-allergic, Th2 high, Th2 low, high eosinophilic, and low eosinophilic asthma. Asthma exacerbations, as used herein, is defined as worsening of asthma requiring either the use of systemic corticosteroids for >3 days; or hospitalization or emergency room visit due to asthma and requiring the use of systemic corticosteroids.

[0061] High eosinophilic asthma, as used herein, is asthma wherein the patient shows an eosinophil count of more than or equal to 0.3 *109cells / L. An exemplary eosinophil count range in high eosinophilic asthma is from 0.3 *109to 0.5 *109cells / L.

[0062] Low eosinophilic asthma, as used herein, is asthma wherein the patient shows an eosinophil count of less than 0.3 *109cells / L. An exemplary eosinophil count range in low eosinophilic asthma is from 0 to less than 0.3 *109cells / L.

[0063] The "GINA guideline", as used herein, refers to the GINA document "Global Strategy for Asthma Management and Prevention (2023 update)", as it can be found under https: / / ginasthma.org / wp-content / uploads / 2023 / 07 / GINA-2023-Full-report-23_07_06- WMS.pdf. The equivalent doses of inhaled corticosteroids can be found in the table in Box 3.14 of this document, for adults and adolescents as well as for children. It has to be noted that the table of equivalent doses deals with different age group of patients, i.e. patients which are at least 12 years old and patients which are less than 12 years old. For sake of simplicity, this patent application mentions only the doses for the patients which are at least 12 years old but they have to be understood to comprise the corresponding for the patients which are less than 12 year old as well. For example, a dose of "more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline" means a dose of more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, if the patient is at least 12 years old; or a dose of more than 200 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, if the patient is less than 12 years old.

[0064] For equivalence of ICSs, it has to be taken into account that the metered doses and the delivered doses can differ for some ICSs, e.g. a metered dose of 200 pg of budesonide corresponds to a delivered dose of 160 pg. The equivalence table in the GINA guideline, and thus also the dosage values throughout this patent application, refer to the metered dose.

[0065] The definition of the Steps of the GINA treatment scale (Steps 1-5) can be derived from the GINA guidelines. Notably, Step 5 corresponds to a treatment with more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

[0066] Fractional exhaled nitric oxide (FeNO), as used herein, is the fraction of nitric oxide (NO) in the exhaled air. It is measured in parts per billion (ppb). An elevated FeNO level is a sign of airway inflammation. A FeNO level is elevated if it is at least 20 ppb.

[0067] A FeNO suppression test, as used herein, is the administration of a relatively high amount of an ICS, such as 500 pg per day of inhaled fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline, to a subject suffering from asthma, optionally combined with another drug such as an LABA, for a short period of time, such as 4 weeks, to monitor whether this treatment lowers the FeNO level under a certain threshold, such as 50 ppb or 20 ppb. It has to be noted that the FeNO suppression test is not part of a long-term standard treatment of the subject.

[0068] Eosinophil count, as used herein, is the number of eosinophilic granulocytes. In the treatments according to the present invention, the eosinophil count is measured in whole blood. Methods to measure the eosinophil count are known in the art, e.g. flow cytometry or counting under a microscope after H&E staining. The eosinophil count is measured in cells / L.

[0069] The forced expiratory volume in one second (FEV1), as used herein, is the volume that has been exhaled at the end of the first second of forced expiration after maximal inspiration. FEV1 can be measured by spirometry.

[0070] Small airways, as used herein, refers to those airways which have a diameter of equal to or less than 2 mm, as commonly defined in the literature (see e.g. McNulty and Usmani, Eur Clin Respir J, 2014;l:10.3402 / ecrj.vl.25898 and Stockley et al., Int J Chron Obstruct Pulmon Dis. 2017;12: 2343-2353). Large airways, as used herein, refers to those airways which have a diameter of more than 2 mm.

[0071] Loss of lung function, as defined herein, means that in the lungs of a subject the airflow is limited or impaired due to a lung disease. This can be determined by measuring parameters for lung function, such as FEVl.

[0072] Type 2 inflammation, as used herein, is an immune response which is characterized by the activation of type 2 T helper cells and / or type 2 innate lymphoid cells. The immune response of a type 2 inflammation is characterized by the release of alarmins (IL-23, IL-33, TSLP) which leads to the activation of type 2 T helper cells and / or type 2 innate lymphoid cells. Those cells secrete IL-4, IL-5 and IL-13, which promotes isotype switching to IgE in B cells and eosinophil recruitment. A type 2 inflammation can be useful for the defense of the body against helminths but is involved in a variety of autoinflammatory diseases. The airway inflammation in asthma patients is often a type 2 inflammation.

[0073] Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), as used herein, refers to chronic rhinosinusitis which occurs in combination with nasal polyps. Chronic rhinosinusitis (CRS) refers to an inflammatory condition of the sinuses characterized by any combination of specific symptoms including, but not limited to, nasal congestion, decreased or lost sense of smell, anterior and / or posterior nasal discharge, facial pain, and / or headache and consequences thereof, often for a period of years. A formal diagnosis is made on the basis of sinus computed tomography (CT) scan and / or sinus endoscopy. Based on endoscopic evaluation, CRS can be clinically divided as CRS with nasal polyps / nasal polyposis (CRSwNP) or CRS without nasal polyps / nasal polyposis.

[0074] Atopic dermatitis (AD), as used herein, means an inflammatory skin disease characterized by intense pruritus (e.g., severe itch) and by scaly and dry eczematous lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergy (e.g., allergy to certain foods, pollen, mold, dust mite, animals, etc.), radiation exposure, and / or asthma. The subject in the present application is suffering from asthma, therefore the terms "subject" and "patient" and "asthma patient" are used synonymously throughout this application.

[0075] The participants of the clinical trial of examples 1 and 2 (PDY16622) and the clinical trial of example 3 consist of asthma patients (see below in example 1). Thus, the terms the terms "participant" and "patient" are used synonymously in the context of those clinical trials.

[0076] The subject of the treatment of the present invention can be any animal, and more specifically a mammal. Among mammals, a distinction can be made between humans and non-human mammals. Non-human animals may be for example companion animals (e.g. dogs, cats), livestock (e.g. bovine, equine, ovine, caprine, or porcine animals), or animals used generally for research purposes and / or for producing antibodies (e.g. mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus monkeys, or camelids, such as llama or alpaca). In one embodiment, the subject is a human subject.

[0077] The expressions "treatment of a disease in a subject" and "treatment of a disease" are used interchangeably herein, as it is evident that a treatment occurs in a subject. Same holds true for variations of this expressions, e.g. "treatment of a pulmonary disease in a subject" is interchangeably used with "treatment of a pulmonary disease".

[0078] Indications of time spans in this application count the day of drug administration as day 1 ("DI"). This means that the day following drug administration is counted as day 2 ("D2"), so that, e.g., a measurement which occurs 24 h after drug administration is on D2 and a measurement which occurs 72 h after drug administration is on D4. This means also that a time span of one week ends on D8, a time span of 2 weeks ends on D15, a time span of three weeks ends on D22, a time span of 4 weeks ends on D29, a time span of 8 weeks ends on D57, and a time span of 10 weeks ends on D71. In the present disclosure, "day" is often abbreviated "D". The terms "day" and "D" are used interchangeably in this closure.

[0079] Placebo, as used herein, is a treatment, or a substance used in such a treatment, which does not include a pharmacologically active compound. In clinical trials, a placebo can be administered to a fraction of the participants to generate a control group for the fraction of participants who receive the pharmacologically active compound to be tested. To serve as a proper control, the treatment with placebo is identical to the treatment it is compared with, the only exception being that a placebo (e.g. an inert pill like a sugar pill) and not the pharmacologically active compound is administered.

[0080] 5.2 "MILD-TO-MODERATE" ASTHMA

[0081] The present invention provides a treatment for mild-to-moderate asthma. Despite "mild- to-moderate" might sound reassuring, this does not mean that this type of asthma is harmless. In fact, there is a subgroup of patients with mild-to-moderate asthma which have a risk for asthma exacerbations which is as high as for patients classified to have severe asthma.

[0082] In the context of the present invention, there are different definitions of mild-to-moderate asthma which are overlapping and not mutually exclusive.

[0083] Definition I.

[0084] Severity of asthma can be classified according to the dosage of inhaled corticosteroids (ICSs) that is administered as maintenance therapy to a subject suffering from asthma.

[0085] In one embodiment, mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

[0086] As described in the definitions section above, the indicated dose is meant for a patient population of at least 12 years of age and comprises the equivalent amount of fluticasone propionate for a patient population of less than 12 years according to the GINA guideline. Accordingly, the above statement of more than 500 pg means that the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, if the subject is at least 12 years old; and that the subject does not receive more than 200 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, if the patient is less than 12 years old. In one embodiment, the subject does not receive more than 500 ng per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, and is at least 12 years old. In one embodiment, the subject does not receive more than 200 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, and is less than 12 years old.

[0087] In some embodiments, the subject receives ICS, but lower as the threshold of more than 500 pg fluticasone propionate per day described above. In one embodiment, the subject receives at least 100 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, but not more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline. In one embodiment, the subject receives at least 250 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, but not more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline. In one embodiment, the subject receives more than 250 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, but not more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

[0088] The definition of mild-to-moderate asthma by the ICS threshold instead of GINA treatment Step definitions (see below) has the advantage that it is easier to automate and perform using the currently available patient-related data streams (e.g. PBX codes, EPIC, etc.).

[0089] In some embodiments, the above definition of mild-to-moderate asthma is slightly limited to exclude patients receiving exactly 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline. This means that in those embodiments the definition reads "receives less than 500 pg per day of inhaled fluticasone propionate" instead of "does not receive more than 500 pg per day of inhaled fluticasone propionate.

[0090] Definitions II and III. Severity of asthma can also be classified according to the treatment according to a Step on the GINA treatment scale which is administered to a subject suffering from asthma. The Steps of the GINA treatment scale are defined in the GINA guideline.

[0091] In one embodiment, mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale.

[0092] In one embodiment, mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale.

[0093] In one embodiment, mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 2-4 of the GINA treatment scale.

[0094] In one embodiment, mild-to-moderate asthma is asthma wherein the subject receives no asthma treatment according to the Steps of the GINA treatment scale.

[0095] Definition IV.

[0096] In one embodiment, mild-to-moderate asthma is asthma wherein the asthma patient is not eligible for asthma treatment with biologies. This is determined according to GINA recommendations and country-level medical guidelines (such as FDA and EMA label) as in force in 2024. Eligibility for different regions can be found for example in Albers et al., J Asthma. 2018 Feb;55(2):152-160, and in Kavanagh et al., Breathe (Sheff). 2021 Dec;17(4):210144.

[0097] The treatment of the current invention can be particularly suitable for patients who are not eligible for treatment with current biologies (as of 2024). As derived from the clinical study in example 1, the inhibition of IL-13 and TSLP leads to major improvements in FeNO levels in patients having elevated markers of type 2 inflammation and suffering from mild-to- moderate asthma, indicating an effective treatment of type 2 airway inflammation. In example 3, a protocol is provided to identify a specific high-risk population of mild-to- moderate asthma patients that will particularly benefit from such effective treatment. This provides a new therapeutic option and subjects who are not eligible to the current biologies (such as anti-IL-5 or anti-IL-4Ra antibodies) may be eligible to treatment with a biologic blocking IL-13 and TSLP simultaneously due to the demonstrated advantages. Thus, the treatment of the present invention can prevent dangerous asthma exacerbations and loss of lung function in this patient population.

[0098] In some embodiments, the asthma patient is not eligible for treatment with dupilumab according to the respective regulations in Europe as of 2024. In some embodiments, the asthma patient is not eligible for treatment with dupilumab according to the respective regulations in the USA as of 2024.

[0099] In some embodiments, the asthma patient is not eligible for treatment with tezepelumab according to the respective regulations in Europe as of 2024. In some embodiments, the asthma patient is not eligible for treatment with tezepelumab according to the respective regulations in the USA as of 2024.

[0100] In some embodiments, the asthma patient is not eligible for treatment with an IL-5 antagonist, such as mepolizumab and benralizumab, according to the respective regulations in Europe as of 2024. In some embodiments, the asthma patient is not eligible for treatment with an IL-5 antagonist, such as mepolizumab and benralizumab, according to the respective regulations in the USA as of 2024.

[0101] Combination of definitions

[0102] All four definitions provided herein for mild-to-moderate asthma are overlapping and not mutually exclusive. It is possible that a subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline (definition I.); receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale (definition IL); receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale (definition III.); and is not eligible for asthma treatment with biologies (definition IV) at the same time.

[0103] In one embodiment, at least definitions I. and II. apply. In one embodiment, at least definitions I. and III. apply. In one embodiment, at least definitions I. and IV. apply. In one embodiment, at least definitions II. and III. apply. In one embodiment, at least definitions II. and IV. apply. In one embodiment, at least definitions III. and IV. apply. In one embodiment, at least definitions I., IL, and III apply. In one embodiment, at least definitions I., IL, and IV apply. In one embodiment, at least definitions L, HL, and IV apply. In one embodiment, at least definitions IL, HL, and IV apply.

[0104] In one embodiment, all of the above definitions, i.e. definition L, IL, III. and IV apply.

[0105] ICS treatment

[0106] In some embodiments, the subject receives inhaled corticosteroids (ICSs). As the subject has mild-to-moderate asthma according to one or more of definitions I to IV, this means that the subject receives ICS in a dose of 500 pg per day or less of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline. For example, the patient can receive <250 pg of fluticasone propionate per day or >250-500 pg of fluticasone propionate per day, or <500 pg of fluticasone propionate per day.

[0107] 5.3 HIGH RISK OF ASTHMA EXACERBATIONS OR LUNG FUNCTION LOSS

[0108] There are several risk factors which enable the identification of a population of asthma patients which are especially prone to asthma exacerbation and / or loss of lung function, despite their asthma disease is not classified as severe but only as mild-to-moderate according to one of the definitions provided above. This patient population benefits from treatment with compounds that bind IL-13 and TSLP as the combined inhibition of these two cytokines has shown to reduce the FeNO level, even in patient with elevated FeNO level despite of ICS treatment, and the eosinophil count.

[0109] The risk factors are overlapping and not mutually exclusive, and an accumulation of risk factors may indicate an even higher risk. a) Elevated FeNO levels It is known that an elevated FeNO level indicates high levels of Type 2 airway inflammation and consequently higher risk for an asthma exacerbation, even for patients with mild-to- moderate asthma (treated according to GINA Steps 1-4) (Couillard et al., Thorax. 2022;77(2):199-202). Moreover, an elevated FeNO level is also a risk factor for loss of lung function of asthma patients (Matsunaga et al., Allergol Int. 2016;65(3):266-71).

[0110] As shown in example 1, the treatment with a compound that blocks IL-13 and TSLP reduces such elevated FeNO levels which indicates reduced airway inflammation resulting in a reduction in risk for asthma exacerbations. In the pre-screening of the clinical study shown in example 2, it was found that a large number of mild-to-moderate asthma patients display FeNO levels which are seen as a risk factor for asthma exacerbations. Thus, there is a considerable population of mild-to-moderate asthma patients which will profit from the treatment of the present invention.

[0111] Several embodiments of the present invention can use different thresholds for the elevated FeNO level.

[0112] In one embodiment, the FeNO level is at least 20 ppb. In one embodiment, the FeNO level is at least 25 ppb. In one embodiment, the FeNO level is at least 30 ppb. In one embodiment, the FeNO level is at least 35 ppb. In one embodiment, the FeNO level is at least 40 ppb. In one embodiment, the FeNO level is at least 50 ppb.

[0113] In one embodiment, the FeNO level is between 20 and 150 ppb. In one embodiment, the FeNO level is between 25 and 150 ppb. In one embodiment, the FeNO level is between 30 and 150 ppb. In one embodiment, the FeNO level is between 35 and 150 ppb. In one embodiment, the FeNO level is between 40 and 150 ppb. In one embodiment, the FeNO level is between 50 and 150 ppb.

[0114] The risk for an asthma exacerbation is even higher if the high FeNO level is resistant to treatment with inhaled corticosteroids (ICSs), i.e. the FeNO level is still elevated (i.e. at least 20 ppb) after ICS treatment (Couillard. et al., Am J Respir Crit Care Med. 2021 Sep 15;204(6):731-734). In the present invention, ICS resistance can be measured by a FeNO suppression test. An exemplary FeNO suppression test comprises: 1. Identifying a subject suffering from asthma with an elevated FeNO level, i.e. a FeNO level above a predefined threshold, such as 20 ppb, 35 ppb, or 50 ppb;

[0115] 2. Administering a relatively high amount of an ICS, such at least 500 pg per day of inhaled fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline, to a subject suffering from asthma, optionally combined with another drug such as an LABA, for a short period of time, such as at least 4 weeks.

[0116] 3. Determining whether the ICS treatment lowers the FeNO level under a predefined threshold, such as 20 ppb, 35 ppb, or 50 ppb, wherein the elevated FeNO level identified in step 1. is resistant to ICS treatment if it is determined in step 3. that the FeNO level is still above the predefined threshold.

[0117] It should be noted that this FeNO suppression test differs from previously published tests in that reduction of FeNO levels under a certain absolute threshold is measured, not percentage of FeNO level decrease. The present approach is advantageous as the predictive value of FeNO level as a high-risk biomarker depends on the absolute level, not the percentage of decrease.

[0118] In one embodiment of the FeNO suppression test, the threshold in step 1 is 50 ppb and the threshold in step 3 is 20 ppb. In one embodiment of the FeNO suppression test, the threshold in step 1 is 50 ppb and the threshold in step 3 is 35 ppb. In another embodiment of the FeNO suppression test, the threshold in step 1 is 50 ppb and the threshold in step 3 is also 50 ppb. In one embodiment of the FeNO suppression test, the threshold in step 1 is 35 ppb and the threshold in step 3 is 20 ppb. In another embodiment of the FeNO suppression test, the threshold in step 1 is 35 ppb and the threshold in step 3 is also 35 PPb.

[0119] In one embodiment of the FeNO suppression test, the amount of ICS in step 2 is 500 pg per day and the short period of time is 4 weeks.

[0120] In some embodiments, the elevated FeNO level is resistant to treatment with inhaled corticosteroids. In one embodiment, the FeNO level is at least 20 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 20 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 25 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 20 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 30 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 20 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 35 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 20 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 40 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 20 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 50 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 20 ppb after a FeNO suppression test.

[0121] In one embodiment, the FeNO level is at least 35 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 35 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 40 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 35 ppb after a FeNO suppression test. In one embodiment, the FeNO level is at least 50 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 35 ppb after a FeNO suppression test.

[0122] In one particular embodiment, the FeNO level is at least 50 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is at least 50 ppb after a FeNO suppression test.

[0123] In one embodiment, the FeNO level is between 20 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 20 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 25 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 20 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 30 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 20 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 35 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 20 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 40 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 20 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 50 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 20 and 150 ppb after a FeNO suppression test.

[0124] In one embodiment, the FeNO level is between 35 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 35 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 40 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 35 and 150 ppb after a FeNO suppression test. In one embodiment, the FeNO level is between 50 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 35 and 150 ppb after a FeNO suppression test.

[0125] In one particular embodiment, the FeNO level is between 50 and 150 ppb and is resistant to treatment with inhaled corticosteroids, wherein the FeNO level is between 50 and 150 ppb after a FeNO suppression test. b) Elevated eosinophil count in blood

[0126] An elevated eosinophil count in blood indicates a higher risk for an asthma exacerbation for patients with mild-to-moderate asthma (treated according to GINA Steps 1-4 (Couillard et al., Thorax. 2022;77(2):199-202).

[0127] As shown in example 1, the treatment of the present invention reduces such elevated eosinophil counts which will lead to a reduction in risk for asthma exacerbations.

[0128] In the final screening of the clinical study shown in example 2, it was found that 68% of mild-to-moderate asthma patients that showed elevated FeNO levels of at least 50 ppb also showed an elevated eosinophil count in blood of at least 0.3 *109cells / L. Several embodiments of the present invention use different thresholds for the elevated eosinophil count in blood.

[0129] In one embodiment, the eosinophil count in blood is at least 0.15 *109cells / L. In one embodiment, the eosinophil count in blood is at least 0.2 *109cells / L. In one embodiment, the eosinophil count in blood is at least 0.25 *109cells / L. In one embodiment, the eosinophil count in blood is at least 0.3 *109cells / L.

[0130] In one embodiment, the eosinophil count in blood is between 0.15 *109and 0.6 *109. In one embodiment, the eosinophil count in blood is between 0.2 *109and 0.6 *109. In one embodiment, the eosinophil count in blood is between 0.25 *109and 0.6 *109. In one embodiment, the eosinophil count in blood is between 0.3 *109and 0.6 *109. c) Asthma exacerbations in the past

[0131] A further risk factor for an asthma exacerbation for patients with mild-to-moderate asthma (treated according to GINA Steps 1-4) is the patients' history of asthma exacerbations. (Couillard et al., Thorax. 2022;77(2):199-202). Exacerbations are more frequent to occur for patients which had already one or more asthma exacerbation in the past 12 months.

[0132] Other risk factors:

[0133] Further risk factors for asthma exacerbations and / or asthma-related loss of lung function have been identified. Although they might not be as predictive as the risk factors a), b), and c), at least when taken alone, those further risk factors can contribute to the overall risk. The risk factors are diverse, may be overlapping and not mutually exclusive. A particularly high risk consists for patient which fulfills several of those risk factors, for example at least 2. d) Type 2 high phenotype

[0134] Asthma is classified as type 2 high phenotype, when there are biomarkers pointing to type

[0135] 2 inflammation. Besides elevated levels of FeNO and eosinophil count in blood, those are in particular certain cytokines which are linked with type 2 inflammation. In particular, the type 2 high phenotype is characterized by high expression of type 2 cytokines, such as IL-4, IL-5, IL-6 and IL-13. Type 2 cytokines are well known and characterized in the literature (see e.g. Wynn, Nat Rev Immunol. 2015 May;15(5):271-82). e) Small airway obstruction

[0136] Small airway obstruction can be measured by several measurement techniques. It can be measured by oscillometry, where it is characterized by high frequency dependence of the resistance, and a high reactance area. It can also be measured by spirometry, where it is characterized by a low FEF25-75. Another way to measure small airway obstruction is imaging where small airway obstruction can be seen as air trapping (regional oligemia / mosaic attenuation) on CT scan. f) Asthma Control Questionnaire

[0137] Severity of asthma symptoms and control of asthma can be assessed by the Asthma Control Questionnaire, for example by the version of this questionnaire provided by the American Thoracic Society in 2024. A score >1.5 is considered to be a risk factor. g) Low FEV1

[0138] As described above, lung function can be assessed by measuring the forced expiratory volume in 1 second (FEV1). If FEV1 is lower than 80% of a reference FEV1 which reflects the average value for a person with the participant's demographics, like age, sex, and body composition, this indicates an impaired lung function and is considered as risk factor. h) Frequent use of asthma reliever medication

[0139] Asthma reliever medications are fast-acting medicines that quickly relieve asthma symptoms like coughing, wheezing, being short of breath and a tight chest. They work within minutes and can last for up to four hours. Examples for asthma reliever medications are short-acting [52 adrenergic receptor agonists (SABAs) and low doses of a combination of ICSs and long-acting [52 adrenergic receptor agonists (LABAs). An exemplary SABA used asthma reliever medication is salbutamol, also known as albuterol, which causes relaxation of airway smooth muscle. If asthma patients need more than 200 doses of asthma reliever medication, such as salbutamol, per month, this is considered as risk factor. i) comorbidities

[0140] Asthma patients can suffer from additional diseases, especially inflammatory diseases linked to type-2 inflammation. Comorbidities, or a history of comorbidities, can be regarded as risk factor. Comorbidities which can be relevant in this respect comprise one or more of chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), allergy, eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), obesity, and psychiatric disease. In particular, comorbidity, or a history of comorbidity, with CRSwNP and / or AD is regarded as a risk factor. In some embodiments, a current comorbidity with CRSwNP and / or AD is regarded as a risk factor. In some embodiments, a history of comorbidity with CRSwNP and / or AD is regarded as a risk factor. j) previous intubation or intensive care unit admission for asthma

[0141] To treat severe asthma exacerbations, it can be necessary to intubate patients and / or to treat them in the intensive care unit. When such treatment was necessary in the past, this is also regarded as risk factor for further asthma exacerbations and / or loss of lung function. k) harmful environmental exposure

[0142] If the lung is exposed to harmful environmental factor over a longer period of time, this can enhance inflammation and lead to further damages. In particular, exposure to tobacco smoke, allergens (if the patient displays an allergy), and highly polluted air (e.g. exhaust fumes) are considered as risk factors. l) eosinophil count in sputum

[0143] Not only eosinophil count in blood, but also eosinophil count in sputum can be taken as a biomarker to indicate the risk of asthma exacerbations and / or loss of lung function. If the eosinophil count in sputum is at least 3% of total non-squamous cell count this can be considered as risk factor.

[0144] Accumulation of risk factors: It was shown that the accumulation of risk factors leads to much higher overall risk. For example, the risk of an asthma exacerbation for a patient with an FeNO level of at least 50 ppb, an eosinophil count in blood of at least 0.3 *109cells / L with an asthma exacerbation during last 12 months is almost independent from whether the patient receives treatment according to GINA step 2, 3, or 4 (Couillard et al., Thorax. 2022;77(2):199-202).

[0145] Accordingly, in one embodiment, the present invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; and receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils the following high-risk criteria: a FeNO level of at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; an eosinophil count in blood of at least 0.3 *109cells / L; and one or more asthma exacerbation in the past 12 months.

[0146] 5.4 COMPOUNDS FOR USE ACCORDING TO THE PRESENT INVENTION

[0147] The compound that binds TSLP and IL-13 for use in the present invention can be a polypeptide. Suitable polypeptides have been described in the patent application WO2021116182, which is herewith incorporated in its entirety.

[0148] Compounds (including polypeptides and nucleic acid molecules) or compositions used in the present invention may be administered to a subject by any suitable route of administration, for example by enteral (such as oral or rectal) or parenteral (such as epicutaneous, sublingual, buccal, nasal, intra-articular, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous (SC), transdermal, or transmucosal) administration. In one embodiment, substances are administered by parenteral administration, such as intramuscular, subcutaneous or intradermal administration. In one embodiment, subcutaneous administration is used.

[0149] An effective amount of a polypeptide, a nucleic acid molecule, or a composition comprising the polypeptide or nucleic acid molecule can be administered to a subject in order to provide the intended treatment results.

[0150] One or more doses can be administered. If more than one dose is administered, the doses can be administered in suitable intervals in orderto maximize the effect of the polypeptide, composition, nucleic acid molecule or vector.

[0151] In some embodiments, the administered amount of the compound that binds TSLP and IL- 13 is 400 mg. In some embodiments, the compound that binds TSLP and IL-13 is administered subcutaneously (SC). In some embodiments, only one dose of the compound that binds TSLP and IL-13 is administered.

[0152] In some embodiments, the administered amount of the compound that binds TSLP and IL- 13 is 400 mg and the compound that binds TSLP and IL-13 is administered subcutaneously (SC). In some embodiments, the administered amount of the compound that binds TSLP and IL-13 is 400 mg and only one dose of the compound that binds TSLP and IL-13 is administered. In some embodiments, the compound that binds TSLP and IL-13 is administered subcutaneously (SC) and only one dose of the compound that binds TSLP and IL-13 is administered. In some embodiments, the administered amount of the compound that binds TSLP and IL-13 is 400 mg, the compound that binds TSLP and IL-13 is administered subcutaneously (SC), and only one dose of the compound that binds TSLP and IL-13 is administered. In some embodiments, the polypeptide is an antibody or an antibody fragment. Exemplary polypeptides for use in the present invention are polypeptides which comprise immunoglobulin single variable domains (ISVDs). ISVDs which bind TSLP and IL-13 can be found in Tables A-l to A-6 of WO2021116182.

[0153] In some embodiments, the polypeptide comprises or consists of at least four ISVDs, wherein two ISVDs specifically bind IL-13 and two ISVDs specifically bind TSLP, wherein each of said at least four ISVDs comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least four ISVDs are optionally linked via one or more peptidic linkers, and wherein: a first ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 7, a CDR2 that is the amino acid sequence of SEQ ID NO: 12 and a CDR3 that is the amino acid sequence of SEQ ID NO: 17, a second ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 8, a CDR2 that is the amino acid sequence of SEQ ID NO: 13 and a CDR3 that is the amino acid sequence of SEQ ID NO: 18, a third ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 9, a CDR2 that is the amino acid sequence of SEQ ID NO: 14 and a CDR3 that is the amino acid sequence of SEQ ID NO: 19, and a fourth ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 11, a CDR2 that is the amino acid sequence of SEQ ID NO: 16 and a CDR3 that is the amino acid sequence of SEQ ID NO: 21.

[0154] In some embodiments, the compound comprises: a first ISVD comprising the amino acid sequence of SEQ ID NO: 2, a second ISVD comprising the amino acid sequence of SEQ ID NO: 3, a third ISVD comprising the amino acid sequence of SEQ ID NO: 4, and a fourth ISVD comprising the amino acid sequence of SEQ ID NO: 6.

[0155] In some embodiment, the order of the ISVDs above indicates their relative position to each other considered from the N-terminus to the C-terminus of said polypeptide.

[0156] In some embodiments, the compound comprises a further ISVD that binds to human serum albumin, wherein the further ISVD comprises: a CDR1 that is the amino acid sequence of SEQ I D NO: 10; a CDR2 that is the amino acid sequence of SEQ ID NO: 15; and a CDR3 that is the amino acid sequence of SEQ ID NO: 20. In some embodiments, this further ISVD is positioned between the third and the forth ISVD above.

[0157] In some embodiments, the compound comprises: a first ISVD comprising the amino acid sequence of SEQ ID NO: 2, a second ISVD comprising the amino acid sequence of SEQ ID NO: 3, a third ISVD comprising the amino acid sequence of SEQ ID NO: 4, a fourth ISVD comprising the amino acid sequence of SEQ ID NO: 6, and a further ISVD that binds to human serum albumin and comprises the amino acid sequence of SEQ ID NO: 5.

[0158] An exemplary polypeptide that binds TSLP and IL-13 is SAR443765 (SEQ ID NO: 1). In some embodiments, the polypeptide that binds TSLP and IL-13 comprises SAR443765 (SEQ ID NO: 1). In some embodiments, the polypeptide that binds TSLP and IL-13 is SAR443765 (SEQ ID NO: 1). SEQ ID NO: 1 is:

[0159] DVQLVESGGGVVQPGGSLRLSCAASGRTFSSYRMGWFRQAPGKEREFVAALSGDGYSTYTANSVKG RFTISRDNSKNTVYLQMNSLRPEDTALYYCAAKLQYVSGWSYDYPYWGQGTLVTVSSGGGGSGGGG SGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGGSLRLSCAASGFTFNNYAMKWV RQAPGKGLEWVSSITTGGGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCANVPFGYYS EHFSGLSFDYRGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSLRLSCAASGSGFGVNILYWY RQAAGI ERELIASITSGGITNYVDSVKGRFTISRDNSENTMYLQIVINSLRAEDTGLYYCASRNIFDGTTE WGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSLRLSCAASGFTFRSFGIVISWVRQAPGKG PEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVS SGGGGSGGGSEVQLVESGGGVVQPGGSLRLSCAASGFTFADYDYDIGWFRQAPGKEREGVSCISNR DGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAVEIHCDDYGVENFDFDPWGQGTLV TVSSA.

[0160] The therapeutic effect of SAR443765 was established in the clinical trial shown in example 1 below.

[0161] 5.4.1 Immunoglobulin single variable domains

[0162] As stated above, in some embodiments the polypeptide for use in the present invention is a polypeptide which comprise immunoglobulin single variable domains (ISVDs).

[0163] The term "immunoglobulin single variable domain" (ISVD), interchangeably used with "single variable domain", defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. This sets ISVDs apart from "conventional" immunoglobulins (e.g., monoclonal antibodies) or their fragments (such as Fab, Fab', Ffab' , scFv, di-scFv), wherein two immunoglobulin domains, in particular two variable domains, interact to form an antigen binding site. Typically, in conventional immunoglobulins, a heavy chain variable domain (VH) and a light chain variable domain (VL) interact to form an antigen binding site. In this case, the complementarity determining regions (CDRs) of both VH and VL will contribute to the antigen binding site, i.e. a total of 6 CDRs will be involved in antigen binding site formation.

[0164] In view of the above definition, the antigen-binding domain of a conventional 4-chain antibody (such as an IgG, IgM, IgA, IgD or IgE molecule; known in the art) or of a Fab fragment, a F(ab')2 fragment, an Fv fragment such as a disulfide linked Fv or a scFv fragment, or a diabody (all known in the art) derived from such conventional 4-chain antibody, would normally not be regarded as an ISVD, as, in these cases, binding to the respective epitope of an antigen would normally not occur by one (single) immunoglobulin domain but by a pair of (associating) immunoglobulin domains such as light and heavy chain variable domains, i.e., by a VH-VL pair of immunoglobulin domains, which jointly bind to an epitope of the respective antigen. In contrast, ISVDs are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain. The binding site of an ISVD is formed by a single VH, a single VHH or single VL domain.

[0165] As such, the single variable domain may be a light chain variable domain sequence (e.g., a V sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g., a VH-sequence or VHH sequence) or a suitable fragment thereof; as long as it is capable of forming a single antigen binding unit (i.e., a functional antigen binding unit that essentially consists of the single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit).

[0166] An ISVD can for example be a heavy chain ISVD, such as a VH, VHH, including a camelized VH or humanized VHH. In one embodiment, it is a VHH, including a camelized VH or humanized VHH. Heavy chain ISVDs can be derived from a conventional four-chain antibody or from a heavy chain antibody.

[0167] For example, the ISVD may be a single domain antibody (or an amino acid sequence that is suitable for use as a single domain antibody), a "dAb" or dAb (or an amino acid sequence that is suitable for use as a dAb) or a Nanobody® (as defined herein, and including but not limited to a VHH); other single variable domains, or any suitable fragment of any one thereof.

[0168] In particular, the ISVD may be a Nanobody® (such as a VHH, including a humanized VHH or camelized VH) or a suitable fragment thereof. Nanobody®, Nanobodies® and Nanoclone® are registered trademarks of Sanofi or its affiliates.

[0169] "VHH domains", also known as VHHS, VHH antibody fragments, and VHH antibodies, have originally been described as the antigen binding immunoglobulin variable domain of "heavy chain antibodies" (i.e., of "antibodies devoid of light chains"; Hamers-Casterman et al. Nature 363: 446-448, 1993). The term "VHH domain" has been chosen in orderto distinguish these variable domains from the heavy chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as "VH domains") and from the light chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as "VL domains"). For a furtherdescription of VHH'S, reference is made to the review article by Muyldermans (Reviews in Molecular Biotechnology 74: 277-302, 2001).

[0170] Typically, the generation of immunoglobulins involves the immunization of experimental animals, fusion of immunoglobulin producing cells to create hybridomas and screening for the desired specificities. Alternatively, immunoglobulins can be generated by screening of naive or synthetic libraries e.g. by phage display.

[0171] The generation of immunoglobulin sequences, such as Nanobodies®, has been described extensively in various publications, among which WO 94 / 04678, Hamers-Casterman et al. 1993 and Muyldermans, 2001 can be exemplified. In these methods, camelids are immunized with the target antigen in order to induce an immune response against said target antigen. The repertoire of Nanobodies obtained from said immunization is further screened for Nanobodies that bind the target antigen.

[0172] In these instances, the generation of antibodies requires purified antigen for immunization and / or screening. Antigens can be purified from natural sources, or in the course of recombinant production.

[0173] Immunization and / or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens.

[0174] The present invention may use immunoglobulin sequences of different origin, comprising mouse, rat, rabbit, donkey, human and camelid immunoglobulin sequences. The present invention may also use fully human, humanized or chimeric sequences. For example, the present invention uses camelid immunoglobulin sequences and humanized camelid immunoglobulin sequences, or camelized domain antibodies, e.g. camelized dAb as described by Ward et al (see for example WO 94 / 04678 and Davies and Riechmann (1994 and 1996)). Moreover, the present invention also uses fused immunoglobulin sequences, e.g. forming a multivalent and / or multispecific construct (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al., J. Biol. Chem., Vol. 276, 10. 7346-7350, 2001, as well as to for example WO 96 / 34103 and WO 99 / 23221), and immunoglobulin sequences comprising tags or other functional moieties, e.g. toxins, labels, radiochemicals, etc., which are derivable from the immunoglobulin sequences of compound used in the present invention.

[0175] 5.4.2 Antibodies

[0176] As stated above, in some embodiments the polypeptide for use in the present invention is an antibody. Antibodies which bind TSLP and IL-13 can be found in Venkataramani et al. (Biochem Biophys Res Commun. 2018 Sep 26;504(l):19-24.

[0177] 5.4.3 Binding / Blocking

[0178] The compounds of the present invention bind to TSLP and IL-13. In some embodiments, the compound of the present invention can block its target molecules. For example, the compound can block the interaction between IL-13 and IL-13Ral (Interleukin 13 receptor, alpha 1) and / or the interaction between I L-13 / IL-13Ral complex and IL-4Ra (alpha interleukin-4 receptor), and / or can block the interaction between TSLP and TSLPR (TSLP receptor) and / or TSLP / TSLPR complex and IL-7Ra (lnterleukin-7 receptor subunit alpha). In some embodiments, the compound of the present invention can block the interaction between IL-13 and IL-13Ral (Interleukin 13 receptor, alpha 1) and / or the interaction between IL-13 / 1 L-13Ral complex and IL-4Ra (alpha interleukin-4 receptor), and can block the interaction between TSLP and TSLPR (TSLP receptor) and / or TSLP / TSLPR complex and IL-7Ra (lnterleukin-7 receptor subunit alpha).

[0179] In some embodiments, the compound for use in the present invention can bind human IL- 13 (Uniprot accession P35225) and human TSLP (Uniprot accession Q969D9). In some embodiments, the compound for use in the present invention can bind IL-13 and TSLP from other mammals, for example IL-13 and TSLP from mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus monkeys (also referred to herein as "cyno"), or camelids, such as llama or alpaca.

[0180] In relation to the compounds of the present invention, binding to IL-13 and TSLP means specific binding to IL-13 and TSLP. The binding of a compound to its target can be determined based on affinity. The affinity denotes the strength or stability of a molecular interaction. The affinity is commonly given as by the KD, or dissociation constant, which has units of mol / liter (or M). The affinity can also be expressed as an association constant, KA, which equals 1 / KD and has units of (mol / liter)1(or M1).

[0181] The affinity is a measure for the binding strength between a moiety and a binding site on the target molecule: the lower the value of the KD, the stronger the binding strength between a target molecule and a targeting moiety.

[0182] Typically, binding units used in the present invention will bind to their targets with a dissociation constant (KD) of IO-5to 1012moles / liter or less, or 10-7to 1012moles / liter or less, or IO-8to 1012moles / liter (i.e. with an association constant (KA) of 105to 1012liter / moles or more, or 107to 1012liter / moles or more, or 108to 1012liter / moles).

[0183] Any KD value greater than IO-4mol / liter (or any KA value lower than 104liters / mol) is generally considered to indicate non-specific interaction.

[0184] The KD for biological interactions, such as the binding of immunoglobulin sequences to an antigen, which are considered specific are typically in the range of IO-5moles / liter (10000 nM or 10pM) to 1012moles / liter (0.001 nM or 1 pM) or less.

[0185] Accordingly, specific / selective binding may mean that - using the same measurement method, e.g. SPR - a compound binds to IL13 and / or TSLP with a KD value of 10-5to 1012moles / liter or less and binds to related cytokines with a KD value greater than IO-4moles / liter. Examples of IL13 related targets are human IL4. Examples of related cytokines for TSLP are human IL7. Thus, in some embodiments, the compound used in the present invention binds to IL13 with a KD value of 10-5to 1012moles / liter or less and binds to IL4 of the same species with a KD value greater than IO-4moles / liter, and binds to TSLP with a KD value of 10-5to 1012moles / liter or less and binds to human IL7 of the same species with a KD value greater than IO-4moles / liter.

[0186] In some embodiments, the polypeptides used in the present invention have at least half the binding affinity, or at least the same binding affinity, to human IL13 and to human TSLP as compared to a polypeptide consisting of the amino acid of SEQ ID NO: 1, wherein the binding affinity is measured using the same method, such as SPR. Specific binding to a certain target from a certain species does not exclude that the binding unit can also specifically bind to the analogous target from a different species. For example, specific binding to human IL13 does not exclude that the binding unit (or a polypeptide comprising the same) can also specifically bind to I L13 from cynomolgus monkeys. Likewise, for example, specific binding to human TSLP does not exclude that the binding unit (or a polypeptide comprising the same) can also specifically bind to TSLP from cynomolgus monkeys ("cyno").

[0187] Specific binding of a binding unit to its designated target can be determined in any suitable manner known per se, including, for example, Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known per se in the art; as well as the other techniques mentioned herein.

[0188] The dissociation constant may be the actual or apparent dissociation constant, as will be clear to the skilled person. Methods for determining the dissociation constant will be clear to the skilled person, and for example include the techniques mentioned below. In this respect, it will also be clear that it may not be possible to measure dissociation constants of more than IO-4moles / liter or 10-3moles / liter (e.g. of 10-2moles / liter). Optionally, as will also be clear to the skilled person, the (actual or apparent) dissociation constant may be calculated on the basis of the (actual or apparent) association constant (KA), by means of the relationship [KD = 1 / KA],

[0189] The affinity of a molecular interaction between two molecules can be measured via different techniques known per se, such as the well-known surface plasmon resonance (SPR) biosensor technique (see for example Ober et al. 2001, Intern. Immunology 13: 1551- 1559). The term "surface plasmon resonance", as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, where one molecule is immobilized on the biosensor chip and the other molecule is passed over the immobilized molecule under flow conditions yielding kon, kOff measurements and hence KD (or K ) values. This can for example be performed using the well-known BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, NJ). For further descriptions, see Jonsson et al. (1993, Ann. Biol. Clin. 51: 19-26), Jonsson et al. (1991 Biotechniques 11: 620-627), Johnsson et al. (1995, J. Mol. Recognit. 8: 125-131), and Johnnson et al. (1991, Anal. Biochem. 198: 268-277).

[0190] Another well-known biosensor technique to determine affinities of biomolecular interactions is bio-layer interferometry (BLI) (see for example Abdiche et al. 2008, Anal. Biochem. 377: 209-217). The term "bio-layer Interferometry" or "BLI", as used herein, refers to a label-free optical technique that analyzes the interference pattern of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized protein on the biosensor tip (signal beam). A change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the biosensor tip surface. Since the interactions can be measured in real-time, association and dissociation rates and affinities can be determined. BLI can for example be performed using the well-known Octet® Systems (ForteBio, a division of Pall Life Sciences, Menlo Park, USA).

[0191] Alternatively, affinities can be measured in Kinetic Exclusion Assay (KinExA) (see for example Drake et al. 2004, Anal. Biochem., 328: 35-43), using the KinExA® platform (Sapidyne Instruments Inc, Boise, USA). The term "KinExA", as used herein, refers to a solution-based method to measure true equilibrium binding affinity and kinetics of unmodified molecules. Equilibrated solutions of an antibody / antigen complex are passed over a column with beads precoated with antigen (or antibody), allowing the free antibody (or antigen) to bind to the coated molecule. Detection of the antibody (or antigen) thus captured is accomplished with a fluorescently labeled protein binding the antibody (or antigen).

[0192] The GYROLAB® immunoassay system provides a platform for automated bioanalysis and rapid sample turnaround (Fraley et al. 2013, Bioanalysis 5: 1765-74). 5.4.4 Nucleic acid molecules

[0193] In some embodiments, the present invention provides a nucleic acid for use in the present invention, wherein the nucleic acid encodes a compound that binds IL-13 and TSLP.

[0194] A "nucleic acid molecule" (used interchangeably with "nucleic acid") is a chain of nucleotide monomers linked to each other via a phosphate backbone to form a nucleotide sequence. A nucleic acid may be used to transform / transfect a host cell or host organism, e.g. for expression and / or production of a polypeptide. Suitable hosts or host cells for production purposes will be clear to the skilled person, and may for example be any suitable fungal, prokaryotic or eukaryotic cell or cell line or any suitable fungal, prokaryotic or eukaryotic organism. A host or host cell comprising a nucleic acid encoding the polypeptide of the present invention is also encompassed by the present invention.

[0195] A nucleic acid may be for example DNA, RNA, or a hybrid thereof, and may also comprise (e.g., chemically) modified nucleotides, like PNA. It can be single- or double-stranded. In one embodiment, it is in the form of double-stranded DNA. For example, the nucleotide sequences of the present invention may be genomic DNA, cDNA.

[0196] The nucleic acids of the present invention can be prepared or obtained in a manner known per se, and / or can be isolated from a suitable natural source. Nucleotide sequences encoding naturally occurring (poly)peptides can for example be subjected to site-directed mutagenesis, so as to provide a nucleic acid molecule encoding polypeptide with sequence variation. Also, as will be clear to the skilled person, to prepare a nucleic acid, also several nucleotide sequences, such as at least one nucleotide sequence encoding a targeting moiety and for example nucleic acids encoding one or more linkers can be linked together in a suitable manner.

[0197] Techniques for generating nucleic acids will be clear to the skilled person and may for instance include, but are not limited to, automated DNA synthesis; site-directed mutagenesis; combining two or more naturally occurring and / or synthetic sequences (or two or more parts thereof), introduction of mutations that lead to the expression of a truncated expression product; introduction of one or more restriction sites (e.g. to create cassettes and / or regions that may easily be digested and / or ligated using suitable restriction enzymes), and / or the introduction of mutations by means of a PCR reaction using one or more "mismatched" primers.

[0198] 5.4.5 Compositions

[0199] The present invention also provides a pharmaceutical composition for use in the present invention, wherein the pharmaceutical composition comprises at least one compound that binds to TSLP and IL-13, and / or at least one nucleic acid molecule encoding a compound that binds to TSLP and IL-13. The composition may further comprise at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprise one or more further pharmaceutically active polypeptides and / or compounds.

[0200] In some embodiments, the invention provides a pharmaceutical composition comprising a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein the composition further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[0201] 5.4.6 Compounds which bind IL-13 or TSLP

[0202] In another aspect, the invention provides a compound that binds IL-13 or TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma as defined above for compounds that bind IL-13 and TSLP, and wherein high risk of asthma exacerbations or lung function loss is present if the asthma patient fulfils one or more of the high-risk criteria defined above for compounds that bind IL-13 and TSLP. In particular, the high-risk criteria can include a) a FeNO level of at least 20 ppb, at least 25, at least 35, or at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; and / or b) an eosinophil count in blood of at least 0.15 *109cells / L, or at least 0.3 *109cells / L; and / or c) one or more asthma exacerbation in the past 12 months. In some embodiments, the high-risk criteria include a) a FeNO level of at least 20 ppb; and b) an eosinophil count in blood of at least 0.15 *109cells / L In some embodiments, the high- risk criteria include a) a FeNO level of at least 50 ppb; and b) an eosinophil count in blood of at least 0.15 *109cells / L. In some embodiments, the high-risk criteria include a) a FeNO level of at least 50 ppb; and b) an eosinophil count in blood of at least 0.3 *109cells / L.

[0203] In some embodiments, said compound is a compound which binds to IL-13. Exemplary compounds which bind 11-13 are the antibodies anrukinzumab, lebrikizumab and tralokinumab.

[0204] In some embodiments, said compound is a compound which binds to TSLP. An exemplary compound which binds TSLP is the antibody Tezepelumab.

[0205] 5.4.7 Combination therapies

[0206] In another aspect, the present invention provides a combination of (i) a compound that binds IL-13 and TSLP and (ii) an additional compound for use in the treatment of mild-to- moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma as defined above for compounds that bind IL-13 and TSLP, and wherein high risk of asthma exacerbations or lung function loss is present if the asthma patient fulfils one or more of the high-risk criteria defined above for treatments as defined above for compounds that bind IL-13 and TSLP.

[0207] In some embodiments, the additional compound is an inhaled corticosteroid. In some embodiments, the additional compound is inhaled fluticasone propionate. In some embodiments, the additional compound is inhaled budesonide.

[0208] In some embodiments, the additional compound is an inhaled corticosteroid at a dose of 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline. In some embodiments, the additional compound is inhaled fluticasone propionate at a dose of 500 pg per day. In some embodiments, the additional compound is inhaled budesonide at a dose of 800 pg per day.

[0209] In some embodiments, the present invention provides a combination of (i) a compound that binds IL-13 and TSLP, (ii) an additional compound, and (iii) a third compound for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma as defined above for compounds that bind IL-13 and TSLP, and wherein high risk of asthma exacerbations or lung function loss is present if the asthma patient fulfils one or more of the high-risk criteria defined above for treatments as defined above for compounds that bind IL-13 and TSLP.

[0210] In some embodiments, the additional compound is an inhaled corticosteroid, and the third compound is a long-acting beta-agonist (LABA). In some embodiments, the long-acting beta-agonist is salmeterol or formoterol. In some embodiments, the additional compound is inhaled fluticasone propionate, and the third compound is salmeterol. In some embodiments, the additional compound is inhaled budesonide, and the third compound is form otero I.

[0211] In some embodiments, the additional compound is an inhaled corticosteroid at a dose of 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline, and the third compound is a long-acting beta agonist. In some embodiments, the long-acting beta-agonist is salmeterol or formoterol. In some embodiments, the additional compound is inhaled fluticasone propionate at a dose of 500 pg per day, and the additional compound is salmeterol. In some embodiments, the additional compound is inhaled budesonide at a dose of 800 pg per day, and the third compound is formoterol.

[0212] 5.5 EMBODIMENTS OF THE INVENTION

[0213] In the following exemplary embodiments of the present invention are given for illustrative purposes.

[0214] Mild-to-moderate definition I.

[0215] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 ng per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb.

[0216] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb.

[0217] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb.

[0218] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb.

[0219] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 ng per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0220] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0221] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0222] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0223] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives less than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0224] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives less than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0225] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb and an eosinophil count in blood of at least 0.15 *109cells / L.

[0226] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 ng per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb and an eosinophil count in blood of at least 0.15 *109cells / L.

[0227] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb and an eosinophil count in blood of at least 0.15 *109cells / L.

[0228] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb and an eosinophil count in blood of at least 0.15 *109cells / L.

[0229] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L.

[0230] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L.

[0231] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb and an eosinophil count in blood of at least 0.3 *109cells / L.

[0232] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb and an eosinophil count in blood of at least 0.3 *109cells / L. In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb and an eosinophil count in blood of at least 0.3 *109cells / L.

[0233] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb and an eosinophil count in blood of at least 0.3 *109cells / L.

[0234] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L.

[0235] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L.

[0236] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives less than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L.

[0237] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives less than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L.

[0238] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L and had one or more asthma exacerbation in the past 12 months.

[0239] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L and had one or more asthma exacerbation in the past 12 months.

[0240] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L and had one or more asthma exacerbation in the past 12 months.

[0241] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L and had one or more asthma exacerbation in the past 12 months.

[0242] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L and had one or more asthma exacerbation in the past 12 months, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0243] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L and had one or more asthma exacerbation in the past 12 months, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0244] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L and had one or more asthma exacerbation in the past 12 months, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0245] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations, wherein mild-to-moderate asthma is asthma wherein the subject does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L and had one or more asthma exacerbation in the past 12 months, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0246] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations, wherein mild-to-moderate asthma is asthma wherein the subject receives less than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0247] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations, wherein mild-to-moderate asthma is asthma wherein the subject receives less than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L and had one or more asthma exacerbation in the past 12 months, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0248] Mild-to-moderate definition II.

[0249] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb.

[0250] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb.

[0251] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb.

[0252] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb.

[0253] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0254] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0255] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0256] Mild-to-moderate definition III.

[0257] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb.

[0258] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb.

[0259] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb.

[0260] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb.

[0261] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0262] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0263] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0264] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0265] Mild-to-moderate definition IV.

[0266] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 20 ppb.

[0267] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 25 ppb. In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb.

[0268] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb.

[0269] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0270] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids.

[0271] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.15 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0272] In one embodiment, the invention provides a compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject has a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, and an eosinophil count in blood of at least 0.3 *109cells / L, wherein the compound is a polypeptide which comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0273] Accumulation of risk factors

[0274] In some embodiments, at least the risk factors a) and b) apply. In some embodiments, at least the risk factors a) and c) apply. In some embodiments, at least the risk factors b) and c) apply.

[0275] In some embodiments, at least one of the risk factors d)-l) applies in addition to one or more of the risk factors a)-c). In some embodiments, at least risk factor d) applies. In some embodiments, at least risk factor e) applies. In some embodiments, at least risk factor f) applies. In some embodiments, at least riskfactor g) applies. In some embodiments, at least risk factor h) applies. In some embodiments, at least risk factor i) applies. In some embodiments, at least risk factor j) applies. In some embodiments, at least risk factor k) applies. In some embodiments, at least risk factor I) applies. In some embodiments, at least two of the risk factors d)-l) apply in addition to one or more of the risk factors a)-c). In some embodiments, at least risk factors d) and e) apply. In some embodiments, at least risk factors d) and f) apply. In some embodiments, at least risk factors d) and g) apply. In some embodiments, at least risk factors d) and h) apply. In some embodiments, at least risk factors d) and i) apply. In some embodiments, at least risk factors d) and j) apply. In some embodiments, at least risk factors d) and k) apply. In some embodiments, at least risk factors d) and I) apply.

[0276] In some embodiments, at least risk factors e) and f) apply. In some embodiments, at least risk factors e) and g) apply. In some embodiments, at least risk factors e) and h) apply. In some embodiments, at least risk factors e) and i) apply. In some embodiments, at least risk factors e) and j) apply. In some embodiments, at least risk factors e) and k) apply. In some embodiments, at least risk factors e) and I) apply.

[0277] In some embodiments, at least risk factors f) and g) apply. In some embodiments, at least risk factors f) and h) apply. In some embodiments, at least risk factors f) and i) apply. In some embodiments, at least risk factors f) and j) apply. In some embodiments, at least risk factors f) and k) apply. In some embodiments, at least risk factors f) and I) apply.

[0278] In some embodiments, at least risk factors g) and h) apply. In some embodiments, at least risk factors g) and i) apply. In some embodiments, at least risk factors g) and j) apply. In some embodiments, at least risk factors g) and k) apply. In some embodiments, at least risk factors g) and I) apply.

[0279] In some embodiments, at least risk factors h) and i) apply. In some embodiments, at least risk factors h) and j) apply. In some embodiments, at least risk factors h) and k) apply. In some embodiments, at least risk factors h) and I) apply.

[0280] In some embodiments, at least risk factors i) and j) apply. In some embodiments, at least risk factors i) and k) apply. In some embodiments, at least risk factors i) and I) apply.

[0281] In some embodiments, at least risk factors j) and k) apply. In some embodiments, at least risk factors j) and I) apply. In some embodiments, at least risk factors k) and I) apply.

[0282] In some embodiments, at least three of the risk factors d)-l) apply in addition to one or more of the risk factors a)-c).

[0283] In some embodiments, at least four of the risk factors d)-l) apply in addition to one or more of the risk factors a)-c).

[0284] Methods of treatment of asthma

[0285] The present invention also provides methods for treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, comprising administering a compound that binds IL-13 and TSLP to the subject.

[0286] All embodiments, examples, definition of mild-to-moderate asthma, and high-risk criteria given above for compounds that binds IL-13 and TSLP for use in the treatment of mild-to- moderate asthma can be transferred to methods for treatment of mild-to-moderate asthma.

[0287] E.g., in some embodiments, the invention provides a method for treatment of mild-to- moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, comprising administering a compound that binds IL-13 and TSLP to the subject, wherein mild-to-moderate asthma is asthma wherein the subject

[0288] I. does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline;

[0289] II. receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale;

[0290] III. receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; and / or

[0291] IV. is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils one or more of the following high-risk criteria: a) a FeNO level of i. at least 20 ppb, ii. at least 25 ppb, iii. at least 35 ppb, or iv. at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; b) Eosinophil count i. in blood of at least 0.15 *109cells / L; ii. in blood of at least 0.3 *109cells / L; c) One or more asthma exacerbation in the past 12 months.

[0292] Use of a compound that binds IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of asthma

[0293] The present invention also provides the use of a compound that binds IL-13 and TSLP in the preparation of a pharmaceutical composition for treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss.

[0294] All embodiments, examples, definition of mild-to-moderate asthma, and high-risk criteria given above for compounds that binds IL-13 and TSLP for use in the treatment of mild-to- moderate asthma can be transferred to uses of a compound that binds IL-13 and TSLP in the preparation of a pharmaceutical composition for treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss.

[0295] E.g., in some embodiments, the invention provides the use of a compound that binds IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of mild-to- moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject

[0296] I. does not receive more than 500 ng per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline;

[0297] II. receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale;

[0298] III. receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; and / or

[0299] IV. is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils one or more of the following high-risk criteria: a) a FeNO level of i. at least 20 ppb, ii. at least 25 ppb, iii. at least 35 ppb, or iv. at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; b) Eosinophil count i. in blood of at least 0.15 *109cells / L; ii. in blood of at least 0.3 *109cells / L; c) One or more asthma exacerbation in the past 12 months.

[0300] Use of a com that binds IL-13 and TSLP r a com for the manufacture of a medicament for the treatment of mild-to-moderate asthma The present invention also provides the use of a compound that binds IL-13 and TSLP (or a composition thereof) for the manufacture of a medicament for the treatment of mild-to- moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss.

[0301] All embodiments, examples, definition of mild-to-moderate asthma, and high-risk criteria given above for compounds that binds IL-13 and TSLP for use in the treatment of mild-to- moderate asthma can be transferred to uses of a compound that binds IL-13 and TSLP (or a composition thereof) for the manufacture of a medicament for the treatment of mild-to- moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss.

[0302] E.g., in some embodiments, the invention provides the use of a compound that binds IL-13 and TSLP (or a composition thereof) for the manufacture of a medicament for the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject

[0303] I. does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline;

[0304] II. receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale;

[0305] III. receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; and / or

[0306] IV. is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils one or more of the following high-risk criteria: a) a FeNO level of i. at least 20 ppb, ii. at least 25 ppb, iii. at least 35 ppb, or iv. at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; b) Eosinophil count i. in blood of at least 0.15 *109cells / L; ii. in blood of at least 0.3 *109cells / L; c) One or more asthma exacerbation in the past 12 months.

[0307] Use of a compound that binds IL-13 and TSLP for the treatment of asthma

[0308] The present invention also provides the use of a compound that binds IL-13 and TSLP for the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss.

[0309] All embodiments, examples, definition of mild-to-moderate asthma, and high-risk criteria given above for compounds that binds IL-13 and TSLP for use in the treatment of mild-to- moderate asthma can be transferred to uses of a compound that binds IL-13 and TSLP for the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss.

[0310] E.g., in some embodiments, the invention provides the use of a compound that binds IL-13 and TSLP for the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subject

[0311] I. does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline;

[0312] II. receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale; III. receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; and / or

[0313] IV. is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils one or more of the following high-risk criteria: a) a FeNO level of i. at least 20 ppb, ii. at least 25 ppb, iii. at least 35 ppb, or iv. at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; b) Eosinophil count i. in blood of at least 0.15 *109cells / L; ii. in blood of at least 0.3 *109cells / L; c) One or more asthma exacerbation in the past 12 months.

[0314] 5.6 INDUSTRIAL APPLICABILITY

[0315] The compound for use according to the present invention may be used in the treatment of subjects suffering from asthma. 6 EXAMPLES

[0316] 6.1 EXAMPLE 1: PDY16622 - A DOUBLE-BLIND, RANDOMIZED, PLACEBO- CONTROLLED, PARALLEL DESIGN, SINGLE DOSE ASTHMA STUDY IN THREE CENTERS.

[0317] The efficacy of SAR443765 for the treatment of asthma was tested in a phase I trial (PDY16622) detailed below. The schedule of the trial is depicted in Fig. 1.

[0318] Methods

[0319] Patient cohort

[0320] A total of up to 36 participants with mild-to-moderate asthma was enrolled for this study. The participants were randomized in SAR443765 and placebo groups (24 SAR443765 and 12 placebo). The participants received a single dose at the highest safe and well tolerated dose level as assessed earlier in a study part with healthy adult participants (400 mg SC max).

[0321] The participants had to fulfil the following criteria:

[0322] • Diagnosis of asthma for at least 12 months and confirmed at screening based on the Global Initiative for Asthma (GINA) 2020 Guidelines, all steps except Step 4 with high inhaled corticosteroid (ICS) dose and Step 5.

[0323] • Controlled asthma defined as an Asthma Control Questionnaire (ACQ)-5 score of <1.5.

[0324] • Participants using as-needed short acting beta-agonist (SABA), ICS-naive or with existing stable treatment (at least for 3 months prior to screening) with low to medium daily dose ICS (<500 mcg of fluticasone propionate or comparable ICS total daily dosage) potentially in combination with a long-acting beta-agonist (LABA) and / or long acting muscarinic agonist (LAMA) as second controller, and / or with stable daily leukotriene receptor antagonist, leukotriene synthesis inhibitor and / or chromones. Participants with elevated FeNO level defined as >25 ppb at screening and baseline.

[0325] Participants with prebronchodilator FEV1 >60% of predicted normal at screening.

[0326] Reversibility of at least 12% and 200 mL in FEV1 or forced vital capacity (FVC) after administration of 4 puffs (400 mcg) of albuterol / salbutamol or levalbuterol / levosalbutamol during screening or documented history of a reversibility test that meets these criteria within 5 years prior to screening or documented positive response to methacholine challenge (a decrease in FEV1 by 20% [PC20] of <8 mg / mL) within 5 years prior to screening visit.

[0327] • Normal or clinically acceptable vital signs (pulse rate, SBP and DBP) after 10 minutes resting in supine position at screening and at baseline.

[0328] • Normal or clinically acceptable standard 12-lead electrocardiogram (ECG) parameters and tracing after 10 minutes resting in supine position at screening and at baseline; normal ECG tracing unless the Investigator considers an ECG tracing abnormality to be not clinically relevant.

[0329] • Laboratory parameters within the normal range (or defined screening threshold for the Investigator site) at screening and at baseline, unless the Investigator considers an abnormality to be clinically irrelevant; however, serum creatinine, alkaline phosphatase, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) should not exceed 1.25-fold the upper laboratory norm. Total bilirubin out of normal range can be acceptable if total bilirubin does not exceed 1.5-fold the upper limit with normal conjugated bilirubin values (unless the participant has documented Gilbert syndrome).

[0330] • Body weight between 50.0 kg and 105.0 kg, inclusive, if male, and between 40.0 kg and 95.0 kg, inclusive, if female, body mass index between 18.0 kg / m2and 32.0 kg / m2, inclusive, at screening and at baseline.

[0331] • Nonsmokers.

[0332] Participants were dosed in subgroups of maximum 4 participants, at least 10 minutes apart, with a dosing interval of at least 2 days between subgroups. Initiation of the Asthma cohort was based on the blinded safety and PK data of an earlier study part with healthy adult participants.

[0333] All participants were screened within 28 days to ensure that they meet the study requirements. Eligible participants were admitted on the day prior to each dosing and participants included in the study remained institutionalized for 1 day after study drug administration in the Asthma cohort, taking into account emerging safety, PK and PD data. Prior to each drug administration, participants were assessed for SARS-CoV-2 infection and underwent intensive monitoring including physical examination, AE assessment, vital signs, ECGs, and routine laboratory assessment (complete blood count with differential, chemistry, aPTT, PT-INR, high-sensitivity cardiac troponin T and urinalysis). After institutionalization period(s), participants underwent clinical assessment including vital signs, ECG, routine laboratory assessment, and ADA assessment at varying intervals until study completion. Taking into account the range for half-life of serum albumin-binding nanobodies, the treatment emergent adverse events observation period for this study was therefore ended 70 days after the last dose.

[0334] Fractional Exhaled Nitric Oxide (FeNO) level analysis

[0335] Fraction of exhaled nitric oxide (FeNO) was measured at the time points specified in the schedule of the study (Fig. 1), i.e. baseline, D8, D15, D29, and D57. FeNO is a measure of NO production by epithelial cells in the lung and considered a biomarker for airway inflammation in asthma.

[0336] FeNO levels (ppb) were collected on site with a dedicated medical device such as a commercially available device (NIOX VERO®). The FeNO test needs to be completed prior to impulse oscillometry and spirometry in order to avoid any impact on the nitric oxide measurement. Considering the diurnal variation in FeNO, the assessment needs to be performed at approximately the same time of day throughout the study (±2 hours). Participants should not eat or drink 1 hour prior to FeNO measurement, as this may affect the results. All carbonated drinks and nitrate rich foods (e.g., vegetable juices, salads, lettuce, radishes, celery, broccoli, cauliflower, spinach, rocket, beets, parsley, leeks, cabbage, fennel, turnips, carrots, cured meats, sausage, bacon) should be withheld for at least 2 hours prior to the FeNO measurement. ICS, if any, should be withheld for at least 4 hours prior to FeNO measurement. The participant should be sitting during FeNO testing; however, if the participant is unable to sit, then standing is acceptable. The position (sitting or standing) should remain the same for a participant throughout the study. Participants are to inhale to total lung capacity through the hand worn device (NIOX VERO®) and then exhale for 10 seconds at 50 mL / sec (assisted by visual and auditory cues).

[0337] Eosinophil count

[0338] The eosinophil count in whole blood was determined at the time points specified in the schedule of the study (Fig. 1), i.e. at baseline and at D2 (24 h), D4 (72 h) D8 (1 week), D15 (2 weeks), D29 (4 weeks), D57 (8 weeks), and D71 (10 weeks) using flow cytometry.

[0339] Spirometry measurements (FEV1 and FEF25-75)

[0340] FEV1 and FEF25-75 were determined by spirometry at the time points specified in the schedule of the study (Fig. 1).

[0341] Spirometry was performed in accordance with the American Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines (2019 update). For the measured parameters, including FEV1, peak exploratory flow (PEF), FVC and forced exploratory flow (FEF) 25%-75%, spirometry was performed after a wash out period of bronchodilators according to their action duration as detailed in the ATS guidelines. For example, bronchodilator withholding time is at least 6 hours for SABA, at least 24 hours for LABA and 36-48 hours for LAMA. Chromones need to be withheld for at least 24 hours before spirometry. ICS, leukotriene receptorantagonists and leukotriene synthesis inhibitors need not to be withheld prior to spirometry, however ICS need to be withheld prior to FeNO assessment.

[0342] At all visits, spirometry was performed preferably in the morning, afternoon was allowable in the exceptional circumstance when morning spirometry could not be performed. Spirometry was done at approximately the same time at each visit throughout the study (±2 hours). The same spirometer and standard spirometric techniques, including calibration, was used to perform spirometry at all visits, and whenever possible, the same person performed the measurements. Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained at every visit.

[0343] Reversibility was determined by a postbronchodilator spirometry measurement. Reversibility is defined as an increase of the absolute FEV1 and / or FVC after administration of bronchodilator and is measured by spirometry as postbronchodilator increase in FEV1 or FVC in percent of the prebronchodilator FEV1 or FVC, respectively. After spirometry for measuring prebronchodilator FEV1, participants received 4 puffs of albuterol / salbutamol or levalbuterol / levosalbutamol from a primed metered dose inhaler (MDI). The postbronchodilator spirometry should be performed after a waiting time of at least 10 minutes and may be repeated several times within approximately 30 minutes after administration of bronchodilator.

[0344] Impulse oscillometry measurements (R5-20 and AX)

[0345] R5-20 and AX were determined by oscillometry at the time points specified in the schedule of the study (Fig. 1).

[0346] Oscillometry is a complementary technique to spirometry determining the mechanic properties of the lung. Whereas spirometry is the most commonly used technique examining airway function, it is unable to sensitively evaluate small airways, becoming abnormal only when approximately 75% of small airways are obstructed. Oscillometry is more sensitive in detecting small airway disease, which correlates with poor disease control and type 2 inflammation. Thus, oscillometry allows to assess the relative contribution of the large and small airways in asthma. Oscillometry was conducted during tidal breathing using the Tremoflo® device (Thorasys, Montreal, Canada) according to ERS recommended guidelines (Oostveen et al., Eur Respir J. 2003;22(6):1026-41). Oscillometry was performed immediately prior to spirometry according to the study protocol. A multi-frequency signal from 5 to 37 Hz super-imposed oscillatory pressure and flow on the participant's spontaneous breathing. Measurements of 20 sec were repeated with breaks of about 20 sec. Artefacts due to cough or glottis closure were removed by automatic rejection by the software. A minimum of 3 recordings that achieved coefficient of variation of <15% was required for quality control (Peters et al., Appl Physiol Nutr Metab. 2016;41(5):538-47). Only these data were used for the data analysis.

[0347] Low frequencies (e.g. at 5Hz) reach the small airways and reflect the total airway whereas high frequencies (e.g. at 20 Hz) do not reach the small airways and therefore reflect only the central airways. Respiratory resistance (Rrs) reflects the energy needed to propagate the pressure wave through the airways and distend the lunch parenchyma. Total airway resistance is determined predominantly by the central airways (80%) and to a lesser extent by the smaller airways (20%). As such, in health there is a low frequency dependence of Rrs (Pride, Thorax. 1992;47(4):317-20) and R5-20 (the difference between Rrs at 5Hz (R5) and at 20Hz (R20)) is low. Central airway flow obstruction, a component of asthmatic airflow limitation, increases Rrs at all frequencies (i.e. both R5 and R20 are increased) and R5-20 is low, (Landseret ai., Chest. 1982;81(5):586-91). In small airway disease, also frequently seen in asthma, Rrs increase in a frequency-dependent fashion at low frequencies (i.e. R5 increases more than R20) . (Clement et al., Chest. 1983;83(2):215-20). Thus, the frequency dependence of Rrs (called R5-20; the difference between Rrs at 5Hz and 20Hz) reflects airway heterogeneity and increases with small airway obstruction (Otis et al., J Appl Physiol. 1956;8(4):427-43).

[0348] Respiratory reactance (Xrs) is driven by the capacitance (recoil) properties of the respiratory system at low frequencies where it reflects the soft tissue and lung parenchyma. At higher frequencies, however, Xrs is driven by the inertia of the moving air column in the conducting airways. The resonant frequency (fres) is the point at which the magnitudes of capacitive and inertive reactance are equal; fres is increased in both obstructive and restrictive lung diseases (Pride, Thorax. 1992;47(4):317-20, Clement et al., Chest. 1983;83(2):215-20). AX is an integrative index of total respiratory reactance at all frequencies between 5 Hz and fres (area under the reactance curve) and has the units of elastance, and is a measurement of small airways disease and closure, as seen in asthma.

[0349] R5, R5-20, and AX are the most sensitive oscillometry metrics of small airway function (Goldman et al.; Oostveen et al., Eur Respir J. 2003;22(6):1026-41; Oostveen E, et al. Eur Respir J. 2013;42(6):1513-23). Thus, AX, R5, and R5-20 were the focus of the analysis for detection of treatment effect.

[0350] Results

[0351] The following data were collected at the time points indicated in Fig. 1: FeNO levels (Fig. 2 and 3); eosinophil count in blood (Fig. 4 and 5), FEV1 (Fig. 6,7, 8), FEF25-75 (Fig. 9), R5-20 (Fig. 10), AX (Fig. 11), other biomarkers in serum / plasma (Fig. 12).

[0352] FeNO level

[0353] Fig. 2 shows the change from baseline in FeNO level of participants which have been treated with SAR443765 (dashed line) or placebo (solid line). The dose of SAR443765 was 400 mg, FeNO levels were measured one week (D8), two weeks (D15), 4 weeks (D29), and 8 weeks (D57) after the administration of SAR443765 or placebo. Table 1 shows the results of those FeNO level measurements. The baseline value is defined as the last available value before and closest to the first dose of investigational medicinal product. SAR443765 treatment was determined to reduce the FeNO level by 31.1 ppb (-31.9 ppb - -0.8 ppb) after one week (D8), by 54.0 ppb (-35.2 ppb - 18.8 ppb) after 2 weeks (D15), by 39.9 ppb (-39.1 ppb - 0.8 ppb) after 4 weeks (D29), and by 35.9 ppb (-32.0 ppb - 3.9 ppb) after 8 weeks (D57) compared to placebo.

[0354] In the SAR443765 group, 37% of the participants had a normal FeNO level (below 25 ppb) at the end of the study, while this was only the case for 8% of the placebo group.

[0355] Table 1: Change in FeNO levels after SAR443765 treatment. All FeNO levels are indicated in PPb.

[0356] Table 2 presents the baseline FeNO values as well as the reduction after 4 weeks (D29) of the present study and multiple published results of studies with other biologies, including tezepelumab (anti-TSLP), lebrikizumab (anti-IL-13), tralokinumab (anti-IL-13), benralizumab (a nti-l L-5Ra), dupilumab (a nti-l L4Ra) and itepekimab (anti-IL-33). SAR443765 shows a stronger reduction of FeNO levels than all other compounds, with a more than 2- fold higher reduction compared to the highest reduction reached in a trial with another compound (18 ppb in a lebrikizumab trial). The present trial shows that the administration of a compound which blocks both IL-13 and TSLP can massively increase the FeNO reduction by a factor of approximately 2 to 4 compared to monospecific approaches.

[0357] Table 2: Comparison of SAR443765 to other biologies used for asthma treatment. All FeNO levels are indicated in ppb.

[0358]

[0359] Subgroup analysis: Eosinophil count baseline and ICS use

[0360] Fig. 3 shows the same measurements as Fig. 2 separated according to the criteria eosinophil count baseline (Fig. 3A) or inhaled corticosteroid (ICS) use (Fig. 3B). In Fig. 3A, the following groups are depicted: SAR443765 with high baseline eosinophil count (> 0.3 *109cells / L) (lower dashed line), SAR443765 with low baseline eosinophil count (< 0.3 *109cells / L) (lower solid line), placebo with high baseline eosinophil count (> 0.3 *109cells / L) (upper dashed line), placebo with low baseline eosinophil count (< 0.3 *109cells / L) (upper solid line). The results of those four groups at D29 (4 weeks) are also depicted in Table 3A.

[0361] Table 3A: Change in FeNO levels after SAR443765 treatment for high eosinophilic and low eosinophilic subgroups. All FeNO levels are indicated in ppb.

[0362] The present treatment led to a remarkable reduction of FeNO level in both groups. For participants with high eosinophil count, the reduction compared to placebo is 53.0 ppb, for participants with low eosinophil count, the reduction compared to placebo is 33.5 ppb. This shows that the present treatment lead in both participant groups to similar FeNO reduction which exceed the FeNO reductions seen for any other biologic (see Table 2).

[0363] In Fig. 3B, the change in FeNO from baseline was explored for participants were on a stable daily dose of ICS and for those that were ICS-naive. The following groups are depicted: SAR443765 without ICS use (lower dashed line), SAR443765 with ICS use (lower solid line), placebo without ICS use (upper dashed line), placebo with ICS use (upper solid line). The results of those four groups at D29 (4 weeks) are also depicted in Table 3B.

[0364] Table 3B: Change in FeNO levels after SAR443765 treatment for ICS use subgroups. All FeNO levels are indicated in ppb.

[0365] The present treatment led to a remarkable reduction of FeNO level in both groups, with and without ICS use. For participants with ISC use, the reduction compared to placebo is 30.8 ppb, for participants without ICS use, the reduction compared to placebo is 47.2 ppb. This shows that the present treatment lead in both participant groups to similar FeNO reduction which exceed the FeNO reductions seen for any other biologic (see Table 2).

[0366] Eosinophil count Fig. 4 shows the change in eosinophil count of participants which have been treated with SAR443765 (right column) or placebo (left column) at D29 (4 weeks). The present treatment led to a median change in eosinophil count of -42.42 %, while the placebo group showed a median change in eosinophil count of -0.38%. This demonstrated that SAR443765 led to a strong reduction in eosinophil count compared to placebo. Fig. 5 shows the change in eosinophil count at D29 for SAR443765 and other biologies (lebrikizumab, tezepelumab and dupilumab). SAR443765 shows a decrease in the same range as tezepelumab. Note that dupilumab, which like SAR443765 blocks IL-13 signaling, shows here an increase in eosinophil count. Such an eosinophil increase was not seen for SAR443765. Table 4 shows the results of eosinophil counts after SAR443765 treatment at D2, D4, D8, D15, D29, D57 and D71.

[0367] Table 4: Change in eosinophil count after SAR443765 treatment. All eosinophil counts are indicated in 109cells / L.

[0368] FEV1

[0369] FEV1 (forced expiratory volume in one second) is the maximal air volume which can be exhaled in the first second of expiration, starting from maximal inspiration. In this study, FEV1 was determined by spirometry as described above. Fig. 6 shows the change (compared to baseline) of FEV1 of participants which have been treated with SAR443765 (dashed line) or placebo (solid line). The dose of SAR443765 was 400 mg. Fig. 6 depicts all available FEV1 measurements. Fig. 7 shows the same measurements, but excludes values where the measurement did not meet all quality standards, meaning the difference between the 2 largest FEV1 values in a triplicate was >0.150 L. Taking the results from Fig. 6, the present treatment led to an increase in FEV1 of ca. 0.25 L after one week (D8), ca. 0.2 L after 2 weeks (D15), ca. 0.07 L after 4 weeks (D29) and 8 weeks (D57) compared to placebo. The results from Fig. 7 are similar for D8 and D29 but show a smaller difference for D15 and no meaningful difference at D57. Those results indicate that SAR443765 improves FEVl. However, further studies with a larger patient cohort and more impaired FEB1 at baseline are needed to corroborate this finding.

[0370] To get more insight in different patient subpopulations, the FEVl improvement was analyzed for subpopulations with normal and impaired lung function at baseline. The criterion to classify a participant in one of those group was the "percent predicted FEVl" at baseline, i.e. before the start of the treatment with SAR443765 or placebo. The percent predicted FEVl (abbreviated as "ppFEVl") is the ratio (in %) between the actual FEVl of the participant and a reference FEVl which reflects the average value for a person with the participant's demographics, like age, sex, and body composition. Participants whose baseline ppFEVl was >80 % were classified in the normal baseline lung function subpopulation, while participants whose baseline ppFEVl was <80% were classified in the impaired baseline lung function subpopulation. So the data for the SAR443765 group and the placebo group were both divided into two subpopulations according to this criterion. The FEVl results for those 4 subgroups are shown in Fig. 8. The results indicate that the overall improvement of FEV1 seen in Fig. 7, especially for D8, D15, and D29 after SAR443765 treatment is mainly due to an improvement in the subpopulation with impaired baseline lung function (ppFEVl <80%), while the normal baseline lung function subpopulation (ppFEVl >80 %) showed hardly any improvement, probably due to a ceiling effect.

[0371] FEF25-75

[0372] FEF25-75 (Forced Expiratory Flow 25-75%) refers to a fraction of the FVC (forced vital capacity) which is the maximal air volume which a patient can expire after maximal inspiration. FEF25-75 is the fraction of the FVC which is exhaled in the time span between exhalation of 25% of the FVC and exhalation of 75% of the FVC, divided by the time in which this volume is exhaled. Impairment in FEF25-75 can be indicative of obstruction of the small airways. In this study, FEF25-75 was determined by spirometry as described above.

[0373] Fig. 9 shows FEF25-75 for the whole patient population (left), as well as for the subpopulations (right) with normal baseline lung function (ppFEVl >80 %) and impaired baseline lung function (ppFEVl <80%) as explained above for the FEV1 results of Fig. 8. SAR443765 improved the FEF25-75 in the whole patient population (left panel), especially for D8 and D15. The results for the subpopulations (right panel) indicate that this overall improvement of FEF25-75 seen in the left panel is mainly due to the SAR443765 subpopulation with impaired baseline lung function (ppFEVl <80%), which shows an improvement of around 0.4-0.5 L / s, while the normal baseline lung function subpopulation (ppFEVl >80 %) showed hardly any improvement compared to baseline. This result is evidence that SAR443765 treatment reduces obstruction of the small airways in asthma patients.

[0374] R5-20

[0375] As noted above, R5-20 is the difference between the respiratory resistance at 5 Hz and the respiratory resistance at 20 Hz. The resistance at 5 Hz indicates the resistance of the whole respiratory system (small and large airways) while the resistance at 20 Hz indicates the resistance within the large airways. Accordingly, an elevated R5-20 indicates increased resistance (and thus obstruction) of the small airways. R5-20 was determined by impulse oscillometry as described above.

[0376] Fig. 10 shows R5-20 for the whole patient population (left), as well as for the subpopulations (right) with normal baseline lung function (ppFEVl >80 %) and impaired baseline lung function (ppFEVl <80%) as explained above for the FEV1 results of Fig. 8. R5- 20 was reduced in the whole patient population, the reduction exceeded the value of 0.31 cmH2O*s / L (0.03 kPa*s / L) which is regarded as the clinically meaningful threshold (Foy et al. Am J Respir Grit Care. 2019;200(8):982-991). The effect was most pronounced at D8 and D15. While there was virtually no effect of SAR443765 in the normal baseline lung function subpopulation (ppFEVl >80 %), there was a remarkable reduction of R5-20 in the impaired baseline lung function subpopulation (ppFEVl <80%). This indicates that the SAR443765 treatment reduces obstruction of the small airways especially in asthma patients with impaired lung function.

[0377] As noted above, area of reactance (AX) is calculated from the reactance measurement of the lung (see also Desiraju and Agrawal, 2016). It includes the total area dominated by the capacitance and reflects the capacitance (recoil) properties of the lung. As seen with reactance and fres, AX also increases in any disease of lung periphery. AX was determined by impulse oscillometry as described above.

[0378] Fig. 11 shows AX for the whole patient population (left), as well as for the subpopulations (right) with normal baseline lung function (ppFEVl >80 %) and impaired baseline lung function (ppFEVl <80%) as explained above for the FEV1 results of Fig. 8. SAR443765 reduced AX in the whole patient population, the reduction exceeded the value of 6.65 cmH2O / L (0.65 kPa / L) which is regarded as the clinically meaningful threshold (Abdo et al. Eur Respir J. 2023;61(5): 2201793). The effect was most pronounced at D8 and D15. While there was virtually no effect in the normal baseline lung function subpopulation (ppFEVl >80 %), there was a remarkable reduction in the impaired baseline lung function subpopulation (ppFEVl <80%) by SAR443765 administration. This indicates that the SAR443765 treatment reduces obstruction of the small airways especially in asthma patients with impaired lung function.

[0379] Further biomarkers

[0380] In addition to the parameters shown above, the following biomarkers were determined in the above clinical trial with SAR443765: IL-5 level in serum; CCL26 (eotaxin-3) level in plasma; TARC (CCL17) level in serum; and IgE level in serum. The determination of those biomarker levels was performed according to methods commonly known in the field. The results at D29 are shown in Fig. 12. Treatment with SAR443765 led to a reduction from baseline for all observed biomarkers.

[0381] 6.2 EXAMPLE 2: PREVALENCE OF ELEVATED FENO LEVEL IN PATIENTS WITH MILD- TO-MODERATE ASTHMA

[0382] In the pre-screening of the study described in example 1, the FeNO level of 769 participants with mild-to-moderate asthma was determined. Fig. 13 shows the distribution of FeNO levels. A FeNO level of at least 20 ppb was present in 52% of the screened participants. 42% had a FeNO level of at least 25 ppb, 29% a FeNO level of at least 35% and 19% a FeNO level of at least 50 ppb.

[0383] In a next step, we analyzed the influence of ICS treatment on the FeNO levels. For this purpose, participants were grouped by their FeNO levels (<25 ppb, >25 ppb, >35 ppb, and >50 ppb) determined in the previous step (Fig. 13) and categorized according to the ICS maintenance (>3 months) treatment which they received. The categories for ICS treatments were medium-dose ICS (>250-500 pg of fluticasone propionate or comparable ICS total daily dosage), low-dose ICS (<250 pg of fluticasone propionate or comparable ICS total daily dosage), ICS PRN (no ICS maintenance treatment but occasional ICS administration as reliever treatment) and ICS naive (no ICS treatment at all). 575 of the 769 pre-screened participants could be categorized, for the remaining participants there was no information about ICS dose available. The results are shown in Fig. 14. Surprisingly, we found that the groups with elevated FeNO levels (>25 ppb) and even strongly elevated FeNO levels (>50 ppb) still comprised a considerable number of participants with low-dose ICS (40%) or medium-dose ICS (10% and 9%, respectively). Accordingly, ICS treatment is often not sufficient to normalize the FeNO level.

[0384] In the final screening of the study described in example 1, the FeNO levels and eosinophil counts in blood of 62 participants with mild-to-moderate asthma was determined. Fig. 15 shows the eosinophil count for participants grouped by their FeNO levels (<25 ppb, >25 ppb, >35 ppb, and >50 ppb). It was found that the majority of participants with elevated FeNO levels also had eosinophil counts of > 0.15*109cells / L (150 cells / pL). Most of the participants with highly elevated FeNO levels >50 ppb had even an eosinophil counts of > 0.3*109cells / L (300 cells / pL).

[0385] 6.3 EXAMPLE 3: PHASE 2 STUDY FOR HIGH-RISK ASTHMA

[0386] Based on the result that SAR443765 is able to lowerthe FeNO level even in asthma patients with ICS use (see Fig. 3B and Tab. 3B of example 1) and on the observations of high prevalence of high FeNO levels in mild-to-moderate asthma in example 2, we designed a protocol for the identification and treatment of high-risk asthma patients with mild-to- moderate asthma.

[0387] Study design:

[0388] This is a Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, parallel group, 2-arm study to assess the efficacy, safety, and tolerability of add-on therapy with subcutaneously (SC) administered SAR443765 in adult participants (aged 18 to 80 years, inclusive) with asthma, who are not currently eligible for biologic treatments, and have elevated FeNO levels (ie, >50 ppb) and blood eosinophil counts (ie, >300 cells / pL).

[0389] The study is comprised of 2 parts: Part A, the run-in period, and Part B, the randomized treatment period. Part A of this study includes an enrollment visit and run-in period and will be conducted between Screening (Visit 1) and the Baseline (Visit 3). Following the Screening visit, eligible participants will be treated for the 4-week Part A run-in period of the study with daily maintenance therapy consisting of an ICS / LABA combination. The investigator may choose 1 of 2 possible maintenance and reliever therapy regimens to allow flexibility to follow guideline- based treatment options, and to maintain consistency with a participant's maintenance and reliever therapy prior to Screening and / or local practice, including either:

[0390] • 250 / 50 pg fluticasone propionate / salmeterol, administered as 1 inhalation twice daily (resulting in a total amount of 500 pg fluticasone propionate per day) maintenance therapy with short-acting beta agonist (SABA) used as reliever therapy, or

[0391] • 160 / 4.5 pg delivered dose (metered dose 200 / 6 pg) budesonide / formoterol, administered as 2 inhalations twice daily maintenance therapy with 160 / 4.5 pg budesonide / formoterol used as reliever therapy.

[0392] Part A serves to: (1) establish compliance with a stable background therapy at an increased dose; (2) assess the change in FeNO in response to increased ICS dose among this patient population; (3) select a study sample enriched for patients who continue to demonstrate elevated FeNO levels despite the increased ICS dose; and (4) determine predictive features of patients with high-risk asthma who do not show adequate clinical responsiveness to increasing levels of ICS. Part B of this study will begin at the Baseline (Visit 3), when eligible participants will be randomized in a 1:1 ratio and treated for 52 weeks, receiving SC administrations of SAR443765 or placebo according to the following dosing regimens:

[0393] SAR443765 at adequate dosage and frequency

[0394] Placebo at same frequency as SAR443765 Part B will assess the clinical efficacy of SAR443765 in patients whose FeNO levels remain elevated (ie, >20 ppb) after increasing background maintenance therapy. Randomization will be stratified by FeNO level (>20 to <35 ppb and >35 ppb ) at the Baseline (Visit 3) following Part A of this study. While the primary analysis of this study will be conducted using data from the participants with FeNO level >35 ppb at the Baseline (Visit 3), participants with FeNO level >20 to <35 ppb at the Baseline (Visit 3) will be included as a subgroup to evaluate the efficacy and safety of SAR443765 and the predictive value of changes in FeNO levels in response to increase ICS dosage among these patients.

[0395] Additionally, randomization will be stratified by the background therapy taken (fluticasone / salmeterol with SABA reliever, or budesonide / formoterol maintenance and reliever therapy), the number of asthma exacerbations (as defined in the inclusion criterion I 04) in the previous 12 months (>1 exacerbation versus 1 exacerbation)), and by region.

[0396] During the randomization procedure, the number of asthma exacerbations in the previous 12 months, the background inhaler therapy provided to the patient, and the FeNO value at the Baseline (Visit 3) of Part B must be entered in the IVRS / IWRS. Alerts will be built into the IVRS / IWRS to restrict enrollment of participants in the following stratification group:

[0397] • Participants with a FeNO level >20 ppb to <35 ppb after the run-in period on ICS / LABA (Part A): no more than approximately 20% of participants.

[0398] During the randomized treatment period (Part B), SAR443765 will be administered as an add-on therapy to ICS / LABA (250 / 50 pg fluticasone propionate / salmeterol, administered as 1 inhalation twice daily, or 160 / 4.5 pg budesonide / formoterol, administered as 2 inhalations twice daily).

[0399] This study consists of 4 periods:

[0400] 1. Screening period (up to 4 weeks) to determine eligibility to enter the study. 2. Part A run-in period (4 weeks) with all participants receiving ICS / LABA (250 / 50 pg fluticasone propionate / salmeterol, administered as 1 inhalation twice daily, or 160 / 4.5 pg / budesonide / formoterol, administered as 2 inhalations twice daily).

[0401] 3. Part B randomized treatment period (approximately 52 weeks) with a 1:1 randomization ratio for the following treatment groups: SAR443765+ICS / LABA or Placebo+ICS / LABA (the ICS / LABA chosen in the run-in period will be continued in Part B, either 250 / 50 pg fluticasone propionate / salmeterol, administered as 1 inhalation twice daily, or 160 / 4.5 pg budesonide / formoterol, administered as 2 inhalations twice daily).

[0402] 4. Follow-up period (approximately 4 weeks) to monitor participants after treatment.

[0403] Participants who complete Part A but are not eligible for Part B, for any reason, will enter the follow-up period after the Baseline (Visit 3). This serves to ensure a safe transition of care and follow-up after taking an increased ICS / LABA dose in Part A. These participants will continue safety monitoring and return for a follow-up visit 4 weeks after the Baseline (Visit 3), where the Investigator can ensure continuity of asthma care. During this followup period, the ICS / LABA regimen for patients not entering Part B can be adjusted based on the Investigator's medical judgment of the participant's asthma control status.

[0404] Eligible participants who complete both the Part A and Part B treatment periods will be offered the opportunity to participate in the LTS study with SAR443765. Participants subsequently enrolled in the LTS study will not take part in the follow-up period of this study but will undergo a different follow-up period as part of the LTS study.

[0405] The study design is illustrated in Fig. 16.

[0406] SCIENTIFIC RATIONALE FOR STUDY DESIGN

[0407] A randomized, placebo-controlled study design where the effect of the IMP is assessed on top of background therapy (ICS / LABA) is considered to be the most appropriate design to examine the efficacy and safety of a novel biologic therapy in asthma. The AAER is considered to be a standard primary efficacy assessment for asthma with extensive precedent from Phase 3 trials (Dupilumab Liberty Asthma QUEST and Tezepelumab NAVIGATOR). Change from baseline in FEV1 is also considered an important outcome measure with precedent from prior studies and is included as a key secondary measure. This combination of endpoints provides an objective assessment of efficacy. The 52-week duration of this study allows for assessment of the broad range of short-term and midterm effects SAR443765 may have on asthma, including symptom control, health-related quality of life, and lung function trajectories over time. Based on the inclusion criteria for this study, all study participants will have mild to moderate asthma and elevated Type 2 biomarkers. Type 2 inflammatory biomarkers identify a population with high-risk asthma, which may not be classified as 'severe' according to current guidelines, but carry risk for exacerbations, poor asthma control and accelerated loss of lung function. In study PDY16622 (see example 1), a single dose of SAR443765 (400 mg) led to robust Type 2 suppression and improvement in lung function and measures of small airways disease in participants with mild-to-moderate asthma and FeNO >25 ppb at baseline.

[0408] The Part A study period ensures adherence to background medication and identifies an inhaled corticosteroid-resistant population that is hypothesized to experience clinical benefits from intervention with targeted TSLP and IL-13 suppression. This Part A period serves to predictively enrich the study population with those patients who may benefit most from intervention. It will also support the selection of appropriately patients for future studies based on baseline characteristics and biomarker features that may predict inhaled corticosteroid-resistant inflammation.

[0409] Endpoints

[0410] Table 5 summarizes the objectives and endpoints of the current study. Table 5 - Objectives and endpoints

[0411] Objectives Endpoints

[0412] Primary

[0413] • To eval uate the efficacy of SAR443765 • Annualized rate of asthma exacerbation events compared to placebo on asthma exacerbations over 52 weeks, defined as: in participants with FeNO >35 ppb at the Worsening of asthma requiring the use of baseline visit of Part B systemic corticosteroids for >3 days; or

[0414] Hospitalization or emergency room visit due to asthma and requiring the use of systemic corticosteroids

[0415] Secondary

[0416] • To eval uate the effects of SAR443765 • Change from baseline to Week 52 in pre-BD compared to placebo on lung function in FEV 1 (Key secondary endpoint for participants with FeNO >35 ppb at the baseline participants with FeNO >35 ppb at the visit of Part B baseline visit of Part B)

[0417] • To eval uate the effects of SAR443765 • Change from baseline to Week 52 in the compared to placebo on asthma control in ACQ-5 score participants with FeNO >35 ppb at the baseline visit of Part B

[0418] • To eval uate the effects of SAR443765 • Change from baseline to Week 52 in FeNO compared to placebo on FeNO levels in levels participants with FeNO >35 ppb at the baseline visit of Part B

[0419] • To eval uate the effects of SAR443765 • Annualized rate of LOAC events over compared to placebo on LOAC events in 52 weeks, defined by 1 or more of the following participants with FeNO >35 ppb at the baseline criteria: visit of Part B

[0420] >30% reduction from baseline in morning PEF on 2 consecutive days

[0421] >6 additional reliever puffs of SABA

[0422] OR

[0423] >4 additional puffs of low-dose budesonide / formoterol in a 24-hour period (compared to baseline) on 2 consecutive days

[0424] Worsening of asthma requiring the use of systemic corticosteroids for >3 days Hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids (asthma exacerbation event)

[0425] • To eval uate the effects of SAR443765 • Annualized rate of asthma exacerbation events compared to placebo on asthma exacerbations requiring hospitalization, emergency room, or requiring hospitalization, emergency room visit, urgent care visit over 52 weeks or urgent care visit in participants with FeNO >35 ppb at the baseline visit of Part B • To eval uate the effects of SAR443765 • Total systemic corticosteroid dose exposure compared to placebo on the use of systemic over 52 weeks corticosteroid therapy in participants with FeNO >35 ppb at the baseline visit of Part B

[0426] • To eval uate the effects of SAR443765 compared to placebo on PROs in the • Change from baseline to Week 52 in the population with FeNO >35 ppb at the baseline AQLQ[S] visit at the baseline visit of Part B

[0427] • Change from baseline to Week 52 in the ADSD daily morning score and in the ANSD daily evening score

[0428] • To eval uate the P K of SAR443765 • Serum SAR443765 concentrations measured throughout the study

[0429] • To evaluate immunogenicity of SAR443765 • Incidence and titer of ADA against SAR443765 throughout the study

[0430] • To eval uate the safety of SAR443765 • Incidence of TEAEs, including local reactions, AESIs, and SAEs throughout the study

[0431] The primary and key secondary efficacy and safety assessments used in this study are standard for the evaluation of therapy in participants with asthma, which have been used or are being used in similar designed Phase 2 and 3 studies such as dupilumab (Liberty Asthma QUEST, Phase 3, NCT02414854) and tezepelumab (PATHWAY, Phase 2, NCT02054130, and NAVIGATOR, Phase 3, NCT03347279).

[0432] STUDY POPULATION

[0433] Adult participants (aged 18 to 80 years, inclusive) with mild to moderate asthma for >12 months based on GINA definition Steps 2 to 4, who are on either maintenance or as-needed reliever therapy with a daily ICS dosage of <500 pg / day of fluticasone propionate, <800 pg / day of budesonide, or clinically comparable, with or without LABA.

[0434] INCLUSION CRITERIA Participants are eligible to be included in the study only if all of the following criteria apply: I 01. Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.

[0435] Type of participant and disease characteristics

[0436] 1 02. Physician-diagnosed mild-to-moderate asthma for >12 months based on GINA guidelines (1).

[0437] I 03. Participants with daily asthma treatment including:

[0438] Maintenance therapy with ICS dose of <500 pg / day of fluticasone propionate, <800 pg / day of budesonide, or comparable ICS dosage, with or without LABA for at least 1 month prior to Screening (Visit 1); or

[0439] For participants only prescribed as-needed low-dose ICS / formoterol, without maintenance therapy, they must be taking at least 7 reliever inhalations weekly during the 1 month prior to Screening (Visit 1), for a total ICS dose of <800 pg / day of budesonide or comparable ICS dosage.

[0440] I 04. >1 asthma exacerbation in the year prior to Screening (Visit 1), with at least 1 exacerbation occurring while on treatment with either: (1) maintenance ICS at a dose of <500 pg / day of fluticasone propionate, <800 pg / day of budesonide, or comparable ICS dosage, with or without LABA; or (2) low-dose ICS / formoterol reliever therapy, taken as needed.

[0441] Exacerbations are defined as:

[0442] Treatment with systemic corticosteroids (oral or parenteral) for >3 days for worsening asthma; or

[0443] Hospitalization or emergency medical care visit for worsening asthma, requiring systemic corticosteroids.

[0444] I 05. Participants with pre-BD FEV1 of >40% of predicted normal (by GLI standards) at Screening (Visit 1).

[0445] I 06. BD reversibility at Screening (Visit 1):

[0446] Reversibility of at least 12% and 200 mL in FEV1 determined by (according to site practice): a) Maximal change after the administration of up to 4 puffs (400 pg albuterol metered dose) of albuterol / salbutamol or levalbuterol / levosalbutamol (ATS / ERS methodology); or b) Maximal change in FEVl afterthe administration of 4, 6, or 8 puffs of albuterol (360, 540, or 720 pg albuterol metered dose) (SARP methodology); or c) A documented history within 5 years prior to Screening (Visit 1) of either positive reversibility testing meeting these criteria or a positive bronchoprovocation test with methacholine, mannitol, histamine, or acetylcholine (per local guidelines for use).

[0447] For more guidance on BD testing see Section "EFFICACY ASSESSMENTS" of the protocol.

[0448] I 07. FeNO >50 ppb at Screening visit (Visit 1) and FeNO >20 ppb at Baseline visit (Visit 3).

[0449] I 08. Blood total eosinophil count >300 cells / pL at Screening (Visit 1); or

[0450] Blood total eosinophil count >150 cells / pL at Screening (Visit 1) and blood total eosinophil count >300 cells / pL documented within the 12 months prior to Visit 1.

[0451] Weight

[0452] I 09. BMI within the range 18.5 to 40 kg / m2 (inclusive).

[0453] Sex, contraceptive / barrier method and pregnancy testing reguirements / breastfeeding

[0454] I 10. All

[0455] Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a) Male participants:

[0456] Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 5 months after the last administration of study intervention:

[0457] • Refrain from donating or cryopreserving sperm

[0458] PLUS, either:

[0459] Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or

[0460] Must agree to use contraception / barrier as detailed below:

[0461] • A male condom and an additional highly effective contraceptive method as described in Appendix 4 Contraceptive and barrier guidance when having sexual intercourse with a WOCBP who is not currently pregnant b) Female participants A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:

[0462] Is a WONCBP as defined in Appendix 4 of the protocol; or

[0463] Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 4 of protocol. Contraception and barrier guidance during the study intervention period (to be effective before starting the intervention) and until 5 months after the last administration of study intervention and agrees not to donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this period.

[0464] A WOCBP must have a negative highly sensitive pregnancy test. Serum pregnancy test will be performed at Screening (Visit 1) and urine pregnancy test will be performed at all subsequent study visits prior to IMP administration, at the early termination visit and at EOS.

[0465] Informed Consent

[0466] I 11. Capable of giving signed informed consent as described in Appendix 1 of the protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. In countries where legal age of majority is above 18 years, a specific ICF must also be signed by the participant's legally authorized representative.

[0467] EXCLUSION CRITERIA

[0468] Participants are excluded from the study if any of the following criteria apply:

[0469] Medical conditions

[0470] E 01. Other severe lung diseases (e.g., COPD, bronchiectasis, idiopathic pulmonary fibrosis, etc.) which may impair lung function.

[0471] E 02. Current smoker or former smoker with cessation within 6 months of Screening (Visit 1) or history of >10 pack-years. Active vaping of any products and / or marijuana smoking within 6 months of Screening.

[0472] E 03. Participants who experience a deterioration of asthma that results in emergency treatment or hospitalization, or treatment with systemic steroids within 1 month prior to the Screening (Visit 1) (counting from the date of completion of treatment for asthma exacerbation).

[0473] E 04. Participants who have experienced an upper or lower respiratory tract infection within the 4 weeks prior to Screening (Visit 1).

[0474] E 05. At sites where COVID-19 testing is required per local guidelines, participants are excluded if they have confirmed COVID-19 infection at Screening (Visit 1) or during the screening period, or at Baseline (Visit 3); such participants may be re-screened 4 weeks after resolution of symptoms or, if asymptomatic at time of testing and thereafter, 4 weeks after the positive test.

[0475] E 06. Known history of, or suspected, significant current immunosuppression, including history of invasive opportunistic or helminthic infections despite infection resolution or otherwise recurrent infections of abnormal frequency or prolonged duration.

[0476] E 07. Active / chronic helminthic infection.

[0477] E 08. Evidence of any infection requiring systemic anti-infective treatment within 2 weeks before Screening (Visit 1) or during the screening period. Significant viral infections within 2 weeks before Screening (Visit 1) or during the screening period even if the participant has not received systemic antiviral treatment (eg, influenza receiving only symptomatic treatment).

[0478] E 09. Participants with active TB, latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection, or who are at high risk of contracting TB (such as close contact with individuals with active TB), or received BCG-vaccination within 12 weeks prior to Screening (Visit 1).

[0479] Note: TB testing is mandatory to rule out active / latent TB and should be performed, assessed, and documented according to local guidelines. If no local guidelines are available or are not able to be performed at the site, a blood sample for QuantiFERON® testing should be sent to the central laboratory. Participants with confirmed positive TB test are excluded from the study unless all of the following conditions are met: a) have a history of prior documented completed chemoprophylaxis for latent TB infection (with a treatment regimen as per local guidelines), OR treated for active TB infection, and b) have obtained consultation with a specialist to rule out or treat active TB infection; and c) for whom review and approval from Sponsor have been granted are eligible.

[0480] E 10. A history of malignancy of any type (excluding basal and squamous cell skin cancer and in situ cervical carcinoma that has been excised and cured >3 years prior to Randomization [Visit 3]).

[0481] E 11. History of solid organ transplant.

[0482] E 12. Participants positive for HIV at Screening (Visit 1).

[0483] E 13. Participants with any of the following results at Screening (Visit 1): Positive (or indeterminate) HBsAg or positive IgM HBcAb or positive total HBcAb confirmed by positive HBV DNA or positive HCV antibody confirmed by positive HCV RNA.

[0484] E 14. Clinically significant laboratory abnormalities at Screening (Visit 1): a) Alanine aminotransferase or aspartate aminotransferase >2 times ULN range. b) Serum total bilirubin >1.5xULN (participants with Gilbert's syndrome can be included with total bilirubin >1.5xULN as long as direct bilirubin is <1.5xULN). c) Hemoglobin <10 g / 100 mL for male and <9 g / 100 mL for female. d) Neutrophils <1500 / pL (<1000 / pL for those of African descent). e) Platelets <100000 / pL. f) Creatinine >150 pmol / L.

[0485] E 15. Severe concomitant illness that would in the Investigator's opinion inhibit the participant's participation in the study, including for example, but not limited to, hypertension, renal disease, neurological conditions, heart failure, and pulmonary disease. E 16. History (within last 2 years prior to Baseline [Visit 3]) of prescription drug or substance abuse, including alcohol, considered significant by the Investigator.

[0486] E 17. Elective surgery planned to be scheduled for any time in the period up to 3 months following the last dose of IMP.

[0487] Prior / concomitant therapy

[0488] E 18. Anti-lg E mAb therapy (eg, omalizumab [Xolair®]) within 130 days prior to Screening (Visit 1) or any other biologic therapy (including anti-IL-4 / 4R, IL-5 / 5R, IL-13, or TSLP) or systemic immunosuppressant (eg, methotrexate) to treat inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) and other diseases, within 2 months or 5 half-lives prior to Screening, whichever is longer.

[0489] E 19. Participants who have received bronchial thermoplasty previously.

[0490] E 20. Participants who are receiving LAMA or other controller inhaler in addition to ICS / LABA as controller medication prior to Screening (Visit 1).

[0491] E 21. Treatment with a live (attenuated) immunization within 12 weeks prior to Baseline (Visit 3) or intention to receive any live vaccination during the study. Treatment with any non live vaccine within 2 weeks before Baseline (Visit 3).

[0492] E 22. History of hypersensitivity or allergy to IMP or to any of the excipients used in the presentation or in preparation for administration of IMP, or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.

[0493] Prior / concurrent clinical study experience

[0494] E 23. Investigational therapy for the treatment of asthma or other conditions within 5 half-lives or the limit of PD effects or 3 months where the tl / 2 is unknown prior to Baseline (Visit 3).

[0495] E 24. Concurrent participation in any other clinical study, including noninterventional studies.

[0496] Other exclusion criteria

[0497] E 25. Non-compliance to ICS / LABA treatment during Part A run-in period, defined as: Participants who have taken <70% of total number of prescribed inhalations during the Part A run-in. Compliance will be assessed based on eDiary review or investigator / site staff review with participants.

[0498] E 26. Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.

[0499] E 27. Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures. E 28. Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with section 1.61 of the ICH-GCP Ordinance E6).

[0500] E 29. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.

[0501] E 30. Any country-related specific regulation that would prevent the participant from entering the study.

[0502] LIFESTYLE CONSIDERATIONS

[0503] Meals and dietary restrictions

[0504] • No meals and dietary restrictions are required, except for the FeNO test and blood sample for serum chemistry.

[0505] • Participants should not eat or drink 1 hour prior to having the FeNO test, as this may affect the results.

[0506] Caffeine, alcohol, and tobacco

[0507] • Smoking and / or vaping and / or smoking marijuana will not be allowed from 6 months prior to Screening (Visit 1) until after the final follow-up visit.

[0508] • Use of alcohol and caffeine is allowed. However, 8 hours prior to spirometry, no alcohol should be consumed.

[0509] Activity

[0510] • Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung function assessments at the center.

[0511] All eligible participants will be randomly assigned to receive study intervention in a 1:1 ratio (SAR443765:placebo). The primary population for analysis in this study will be patients with FeNO >35 ppb at the baseline visit, while a subgroup of patients with FeNO >20 to <35 ppb at baseline visit will be enrolled and included in additional analyses. Statistical considerations:

[0512] Sample size

[0513] Approximately 344 participants with FeNO level >35 ppb at randomization as per the IVRS / IWRS (mITT population) will be randomized in a 1:1 ratio to SAR443765 or placebo.

[0514] Assuming the number of asthma exacerbations follows a negative binomial distribution with a dispersion parameter of 2.0, an average treatment duration per participant of 0.90 years (52 weeks with 10% loss of follow-up rate), a placebo AAER of 0.4, with approximately 172 participants per intervention arm in the mITT population, the study will have approximately 83% to 95% power to reject the null hypothesis of no difference between SAR443765 and placebo for the annualized rate of asthma exacerbations over 52 weeks with a z-test and one-sided Type I error rate of 2.5%, under the alternative assumption of a RRR of 55% to 65%.

[0515] With a randomization cap of 20% of participants with FeNO >20 to <35 ppb at randomization in the ITT population, a maximum of approximately 430 participants will be randomized in Part B (215 participants per intervention arm).

[0516] Assuming that 50% of participants have FeNO <35 ppb after completing Part A, a total of approximately 688 participants will need to be enrolled in Part A to ensure that 344 participants with FeNO >35 ppb are included in the mITT population. The total number of participants enrolled in Part A may be adjusted based on the observed proportion of participants with FeNO <35 ppb after Part A to ensure 344 participants with FeNO >35 ppb can be randomized in Part B.

[0517] Analysis population

[0518] The ITT population is defined as all enrolled participants, including all randomized participants. Randomized participants will be analyzed according to the intervention allocated by randomization. This will be the secondary efficacy population. The primary efficacy population will be the mITT population, defined as all participants from the ITT population randomized in Part B with FeNO >35 ppb at randomization as per the IVRS / IWRS. Participants will be analyzed according to the intervention allocated by randomization.

[0519] The safety population will include all enrolled participants, including all randomized participants, who have taken at least 1 dose of study intervention, regardless of the amount of intervention administered. Participants will be analyzed according to the intervention they actually received.

[0520] • Primary endpoint:

[0521] The AAER between SAR443765 and placebo will be analyzed in mITT population using a negative binomial regression model. The model will include the total number of asthma exacerbation events that occur up to Week 52 according to the ICEs strategy as the response variable, with intervention group (SAR443765 or placebo) and randomization stratum as per the IVRS / IWRS (number of asthma exacerbations in the previous 12 months and region), screening ICS dose level, and background therapy track as covariates. Other prognostic covariates may be added to the model as appropriate. Log-transformed observation duration will be the offset variable.

[0522] The estimated AAER for each intervention group and its 2-sided 95% Cl will be derived from the negative binomial model. The AAER relative risk reduction of SAR443765 versus placebo and the corresponding 2-sided 95% Cl will also be reported along with the 1-sided p-value.

[0523] ICEs will be handled with the "treatment policy strategy."

[0524] • Key secondary endpoint:

[0525] The change from baseline to Week 52 in pre-BD FEV1 (absolute change in mL) between SAR443765 compared to placebo will be analyzed in mITT population using an ANCOVA model. The model will include the change from baseline to Week 52 in pre-BD FEV1 as response variable, the intervention group (SAR443765 or placebo), age, sex, height, randomization stratum as per the IVRS / IWRS (number of asthma exacerbations in the previous 12 months and region), and background therapy track as fixed effects, and the screening ICS dose level and baseline pre-BD FEV1 value (continuous variables) as covariates. Other prognostic covariates may be added to the model as appropriate.

[0526] Descriptive statistics including number of participants, mean, SEM, and LS mean will be provided for each intervention group. The difference in LS means between SAR443765 and placebo and the corresponding 2-sided 95% Cl will be reported along with the 1-sided p- value.

[0527] ICEs will be handled with the "treatment policy strategy" and missing data will be handled by multiple imputation.

[0528] For both primary and key secondary endpoint, a supplementary analysis will be conducted using the same analytical approach on the subgroup of participants randomized in Part B from the ITT population by randomization stratum on FeNO level (>20 to <35 ppb, >35 ppb) and overall.

[0529] • Safety analyses: The safety variables, including AEs, laboratory parameters, vital signs, electrocardiography, and physical examinations will be summarized using descriptive statistics.

[0530] • Multiplicity considerations: A hierarchical testing procedure will be applied to control the overall one-sided Type I error rate of 2.5% when testing the null hypotheses of the primary endpoint and then the key secondary endpoint.

[0531] • Interim analyses: Interim analyses may be performed for decision-making on project planning.

[0532] Study interventions Formulation: SAR443765 / placebo solution for injection

[0533] Route(s) of administration: SC injection to the abdomen, thigh, or upper arm. SAR443765 / placebo should not be administered at the exact site of a recent injection or in areas which in the Investigator's opinion are not suitable (e.g., tender, bruised, red, hard, or affected by dermatological lesions).

[0534] ICS / LABA controller combinations

[0535] • Formulation: fluticasone propionate / salmeterol.

[0536] • Route(s) of administration: Oral inhalation.

[0537] • Dose regimen: 250 / 50 pg, administered as 1 inhalation twice daily (resulting in a total amount of 500 pg fluticasone propionate per day).

[0538] OR

[0539] • Formulation: budesonide / formoterol.

[0540] • Route(s) of administration: Oral inhalation.

[0541] • Dose regimen: 160 / 4.5 pg delivered dose (200 / 6 pg metered dose), administered as 2 inhalations twice daily.

[0542] Daily throughout both Part A and Part B of the study, participants will use an eDiary to record their daily use of ICS / LABA.

[0543] • Prior to Screening (Visit 1), participants must have been on maintenance or as- needed reliever therapy consisting of low to medium dose ICS for at least the past 1 month (<500 pg / day of fluticasone propionate or clinically comparable) (see GINA guideline) as described in Section 5.1 (refer also to Section 10.11.1 of the protocol for ICS equivalency chart). Background therapy prior to Screening (Visit 1) may consist of ICS alone or in combination with LABA and may include as needed use of low-dose ICS / LABA.

[0544] Part A run-in period:

[0545] • During the 4-week Part A run-in period, participants will be prescribed 250 / 50 pg fluticasone propionate / salmeterol, administered as 1 inhalation twice daily (resulting in a total amount of 500 pg fluticasone propionate per day), or 160 / 4.5 pg (200 / 6 pg metered dose) budesonide / formoterol, administered as 2 inhalations twice daily. The eDiary will be used to record daily use, and compliance will be assessed at the Baseline (Visit 3).

[0546] Part B randomized treatment period:

[0547] • During the 52-week Part B period, participants will continue to take the same ICS / LABA combination as in Part A (either 500 pg / day of fluticasone propionate / salmeterol or 800 pg / day of budesonide / formoterol) and will use an eDiary to record daily use of all controller medications. The dose and regimen should not be changed during the study.

[0548] Follow-up period:

[0549] • Upon completing the randomized treatment period (Part B), participants will continue to receive the ICS / LABA regimen and dosage as used during the randomized treatment period, which may then be adjusted based on the Investigator's medical judgment of the participant's asthma control status.

[0550] • Participants who complete Part A but are not eligible for Part B, for any reason, will enter the follow-up period after the Baseline (Visit 3). This serves to ensure a safe transition of care and follow up after taking an increased ICS / LABA dose in Part A. These participants will continue safety monitoring and return for a follow-up visit 4 weeks after the Baseline (Visit 3), where the Investigator can ensure continuity of asthma care. The ICS / LABA regimen can be adjusted during this follow-up period for these patients not entering Part B based on the Investigator's medical judgment of the participant's asthma control status.

[0551] Reliever Medication Participants receiving fluticasone / salmeterol during Part A and Part B may receive SABA as reliever medication on an as-needed basis during the study, while those receiving budesonide / formoterol during Part A and Part B may receive as needed low-dose ICS / formoterol (per GINA 2023 guidelines). Nebulizer solutions may be used as an alternative delivery method, if previously used by the participant. Reliever medication use will be recorded in the eDiary. Commonly used asthma reliever medications are shortacting beta agonists (SABA), combinations of SABA and short-acting muscarinic antagonists (SAMA), and combinations of ICS and long-acting beta agonists (LABA).

[0552] Devices

[0553] There are no medical devices which are the object of the clinical trial; however, medical devices are used in the clinical trial. All medical devices (including in vitro diagnostic devices) used for the execution of trial-related activities will be used in accordance with their intended purposes.

[0554] The Sponsor or a designee will provide the following medical devices for the execution of trial related activities:

[0555] • Electronic spirometry devices for daily remote spirometry FEV1 and PEF measurement.

[0556] • Spirometry devices for FEV1, PEF, FVC, and FEF measurement.

[0557] • Impulse oscillometry devices for FOT measurement.

[0558] • FeNO measurement devices.

[0559] • Devices required for clinical laboratory sampling (eg, tubes, needles, and dipsticks). The following devices to be used during the study will not be supplied by the Sponsor:

[0560] • Devices required for monitoring vital signs (eg, ECG, blood pressure, pulse rate, body temperature, and respiratory rate).

[0561] • Sterile needles and syringes to be used for IMP preparation and administration.

[0562] STUDY ASSESSMENTS AND PROCEDURES

[0563] It is recommended that assessments / procedures at a site visit are performed in the following order if applicable and possible: PROs and other questionnaires

[0564] ECG

[0565] Procedures:

[0566] 1. FeNO measurement

[0567] 2. Pre-BD impulse oscillometry

[0568] 3. Pre-BD spirometry

[0569] 4. Post-BD impulse oscillometry

[0570] 5. Post-BD spirometry

[0571] 6. eDiary download

[0572] 7. Safety and laboratory assessments

[0573] 8. Administration of SAR443765 / placebo

[0574] EFFICACY ASSESSMENTS

[0575] Planned timepoints for all efficacy assessments are provided in the schedule.

[0576] Primary endpoint:

[0577] The primary endpoint for this study is the annualized rate of asthma exacerbation events over a period of 52 weeks, lunsekimig compared to placebo.

[0578] Asthma exacerbation events:

[0579] Asthma exacerbation event is defined as:

[0580] • Worsening of asthma requiring the use of systemic corticosteroids for >3 days; or

[0581] • Hospitalization or emergency room visit due to asthma and requiring the use of systemic corticosteroids.

[0582] Secondary endpoints

[0583] Key secondary endpoint:

[0584] The key secondary endpoint for this study is the change from baseline to Week 52 in pre BD FEV1, lunsekimig compared to placebo.

[0585] Disease-specific efficacy measures Spirometry

[0586] Spirometry will be performed in accordance with the ATS / ERS guidelines (Graham et al., Am J Respir Grit Care Med. 2019;200(8):e70-e88) and prior to administration of IMP at the planned time point. For pre-BD measured parameters, including FEV1, PEF, FVC and FEF 25% to 75%, spirometry will be performed after a wash out period of BDs according to their action duration, following the guidance of the ATS / ERS 2019 guidance (Graham et al). For example, withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for at least 6 hours, withholding the last dose of LABA for at least 24 hours, and finally the last dose of ultralong-acting LABA (like vilanterol) or the last dose of LAMA should be withheld for at least 36 hours). This will be verified before performing the measurements. In addition, participants are asked to avoid consuming alcohol 8 hours prior to spirometry, and to avoid engaging in strenuous exertion for at least 30 minutes prior to all lung function assessments.

[0587] At all site visits, spirometry will be performed preferably in the morning, afternoon is allowable in the exceptional circumstance when morning spirometry cannot be performed. Spirometry will be done at approximately the same time at each visit throughout the study. The same spirometer and standard spirometric techniques, including calibration, will be used to perform spirometry at all visits, and whenever possible, the same person should perform the measurements. Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained at every site visit, if possible.

[0588] Reversibility is defined as an increase of the absolute FEV1 after administration of BD and is measured by spirometry as post-BD increase in FEV1 in percent of the pre-BD FEVl. At specified spirometry visits, after spirometry for measuring pre-BD FEVl, participants will receive up to 4 puffs (400 pg) of albuterol / salbutamol or levalbuterol / levosalbutamol from a primed MDL When determining patient eligibility (Visit 1), the Severe Asthma Research Program (SARP) method could be used if it is consistent with usual office practice (to be documented): maximal change in FEVl after the administration of 4, 6, or 8 puffs of albuterol (360, 540, or 720 pg albuterol). Reversibility may be performed using inhalation of nebulized albuterol / salbutamol or levalbuterol / levosalbutamol. The post-BD spirometry should be performed no sooner than 30 minutes and no later than 60 minutes after administration of BD and may be repeated several times within that time window.

[0589] Fractional Nitric Oxide (FeNO)

[0590] Fractional exhaled nitric oxide is a measure of nitric oxide in exhaled breath produced by epithelial cells in the lung and considered as a biomarker of Type-2 inflammation in asthma. The levels of FeNO (ppb) will be collected on site with a dedicated medical device (NIOX VERO®). The FeNO test needs to be completed prior to impulse oscillometry and spirometry in order to avoid any impact on the nitric oxide measurement. In addition, participants should not eat or drink 1 hour prior to having the FeNO test, as this may affect the results. Further details on the procedure for measuring exhaled nitric oxide with NIOX VERO will be provided in a separate instruction manual.

[0591] Oscillatory lung mechanics

[0592] Oscillometry is a complementary technique to spirometry determining the physiological behavior of the lung in asthmatics. Whereas spirometry is the most commonly used technique examining airways resistance, oscillometry has several advantages in determining the relative contributions of small versus large airways disease, which is critical to understanding asthma phenotype and response to treatment. Oscillometry will be conducted during tidal breathing using the tremoflo® device (Thorasys, Montreal, Canada) according to ERS recommended guidelines (Oostveen et al., Eur Respir J. 2003;22(6):1026- 41). Oscillometry will be performed immediately prior to spirometry, both before and 15 minutes after BD administration. A multi-frequency signal from 5 to 37 Hz super-imposes oscillatory pressure and flow on the subject's spontaneous breathing. Measurements of 20 sec are repeated with breaks of about 20 sec. Artefacts due to cough or glottis closure are removed by automatic rejection by the software. A minimum of 3 recordings that achieve coefficient of variation of <15% is required for quality control. Only these data will be used for the data analysis. The individual measurements can be reviewed manually to confirm that a quality measurement was indeed performed.

[0593] Rrs is almost independent of oscillation frequency in health. An increase in Rrs at all frequencies is commonly attributed to central airways obstruction, a component of asthmatic airflow limitation. With small airway disease, also seen in asthma, the respiratory system is better described by a distribution of pathway resistances. Peripheral resistance increases in a heterogeneous manner and consequently Rrs becomes frequency dependent and increases more in the lower frequencies. Thus, the frequency dependence of Rrs (called R5-20; the difference between Rrs at 5 Hz and 20 Hz) reflects small airway heterogeneity and increases with small airway obstruction. The Xrs is driven by the elastic properties of the respiratory system at low frequencies where it reflects the soft tissue and lung parenchyma. At higherfrequencies, however, Xrs is driven by the inertia of the moving air column in the conducting airways. The fres is the point at which the magnitudes of capacitive and inertive reactance are equal; fres is increased in both obstructive and restrictive lung diseases. Ax is an integrative index of total Rrs at all frequencies between 5 Hz and fres (area under the reactance curve) and has the units of elastance, and also is a measurement of small airways disease and closure, as seen in asthma.

[0594] R5, R5-20, and Ax are the most sensitive oscillometry metrics of small airway function. Reference values and BDR cut-offs are derived from Oostveen, et al. (Oostveen et al., Eur Respir J. 2003;22(6):1026-41; Oostveen E, et al. Eur Respir J. 2013;42(6):1513-23). BDR will be defined as an absolute change in R5 >- 1.40 cm H2O-s / L or Ax >-3.98 cm H2O / L after BD administration. Thus, R5, R5-20, and Ax will be the focus of our analysis for detection of treatment effect. Data for all frequencies will be collected and can be analyzed if desired.

[0595] 6.4 EXAMPLE 4: OPTIMIZED PHASE 2 STUDY FOR HIGH-RISK ASTHMA The study design shown in example 3 was further optimized to adjust it to recent scientific findings (Meulmeester et al., Lancet Respir Med. 2025 Jun;13(6):505-516.) and to facilitate efficient participant recruitment.

[0596] All features and parameters of the optimized study correspond to example 3, except of the following modifications:

[0597] The GINA guideline citation was updated, instead of the 2023 version, it is now referred to the latest report from 2024 (Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2024. [Internet], GINA; 2024 [cited 2025 February 11], Available from: https: / / ginasthma.org / wp-content / uploads / 2024 / 05 / GINA-2024-Strategy- Re po rt-24_05_22_WM S . pdf . )

[0598] It the FeNO threshold for screening (Visit 1) was decreased from >50 ppb (example 3) to >35 ppb. Furthermore, it was clarified that a maintenance therapy with ICS dose of exactly 500 pg / day of fluticasone propionate, 800 pg / day of budesonide, orcomparable ICS dosage is allowed. This leads to the changes in the following sections:

[0599] STUDY DESIGN

[0600] This is a Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, parallel group, 2-arm study to assess the efficacy, safety, and tolerability of add-on therapy with subcutaneously (SC) administered SAR443765 in adult participants (aged 18 to 80 years, inclusive) with asthma, who are not currently eligible for biologic treatments, and have elevated FeNO levels (i.e., >35 ppb) and blood eosinophil counts at Screening (Visit 1).

[0601] STUDY POPULATION

[0602] Adult participants (aged 18 to 80 years, inclusive) with mild to moderate asthma for >12 months based on GINA definition Steps 2 to 4, who are on either maintenance or as-needed reliever therapy with a daily ICS dosage of <500 pg / day of fluticasone propionate, <800 pg / day of budesonide, or clinically comparable, with or without LABA. Ill

[0603] INCLUSION CRITERIA

[0604] I 03. Participants with daily asthma treatment including:

[0605] Maintenance therapy with ICS dose of <500 pg / day of fluticasone propionate, <800 pg / day of budesonide, or comparable ICS dosage, with or without LABA for at least 4 weeks prior to Screening (Visit 1). or

[0606] For participants prescribed only as-needed low-dose budesonide / formoterol or as needed budesonide / albuterol without maintenance therapy, they must be taking at least 7 doses of anti-inflammatory / bronchodilator weekly during the month prior to Screening (Visit 1), for a total ICS dose of <800 pg / day of budesonide or a comparable ICS dosage.

[0607] I 04. >1 asthma exacerbation in the year prior to Screening (Visit 1), with at least 1 exacerbation occurring while on treatment with either: (1) maintenance ICS at a dose of <500 pg / day of fluticasone propionate, <800 pg / day of budesonide, or comparable ICS dosage, with or without LABA; or (2) low-dose budesonide / formoterol reliever therapy, taken as needed. Exacerbations are defined as:

[0608] Treatment with systemic corticosteroids (oral or parenteral) for >3 days for worsening asthma; or

[0609] Hospitalization or emergency medical care visit for worsening asthma, requiring systemic corticosteroids.

[0610] I 07. FeNO levels >35 ppb at Screening (Visit 1) and FeNO levels >20 ppb at Baseline (Visit 3). I 12. For participants on an equivalent dose of 500 pg / day fluticasone propionate or clinically comparable at Screening (Visit 1), they must have an ACQ-5 score of <1.5 at Screening (Visit 1) to confirm they are GINA 4.

[0611] STUDY INTERVENTIONS

[0612] Prior to Screening (Visit 1), participants must have been on maintenance or as-needed reliever therapy consisting of low to medium dose ICS for at least the past 1 month (<500 pg / day of fluticasone propionate or clinically comparable) (see GINA guideline) as described in Section 5.1 (refer also to Section 10.11.1 of the protocol for ICS equivalency chart). Background therapy prior to Screening (Visit 1) may consist of ICS alone or in combination with LABA and may include as needed use of low-dose ICS / LABA.

[0613] Moreover, some statistical considerations were modified:

[0614] STATISTICAL CONSIDERATIONS

[0615] • Key secondary endpoint:

[0616] Continuous endpoints such as the change from baseline in pre-bronchodilator (BD) FEV1 at Week 52 will be analyzed using a mixed-effects model with repeated measures (MMRM) model. The model will include change from baseline values up to Week 52 as response variables, study intervention group, age, sex, height, randomization strata (Part A background therapy, number of asthma exacerbations in the previous 12 months, and region), ICS dose level at Screening (Visit 1), visit, study intervention-by-visit interaction, pre-BD FEV1 value at Baseline (Visit 3), and baseline pre BD FEV1 by visit interaction as covariates. Other prognostic covariates may be added to the model as appropriate. An unstructured correlation matrix will be used to model the within-participant errors.

[0617] Descriptive statistics including number of participants, mean, standard error of the mean (SEM), and least squares (LS) mean will be provided for each intervention group. The difference in LS means between lunsekimig and placebo and the corresponding 2-sided 95% Cl will be reported along with the 1-sided p-value.

[0618] ICEs will be handled with the "treatment policy strategy" and missing data will be handled by MMRM.

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[0679] Wenzel et al., Lancet. 2016 Jul 2;388(10039):31-44

[0680] WO 94 / 04678 - IMMUNOGLOBULINS DEVOID OF LIGHT CHAINS

[0681] WO 96 / 34103 - VARIABLE FRAGMENTS OF IMMUNOGLOBULINS - USE FOR THERAPEUTIC

[0682] OR VETERINARY PURPOSES

[0683] WO 99 / 23221 - MULTIVALENT ANTIGEN-BINDING PROTEINS

[0684] WO2021116182 - POLYPEPTIDES COMPRISING IMMUNOGLOBULIN SINGLE VARIABLE

[0685] DOMAINS TARGETING IL-13 AND TSLP

[0686] Wynn, Nat Rev Immunol. 2015 May;15(5):271-82

Claims

CLAIMS1. A compound that binds IL-13 and TSLP for use in the treatment of mild-to-moderate asthma in a subject with high risk of asthma exacerbations and / or lung function loss, wherein mild-to-moderate asthma is asthma wherein the subjectI. does not receive more than 500 pg per day of inhaled fluticasone propionate, or an equivalent dose of inhaled corticosteroid according to the GINA guideline;II. receives asthma treatment according to a Step lower than Step 5 of the GINA treatment scale;III. receives asthma treatment according to one of Steps 1-4 of the GINA treatment scale; and / orIV. is not eligible for asthma treatment with biologies; wherein high risk of asthma exacerbations or lung function loss is present if the subject fulfils one or more of the following high-risk criteria: a) a FeNO level of i. at least 20 ppb, ii. at least 25 ppb, iii. at least 35 ppb, or iv. at least 50 ppb, optionally wherein the FeNO level is resistant to treatment with inhaled corticosteroids; b) Eosinophil count i. in blood of at least 0.15 *109cells / L; ii. in blood of at least 0.3 *109cells / L; c) One or more asthma exacerbation in the past 12 months.

2. The compound for use according to claim 1, wherein the subject fulfils at least high- risk criterion a) iii., i.e. a FeNO level of at least 35 ppb.

3. The compound for use according to any of the previous claims, wherein the subject fulfils at least high-risk criterion a) iv., i.e. a FeNO level of at least 50 ppb.

4. The compound for use according to any of the previous claims, wherein the subject fulfils at least high-risk criterion a) iii., i.e. a FeNO level of at least 35 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, which is determined by a FeNO suppression test, wherein the FeNO suppression test consists of at least 4 weeks of administration of inhaled corticosteroids in an amount of at least 500 pg per day of fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

5. The compound for use according to any of the previous claims, wherein the subject fulfils at least high-risk criterion a) iv., i.e. a FeNO level of at least 50 ppb, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, which is determined by a FeNO suppression test, wherein the FeNO suppression test consists of at least 4 weeks of administration of inhaled corticosteroids in an amount of at least 500 pg per day of fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

6. The compound for use according to any of the previous claims, wherein the FeNO level is resistant to treatment with inhaled corticosteroids, wherein the subject fulfills at least high-risk criterion a) iv. before a FeNO suppression test and fulfills at least high-risk criterion a) iii. after the FeNO suppression test, wherein the FeNO suppression test consists of at least 4 weeks of administration of inhaled corticosteroids in an amount of at least 500 pg per day of fluticasone propionate or an equivalent dose of inhaled corticosteroid according to the GINA guideline.

7. The compound for use according to any of the previous claims, wherein the subject fulfills at least mild-to-moderate asthma criterion I.

8. The compound for use according to any of the previous claims, wherein the subject receives inhaled corticosteroid treatment.

9. The compound for use according to any of the previous claims, wherein the subject further fulfills high-risk criterion b) i., i.e. an eosinophil count in blood of at least 0.15 *109cells / L.11810. The compound for use according to any of the previous claims, wherein the subject further fulfills high-risk criterion b) ii., i.e. an eosinophil count in blood of at least 0.3 *109cells / L.

11. The compound for use according to any of the previous claims, wherein the subject further fulfills high-risk criterion c)., i.e. one or more asthma exacerbation in the past 12 months.

12. The compound for use according to any of the previous claims, wherein the subject further fulfills one or more of the following high-risk criteria: d) type 2 high phenotype, wherein a type 2 high phenotype is characterized by high expression of type 2 cytokines, such as IL-4, IL-5, IL-6 and IL-13; e) Small airway obstruction, as measured by oscillometry, spirometry or imaging. f) Asthma Control Questionnaire score >1.5; g) forced expiratory volume in 1 second <80% predicted; h) use of >200 doses of asthma reliever medication / month; i) comorbidities, or history of comorbidities, wherein the comorbidities comprise one or more of chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), allergy, eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), obesity, and psychiatric disease; j) previous intubation or intensive care unit admission for asthma; k) environmental exposures, wherein the environmental exposure comprise one or more of smoking, allergen, and pollution; l) eosinophil count in sputum of at least 3%, of total non-squamous cell count.

13. The compound for use according to any of the previous claims, wherein the compound that binds IL-13 and TSLP is a polypeptide, such as an antibody or an antibody fragment.

14. The compound for use according to claim 13, wherein the polypeptide comprises or consists of at least four ISVDs, wherein two ISVDs specifically bind IL-13 and two ISVDs specifically bind TSLP, wherein each of said at least four ISVDs comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein119 the at least four ISVDs are optionally linked via one or more peptidic linkers, and wherein: a first ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 7, a CDR2 that is the amino acid sequence of SEQ ID NO: 12 and a CDR3 that is the amino acid sequence of SEQ ID NO: 17, a second ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 8, a CDR2 that is the amino acid sequence of SEQ ID NO: 13 and a CDR3 that is the amino acid sequence of SEQ ID NO: 18, a third ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 9, a CDR2 that is the amino acid sequence of SEQ ID NO: 14 and a CDR3 that is the amino acid sequence of SEQ ID NO: 19, and a fourth ISVD comprises: a CDR1 that is the amino acid sequence of SEQ ID NO: 11, a CDR2 that is the amino acid sequence of SEQ ID NO: 16 and a CDR3 that is the amino acid sequence of SEQ ID NO: 21.

15. The compound for use according to claim 13 or 14, wherein the polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 1.

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