IL-13 antibody for treating chronic rhinosinusitis with nasal polyps

Abstract

Provided herein are methods and uses of antibodies that specifically bind human IL-13 ("anti-IL-13 antibodies") for the treatment of chronic rhinosinusitis with nasal polyps.

Description

[0001] sequence list

[0002] This application is submitted together with a sequence list in ST.26 XML format. This sequence list is provided as a file named “30943_WO_000Sequence Listing ST26”, created on December 11, 2024, and is 20 kilobytes in size. The sequence list information in ST.26 XML format is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to methods and uses of antibodies that specifically bind to human interleukin (IL)-13 (“anti-IL-13 antibody”) for the treatment of chronic sinusitis with nasal polyps (CRSwNP). Background Technology

[0004] Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease with a high incidence rate; it is estimated to affect 1% to 4% of the general population and 25% to 30% of patients with chronic rhinosinusitis (Stevens et al., Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract. 2016;4(4):565-572; Fokkens et al., European position paper on rhinosinusitis and nasal polyps (2020). Rhinology. 58(Suppl S29):1-464). CRSwNP is characterized by loss of the immune barrier and increased or chronic inflammation in the nasal passages. These conditions lead to increased nasal congestion and polyp formation. IL-4 and IL-13 can induce activation of M2 macrophages, which may contribute to the pathogenesis of CRSwNP (Maspero et al., Type 2 inflammation inasthma and other airway diseases. ERJ Open Res. (2022); 8(3):00576-2021). The exact cause of nasal polyps (NP) is unknown, but in adults, allergies, asthma, infections, and aspirin sensitivity are all associated with this complex and refractory disease (Stevens et al., 2016).

[0005] Nasal congestion is the main symptom of CRSwNP. Its direct cause is physical obstruction caused by nasal polyps, but it can also be caused by inflammation of the mucosa due to irritants (e.g., smoke, exhaust fumes, or perfumes) or allergens. Inflammation caused by IL-13 can lead to nasal congestion (Naclerio et al., 2010, Pathophysiology of nasal congestion. Int J Gen Med. (2010);3:47-57).

[0006] Systemic corticosteroids (SCS) and surgery have been used to treat CRSwNP. While these treatments do provide short-term relief, a recent meta-analysis reported that 18.6% of patients had more than one polyp removal surgery (Loftus et al., 2020, Revision surgery rates in chronic rhinosinusitis with nasal polyps: meta-analysis of risk factors. Int Forum Allergy Rhinol. 2020; 10(2): 199-207), and 35% of patients who underwent polyp removal surgery experienced nasal polyp recurrence at 6 months (DeConde, AS et al., Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017:127(3): 550-555). Currently, dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP. However, not all patients respond to these treatments, and rapid disease rebound has been observed after discontinuation of some of these antibody therapies (Bachert et al., Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. (2019); 394(10209);1638-50).

[0007] There is still a need for effective alternative therapies for the treatment of CRSwNP. Furthermore, there is a need to provide treatment and dosing regimens that are more tolerable, convenient, and less risky for patients, thereby improving patient adherence and satisfaction. Summary of the Invention

[0008] This article provides a method and use of an anti-IL-13 antibody (i.e., an antibody that specifically binds to human IL-13) such as lebrikizumab or a pharmaceutical composition containing an anti-IL-13 antibody for the treatment of chronic sinusitis with nasal polyps.

[0009] In one aspect, this article provides a method for treating chronic sinusitis with nasal polyps in patients in need, the method comprising administering a therapeutically effective amount of anti-IL-13 antibody to the patient. In some embodiments, this article provides a method for treating chronic sinusitis with nasal polyps, the method comprising: selecting a patient suffering from chronic sinusitis with nasal polyps and administering a therapeutically effective amount of anti-IL-13 antibody to the patient.

[0010] On the other hand, this invention provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for the treatment of chronic sinusitis with nasal polyps. The invention also provides the use of the anti-IL-13 antibody in the preparation of a medicament for the treatment of chronic sinusitis with nasal polyps.

[0011] In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 11 and VL as shown in SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 13 and a light chain as shown in SEQ ID NO: 14. In some embodiments, the anti-IL-13 antibody is lebrikizumab. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, and a human IgG sequence as shown in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, a human Fc region comprising a human IgG sequence as shown in SEQ ID NO: 15, and a constant light chain sequence as shown in SEQ ID NO: 16.

[0012] In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient. In some embodiments, the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks. In some embodiments, the patient further receives a 500 mg loading dose of the anti-IL-13 antibody. In some embodiments, the loading dose is administered to the patient once or twice. In some embodiments, the loading dose is administered to the patient at week 0 (baseline) and week 2. In some embodiments, the patient receives anti-IL-13 antibody treatment for approximately 24 weeks.

[0013] In some implementations, patients further receive maintenance therapy for approximately 32 weeks. In some implementations, during the maintenance period, patients receive a maintenance dose of 250 mg of anti-IL-13 antibody every 4 weeks. In some implementations, during the maintenance period, patients receive a maintenance dose of 250 mg of anti-IL-13 antibody every 8 weeks.

[0014] In some implementations, patients receive a loading dose of 500 mg anti-IL-13 antibody at week 0 (baseline) and week 2; followed by a 250 mg dose every two weeks for 24 weeks; and then a 250 mg maintenance dose every four weeks for 32 weeks.

[0015] In some embodiments, the methods and uses described herein also include determining a patient's nasal congestion symptom (NCS) severity score before, during, and after treatment. In some embodiments, the methods and uses described herein also include determining a patient's endoscopic nasal polyp score (NPS) before, during, and after treatment.

[0016] In some embodiments, the methods and uses described herein also include administration of an intranasal corticosteroid to a patient. In some embodiments, the intranasal corticosteroid is mometasone furoate. In some embodiments, the intranasal corticosteroid is administered simultaneously, concurrently, or sequentially with an anti-IL-13 antibody.

[0017] In some implementations, the patient has bilateral nasal polyps. In some implementations, the patient has a pre-treatment endoscopic NPS score of at least 5 (out of 8) bilaterally, with each nasal cavity scoring no less than 2. In some implementations, the patient has nasal obstruction, accompanied by at least one other symptom selected from hyposmia, anosmia, anterior nasal discharge, or posterior nasal discharge. In some implementations, the patient is 18 years of age or older. In some implementations, the patient is 12-18 years of age and weighs at least 40 kg. Attached Figure Description

[0018] Figure 1This is a schematic diagram of the phase 3 study design described in Example 1. Abbreviations: CFBL = Change from baseline; INCS = Intranasal corticosteroid; Lebri = Leprizumab; PBO = Placebo; Q2W = Every 2 weeks; Q4W = Every 4 weeks; Q8W = Every 8 weeks. Detailed Implementation

[0019] This article provides a method and use of an anti-IL-13 antibody (e.g., lerechizumab) or a pharmaceutical composition containing an anti-IL-13 antibody (e.g., lerechizumab) for the treatment of chronic sinusitis with nasal polyps.

[0020] In one aspect, this article provides a method for treating chronic sinusitis with nasal polyps in patients in need, the method comprising administering a therapeutically effective amount of anti-IL-13 antibody to the patient. In some embodiments, this article provides a method for treating chronic sinusitis with nasal polyps, the method comprising: selecting a patient suffering from chronic sinusitis with nasal polyps and administering a therapeutically effective amount of anti-IL-13 antibody to the patient.

[0021] On the other hand, this invention provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for the treatment of chronic sinusitis with nasal polyps. The invention also provides the use of the anti-IL-13 antibody in the preparation of a medicament for the treatment of chronic sinusitis with nasal polyps.

[0022] In some embodiments, the methods and uses described herein also include determining a patient's nasal congestion symptom (NCS) severity score before, during, and after treatment. In some embodiments, the methods and uses described herein also include determining a patient's endoscopic nasal polyp score (NPS) before, during, and after treatment.

[0023] In some embodiments, the methods and uses described herein also include administration of an intranasal corticosteroid to a patient. In some embodiments, the intranasal corticosteroid is mometasone furoate. In some embodiments, the intranasal corticosteroid is administered concurrently, in parallel, or sequentially with an anti-IL-13 antibody.

[0024] In some implementations, the patient has bilateral nasal polyps. In some implementations, the patient has a pre-treatment endoscopic bilateral NPS score of at least 5 (out of 8), with each nasal cavity scoring no less than 2. In some implementations, the patient has nasal obstruction, accompanied by at least one other symptom selected from hyposmia, anosmia, anterior nasal discharge, or posterior nasal discharge. In some implementations, the patient is 18 years of age or older. In some implementations, the patient is 12-18 years of age and weighs at least 40 kg.

[0025] Anti-IL-13 antibodies suitable for the methods and uses provided herein have been previously described, for example, WO2005 / 062967. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 11 and VL as shown in SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 13 and a light chain as shown in SEQ ID NO: 14. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, and a human IgG sequence as shown in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, a human Fc region comprising a human IgG sequence as shown in SEQ ID NO: 15, and a constant light chain sequence as shown in SEQ ID NO: 16. In some embodiments, the anti-IL-13 antibody is lerechizumab (CAS No. 953400-68-5). Lerechizumab is a humanized monoclonal IgG4 antibody that binds specifically to IL-13 with high affinity and blocks signal transduction via the active IL-4Rα / IL-13Rα1 heterodimer. The amino acid sequence of lerechizumab is shown in Table 1. C-terminal clipping of IgG antibodies can occur when one or two C-terminal amino acids are removed from the heavy chain. For example, if a C-terminal lysine (K) is present, this amino acid may be truncated or shortened from the heavy chain. The penultimate glycine (G) may also be truncated or shortened from the heavy chain. Modification of the N-terminal amino acids of IgG is also possible.For example, the N-terminal glutamine (Q) or glutamate (E) can spontaneously cyclize to pyroglutamic acid (pE). SEQ ID NO: 9 reflects these potential modifications to the lerechizumab heavy chain. Similarly, SEQ ID NO: 11, 13, and 15 reflect these potential modifications to the lerechizumab variant VH, lerechizumab variant HC, and the human IgG1 Fc region, respectively.

[0026] Table 1. Anti-IL-13 antibody sequences

[0027] In some embodiments, the anti-IL-13 antibody is a lerechizumab variant containing the same HCDR and LCDR sequences as lerechizumab. In some embodiments, the anti-IL-13 antibody is a lerechizumab variant described in WO2023245187, such as constructs 133, 134, 136, and 141. In some embodiments, the anti-IL-13 antibody is APG777. The amino acid sequences of the lerechizumab variants are also shown in Table 1.

[0028] Other exemplary anti-IL-13 antibodies include, but are not limited to, IMA-026, IMA-638 (also known as anrukinzumab, QAX-576, CAS No. 910649-32-0), tralokinumab (also known as CAT-354, CAS No. 1044515-88-9), cendakimab (also known as CC-93538, RPC4046, ABT-308, CAS No. 2151032-62-9), AER-001, and ABT-308 (also known as humanized 13C5.5 antibody). Examples of such anti-IL-13 antibodies and other inhibitors of IL-13 are disclosed in WO2008 / 086395, WO2006 / 085938, US 7,615,213, US 7,501,121, US 7,935,343, US 7,829,090, US7,947,273, WO2007 / 036745, WO2010 / 073119, WO2007 / 045477, and WO 2014 / 165771. In some embodiments, the anti-IL-13 antibody is trorocalumab. In some embodiments, the anti-IL-13 antibody is cedazine.

[0029] Anti-IL-13 antibodies can be formulated with suitable carriers or excipients into pharmaceutical compositions suitable for administration to patients. For example, anti-IL-13 antibodies, such as lerechizumab, can be formulated in pharmaceutical compositions as described in WO 2013 / 066866. The pharmaceutical composition may contain 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-IL-13 antibody. In some embodiments, the pharmaceutical composition contains 250 mg to 500 mg of anti-IL-13 antibody. In some embodiments, the pharmaceutical composition contains 250 mg or 500 mg of anti-IL-13 antibody. In some embodiments, the concentration of anti-IL-13 antibody in the pharmaceutical composition is 100 mg / mL to 150 mg / mL, for example, 125 mg / mL. The pharmaceutical composition may also contain a buffer, such as 5 mM-40 mM histidine acetate buffer, pH 5.4 to 6.0. In some embodiments, the pharmaceutical composition further comprises a polyol (e.g., a sugar) at a concentration of 100 mM to 200 mM, and / or a surfactant (e.g., polysorbate 20) at a concentration of 0.01% to 0.1%. In one embodiment, the pharmaceutical composition comprises 125 mg / mL of an anti-IL-13 antibody (e.g., lerechizumab), 20 mM histidine acetate buffer (pH 5.7), 175 mM sucrose, and 0.03% polysorbate 20. In some embodiments, this document provides pharmaceutical compositions comprising an IL-13 inhibitor and a pharmaceutically acceptable carrier or excipient.

[0030] In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient. The anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody may be administered to the patient at a frequency of approximately once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every two weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every four weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every eight weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient every 8 weeks, every 12 weeks, every 24 weeks, every 36 weeks, or every 52 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient about every 8 weeks, about every 12 weeks, about every 24 weeks, about every 36 weeks, or about every 52 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 8 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 12 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 24 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 36 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 52 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 8 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 12 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 24 weeks.In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 36 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 52 weeks.

[0031] In some embodiments, the patient receives treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 24 weeks or longer. In some embodiments, the patient further receives maintenance treatment for approximately 32 weeks or longer. In some embodiments, the patient receives treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 24 weeks, approximately 26 weeks, approximately 28 weeks, approximately 30 weeks, approximately 32 weeks, approximately 34 weeks, approximately 36 weeks, approximately 38 weeks, approximately 40 weeks, approximately 42 weeks, approximately 44 weeks, approximately 46 weeks, approximately 48 weeks, approximately 50 weeks, approximately 52 weeks, approximately 54 weeks, approximately 56 weeks, approximately 58 weeks, or approximately 60 weeks. In some embodiments, the patient receives treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 24 weeks. In some embodiments, the patient receives maintenance treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 32 weeks. In some implementations, patients receive treatment with anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies for approximately 56 weeks.

[0032] In some implementations, patients receive a loading dose of anti-IL-13 antibody, such as a 500 mg loading dose. The loading dose may be administered to the patient several times at the start of treatment. For example, a 500 mg loading dose of anti-IL-13 antibody may be administered at week 0 (baseline) and week 2. After the loading dose, the anti-IL-13 antibody may be administered to the patient at the following doses: 250 mg every two weeks, 250 mg every four weeks, and 250 mg every eight weeks.

[0033] In some implementations, patients receive a loading dose of 500 mg anti-IL-13 antibody at week 0 (baseline) and week 2; followed by a 250 mg dose every two weeks for 24 weeks; and then a 250 mg maintenance dose every four weeks for 32 weeks.

[0034] In some implementations, patients receive a loading dose of 500 mg anti-IL-13 antibody at week 0 (baseline) and week 2; followed by a 250 mg dose every two weeks for 24 weeks; and then a 250 mg maintenance dose every eight weeks for 32 weeks.

[0035] In some implementations, patients receive a loading dose of 720 mg anti-IL-13 antibody at weeks 0 and 2; followed by a 360 mg dose of anti-IL-13 antibody at weeks 4 and 12; and then a maintenance dose of 360 mg anti-IL-13 antibody every 12 weeks for 32 weeks.

[0036] In some implementations, patients receive a loading dose of 720 mg anti-IL-13 antibody at weeks 0 and 2; followed by a 360 mg dose of anti-IL-13 antibody at weeks 4 and 12; and then a maintenance dose of 360 mg anti-IL-13 antibody every 24 weeks for 32 weeks.

[0037] In some embodiments, anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies are administered to a patient using a subcutaneous administration device. The subcutaneous administration device may be selected from pre-filled syringes, disposable pen-type injection devices, microneedle devices, microinfusion devices, needle-free injection devices, or auto-injector devices. Various subcutaneous administration devices, including auto-injector devices, are known in the art and are commercially available. Exemplary devices include, but are not limited to, pre-filled syringes (e.g., BD HYPAK SCF® from Becton Dickinson, READYFILL). TM and STERIFILL SCF TM ;Clearshot from Baxter TM Copolymer prefilled syringes; and DaikyoSeiko CRYSTAL ZENITH® prefilled syringes available from West Pharmaceutical Services; disposable pen-type injection devices, such as the BD pen from Becton Dickinson; ultra-tipped and microneedle devices (such as the INJECT-EASE from Becton Dickinson). TM and micro-infusion devices; and H-PATCH available from Valeritas. TM This includes needle-free injection devices (e.g., BIOJECTOR® and IJECT® available from Bioject; and SOF-SERTER® and patch devices available from Medtronic). In some embodiments, the subcutaneous administration device is an autoinjector device described in WO 2008 / 112472, WO 2011 / 109205, WO 2014 / 062488, or WO 2016 / 089864.

[0038] Before, during, and after treatment, one or more characteristics of the patient can be assessed, identifying certain signs, symptoms, features, or parameters associated with chronic sinusitis with nasal polyps, and can be evaluated quantitatively or qualitatively. These characteristics include, but are not limited to: severity of NCS, endoscopic NPS, LMK score, FEV1, severity of anosmia, postnasal drip score, anosmia, facial pain / pressure, VAS, SNOT-22, UPSIT, ACQ-6, NPIF, EQ-5D-5L, WPAI+CIQ:CRSwNP, PROMIS Anxiety Summary v1.0-Anxiety 8a, PROMIS Depression Summary v1.0-Depression 8a, symptoms of the most severe nasal discharge in the past 24 hours, PGI-S, PGI-C, receipt of systemic corticosteroids during study treatment, receipt of biologics approved for rescue treatment of CRSwNP, and / or the proportion of subjects scheduled to undergo NP surgery, up to the time of event occurrence.

[0039] Nasal congestion score (NCS) was assessed by study participants using a 4-point scale (ranging from 0 to 3), where 0 corresponds to no symptoms and 3 corresponds to severe symptoms, and was collected on the eDiary. Study participants were instructed to record the severity of their nasal congestion symptoms using the eDiary daily at approximately the same time each day (preferably in the morning). The NCS at each assessment time point was the average score over the previous 14 days. Participants were required to complete the assessment for at least 4 out of 7 days each week for 2 weeks prior to randomization.

[0040] The Endoscopic Nasal Polyp Score (NPS) is assessed through centralized, blinded, and independent viewing of nasal endoscopy video recordings. The total score is the sum of the scores for the right and left nasal cavities. An ENT or allergist with clinical research experience, certified to perform flexible nasal endoscopy, and able to obtain and provide interpretable spirometry results; or an allergist who can designate an ENT physician as an associate investigator to perform the NPS assessment. For each nasal cavity, the endoscopic NPS is scored from 0 to 4 based on polyp size, where 0 = no polyp and 4 = large polyp (Department of Health and Human Services (DHHS), Food and Drug Administration, Center for Drug Evaluation and Research. *Industry Guidance: Chronic Sinusitis with Nasal Polyps: Therapeutic Drug Development*. June 2023. Available at: www.fda.gov / media / 154724 / download). Endoscopic NPS was calculated as the average score obtained by two trained physician evaluators reviewing nasal endoscopy videos, with the evaluators remaining blinded regarding the study treatment grouping of the subjects. An adjudication process was in place to address inconsistencies between the two evaluators' results.

[0041] Sinus opacity can be assessed as follows: Central interpretation of sinus computed tomography (CT) scans to obtain a Lund Mackay (LMK) score. CT scans should be performed at the prescribed time points. In some countries, if a specific approval procedure for CT scans is required by another committee besides the local IEC / IRB, subjects may use CT scans performed within the previous year, or sinus MRIs performed between the first and second visits, to meet inclusion criteria. These countries may exempt all planned study CT scans pending approval from these committees. Review of left and right frontal sinus CT scans includes the use of a scoring system. The LMK scoring system uses a 3-point scale, where 0 = normal, 1 = partially opaque, and 2 = completely opaque. The total score is the sum of the scores for each side, ranging from 0 to 24 points, where 0 points indicates no lesion and 24 points indicates the most severe lesion (Lund, VJ, Kennedy, DWStaging for rhinosinusitis. Otolaryngol Head Neck Surg. (1997); 117(3 Pt 2): S35-40). The LMK scoring system scores each side (right and left) of each sinus separately: frontal sinus, maxillary sinus, sphenoid sinus, ostiomeatal complex, anterior ethmoid sinus, and posterior ethmoid sinus.

[0042] Vital capacity measurement is used to measure the physiological airflow in forced expiratory volume in one second (FEV1). At the screening period (first visit), all subjects underwent vital capacity measurement using a study-provided spirometer conforming to American Thoracic Society / European Respiratory Society recommendations, at least 6 hours after discontinuation of their last short-acting bronchodilator. At subsequent visits, vital capacity measurement was performed only on subjects with asthma at specified time points. Normal FEV1 values ​​are typically ≥80% (Barriero, TJ, Anapproach to interpreting spirometry. Am Fam Physician. (2004); 69(5):1107-14). Lower FEV1 values ​​may indicate more severe asthma or airway restriction or obstruction from other causes. Vital capacity measurement should be performed by trained and qualified personnel following the procedures outlined in the study reference manual. Where feasible, research centers should perform vital capacity measurement within ±1 hour of the baseline time point.

[0043] The severity of anosmia was assessed as follows. Through qualitative interviews with individuals with chronic rhinosinusitis (CRS), patient-reported anosmia has been identified as an important and distressing symptom (Hall, R. et al., Understanding the patient experience of severe, recurrent, bilateral nasal polyps: a qualitative interview study in the United States and Germany. ValueHealth.(2020); 23(5):632-41; O'Quinn, S. et al., Measuring the patient experience of chronic rhinosinusitis with nasal polyposis: qualitative development of a novel symptom diary. Int Forum Allergy Rhinol.(2022); 12(8):996-1005) and is recommended as a secondary endpoint by the FDA guidance (DHHS 2023). Study participants scored their anosmia using a 4-point scale, where 0 points corresponded to no symptoms and 3 points to severe symptoms. Participants were asked to record the severity of their loss of smell at its worst point in the past 24 hours. The severity of loss of smell was collected via eDiary.

[0044] Participants used a 4-point scale to rate postnasal drip, with 0 points corresponding to no symptoms and 3 points to severe symptoms. Participants were asked to record the severity of their worst postnasal drip within the past 24 hours. This assessment was collected in the participants' eDiary.

[0045] Participants used a 4-point scale to rate loss of taste, facial pain / pressure, and nasal discharge, with 0 points corresponding to no symptoms and 3 points to severe symptoms. Participants were asked to record the severity of their loss of taste, facial pain / pressure, and nasal discharge at their most severe point within the past 24 hours using an eDiary. The scores for loss of taste, facial pain / pressure, and nasal discharge at each assessment time point were averaged over the past 14 days. Data on loss of taste, facial pain / pressure, and nasal discharge were collected in the eDiary.

[0046] The Visual Analogue Scale (VAS) for chronic sinusitis (CRS) assesses overall disease severity and data can be collected via tablet computer at research centers. Participants were asked to mark their answers to the following question on a 10 cm CRS symptom VAS: “How bothersome have your CRS symptoms been in the past 7 days?” A score of 0 corresponds to “not bothersome at all,” and a score of 10 corresponds to “the most bothersome I can imagine.” The CRS VAS was assessed during specific research visits. Thresholds for disease severity were defined as mild = 0–3, moderate => 3–7, and severe => 7–10 (Fokkens WJ et al., European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Supplement S29):1-464).

[0047] The Sinus and Nasal Outcome Test (SNOT-22) is a validated participant-reported questionnaire used to assess the impact of disease on health-related quality of life. Data can be collected via tablet at research centers. The questionnaire contains 22 questions assessing sinus and ear function, psychological impact, work productivity, and sleep quality. Participants are asked to recall experiences from the past two weeks and rate their symptoms on a scale of 0 (no problem) to 5 (the most severe problem possible). Scores for each question are summed to obtain a total score, ranging from 0 (no disease) to 110 (the most severe disease). Lower scores indicate less impact. A change in score of 8.9 has been identified as the least clinically significant difference (Hopkins, C. et al., Psychometric validity of the 22-item Sinonasal Outcome Test. Clinical Otolaryngology. (2009); https: / / doi.org / 10.1111 / j.1749-4486.2009.01995.x.).

[0048] The University of Pennsylvania Olfactory Identification Test (UPSIT) is a subject-reported assessment of olfactory function that uses a “scratch and sniff” test with 10 odorants. The scoring range is 0 to 40 points, where: <18 points is equivalent to anosmia (complete loss of smell); 19-25 points = severe olfactory hyposmia; 26-30 points = moderate olfactory hyposmia; 31-34 points = mild olfactory hyposmia; 35-40 points = normal olfactory perception (Doty, RL, Olfactorydysfunction and its measurement in the clinic. World J. Otorhinolaryngol HeadNeck Surg. (2015); 1(1):28-33; Doty, RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol. Behav. (1984); 32(3):489-502).

[0049] The Asthma Control Questionnaire-6 (ACQ-6) is a validated participant-reported questionnaire containing six questions to assess the most common asthma symptoms. Data is collected via tablet computer only from participants with asthma at research centers. Questions include: asthma arousal; symptoms upon waking; activity limitation; shortness of breath; wheezing; and use of inhalers / inhalers. Participants with a history of asthma are asked to recall their asthma control over the past week and answer questions using a 7-point scale, where 0 corresponds to no impairment and 6 corresponds to maximum impairment. The ACQ-6 score is calculated by averaging the scores of each question to arrive at a total control score (out of 6), where 0 corresponds to complete asthma control and 6 corresponds to severe asthma out of control. The minimum clinically significant difference in the ACQ-6 was defined as a change of 0.5 points (Juniper, EF et al., Development and validation of a questionnaire to measure asthma control. Eur Respir J. (1999); 14(4):902-7; Juniper, EF et al., Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. (2005); 99(5):553-8).

[0050] Nasal peak inspiratory flow (NPIF) was measured as the maximum inspiratory flow rate through both nostrils during inspiration, expressed in L / min. An NPIF result >120 L / min indicated the absence of nasal obstruction (Mo, S. et al., Nasal peak inspiratory flow in healthy and obstructed patients: systematic review and meta-analysis. Laryngoscope. (2021); 131(2):260-7). NPIF was performed at specified time points, and the highest of three readings was taken. NPIF measurements should be performed by trained and qualified personnel according to the procedures outlined in the study reference manual.

[0051] The European Five-Dimensional Quality of Life Scale (EQ-5D-5L) is a universal questionnaire for assessing health status, and data can be collected at research centers via tablet computers. The questionnaire contains a descriptive system consisting of five dimensions (mobility, self-care ability, daily activities, pain / discomfort, and anxiety / depression), with each dimension graded on a scale of five: no problem, minor problem, moderate problem, severe problem, and very severe problem. The questionnaire also includes a VAS scale, in which respondents self-assess their health status on the vertical VAS, with the two ends being “the best health status you can imagine” and “the worst health status you can imagine” (EuroQol Group. EuroQol - A new tool for measuring health-related quality of life. HealthPolicy. (1990); 16(3):199-208; Herdman, M. et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. (2011); 20(10):1727-36; Remenschneider, AK et al., The EQ-5D: a new tool for studying clinical outcomes in chronic rhinosinusitis. Laryngoscope. (2015); 125(1):7-15).

[0052] The Work Productivity and Activity Disorders Plus Classroom Disorders Questionnaire: CRSwNP (WPAI+CIQ:CRSwNP) is a patient-reported tool used to assess the degree of impairment in work, classroom, and daily activities experienced by patients with CRSwNP; data can also be collected on tablets at research centers. The questionnaire contains 10 items assessing the following: employment status; time missed due to CRSwNP; time missed due to other reasons; actual working hours; the impact of CRSwNP on productivity during work; attendance in an academic setting; number of class hours missed due to CRSwNP; actual attendance / class hours; the impact of CRSwNP on productivity in the classroom environment; and the impact of CRSwNP on daily activities. WPAI+CIQ:CRSwNP provides four subgroup scores: absenteeism rate (time missed at work or in class); attendance rate (degree of impairment at work or in class / reduction in productivity during work); loss of work productivity (total work or classroom impairment / absenteeism rate plus attendance rate); and activity disorder. The score is calculated as the percentage of impairment (Reilly, MC, Zbrozek, AS, Dukes, EM The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. (1993); 4(5):353-65). The higher the value, the greater the degree of impairment and the lower the productivity, that is, the worse the outcome.

[0053] The PROMIS Anxiety Short Scale v1.0 - Anxiety 8a can be used in the general population and individuals with chronic diseases. The PROMIS Anxiety Item Registry assesses self-reported fears (fear, panic), anxiety distress (worry, apprehension), hyperarousal (nervousness, nervousness, restlessness), and arousal-related physical symptoms (palpitations, dizziness). The PROMIS Anxiety Short Scale 8a (v1.0) contains 8 questions to assess the subject's symptoms over the past 7 days. Response options range from 1=Never; 2=Rarely; 3=Sometimes; 4=Often; 5=Always. The raw total score is converted to a T-score, with higher scores indicating greater anxiety severity (PROMIS Anxiety Scale 2019, published: March 1, 2019. Accessed: March 8, 2021. Access URL: https: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Anxiety_Scoring_Manual.pdf).

[0054] The PROMIS Depression Short Scale v1.0-Depression 8a can be used in the general population and individuals with chronic illnesses. The PROMIS Depression Scale assesses self-reported negative emotions (sadness, guilt), self-perceptions (self-criticism, feelings of worthlessness), and social cognitions (loneliness, social isolation), as well as decreased positive affect and engagement (loss of interest, meaning, and purpose). The PROMIS Depression Short Scale 8a (v1.0) contains eight questions to assess symptoms experienced by the subject over the past seven days. Response options range from 1=Never; 2=Rarely; 3=Sometimes; 4=Often; 5=Always. The raw total score is converted to a T-score, with higher scores indicating more severe depression (PROMIS Depression Scale 2019, published February 28, 2019. Accessed March 8, 2021. Access URL: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Depression_Scoring_Manual.pdf).

[0055] We collected Patient Global Impression Severity (PGI-S) and Patient Global Impression Change (PGI-C) scales to facilitate the assessment of the clinical significance of changes in nasal congestion, anosmia, and postnasal drip in subjects.

[0056] PGI-S: Nasal Congestion. Participants are asked to assess the overall severity of nasal congestion due to chronic sinusitis in the past 14 days. The answer options are: asymptomatic, mild, moderate, severe, and very severe.

[0057] PGI-S: Loss of smell, which asks participants to assess the overall severity of loss of smell due to chronic sinusitis in the past 14 days. The answer options are: asymptomatic, mild, moderate, severe, and very severe.

[0058] PGI-S: Postnasal drip, which asks participants to assess the overall severity of postnasal drip due to chronic sinusitis in the past 14 days. The answer options are: asymptomatic, mild, moderate, severe, and very severe.

[0059] PGI-C: Nasal Congestion. Subjects are asked to describe the overall change in nasal congestion caused by chronic sinusitis since starting to take the new medication. The answer options are: significant improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and significant worsening.

[0060] PGI-C: Loss of smell. Subjects are asked to describe the overall change in their loss of smell due to chronic sinusitis since they started taking the new medication. The answer options are: significant improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and significant worsening.

[0061] PGI-C: Postnasal drip. Subjects are asked to describe the overall change in postnasal drip due to chronic sinusitis since starting to take the new medication. The answer options are: significant improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and significant worsening.

[0062] The proportion of subjects receiving systemic corticosteroids, approved biologics for rescue treatment of CRSwNP, and / or scheduled for nasal polyp (NP) surgery during study treatment, and the time to event occurrence, were assessed as follows. Systemic corticosteroids (SCS) for rescue treatment of nasal polyps or for other reasons were prescribed by the research center in accordance with local laws and regulations and as needed. Patient-reported outcome (PRO) assessments and nasal endoscopy should be completed before initiating SCS treatment. The investigator (or their designated person) recorded the date and dosing information on the appropriate page of the eCRF. The indication for SCS use was recorded as a relevant AE or medical history. Approved biologics for rescue treatment of CRSwNP or for other reasons were prescribed by the research center in accordance with local laws and regulations and as needed. PRO and nasal endoscopy should be performed before initiating treatment with the approved biologic. The investigator (or their designated person) recorded the date and dosing information (daily dose, duration, INP name) on the appropriate page of the eCRF. The indication for biologic use was also recorded as a relevant AE or medical history. For subjects who have undergone or plan to undergo NP sinus surgery, the surgical decision date and surgical date (if applicable) should be recorded. PRO assessment and nasal endoscopy should be performed prior to surgical rescue. Surgical data should be collected during subject safety follow-up (SFU) visits.

[0063] These characteristics can be measured at baseline and at one or more time points after administration of the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody. For example, they can be measured at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer after initial treatment with the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody. The difference between the values ​​at specific time points after initial treatment and the baseline values ​​is used to determine whether the characteristic has improved (e.g., decreased).

[0064] On the other hand, this invention provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for the treatment of chronic sinusitis with nasal polyps. The invention also provides the use of the anti-IL-13 antibody in the preparation of a medicament for the treatment of chronic sinusitis with nasal polyps.

[0065] As used herein, unless otherwise stated herein or clearly contradicted by the context, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (especially in the context of the claims) shall be construed as covering both the singular and the plural.

[0066] As used herein, the term “about” means within a reasonable range of the value, such as within ±10% of the value.

[0067] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Antibody implementations include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugated antibodies. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0068] An exemplary antibody is an immunoglobulin G (IgG) antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC), which are cross-linked by interchain disulfide bonds. Each of the four polypeptide chains has an amino-terminal region comprising a variable region of approximately 100-125 or more amino acids, primarily responsible for antigen recognition. Each of the four polypeptide chains also has a carboxyl-terminal region containing a constant region primarily responsible for effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further subdivided into subtypes (e.g., IgG1, IgG2, IgG3, and IgG4).

[0069] The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), within which more conserved regions called framework regions (FRs) are scattered. CDRs are exposed on the protein surface and are crucial regions for antigen-binding specificity of antibodies. Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this paper, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," while the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain most of the residues that specifically interact with the antigen. The assignment of amino acid residues in the CDR can be determined using well-known schemes, including those described below: Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Maryland (1991)); Chothia (Chothia et al., Canonical structures for the hypervariable regions of immunoglobulins, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., Standard conformations for the canonical structures of immunoglobulins, Journal of Molecular Biology, 273, 927-948 (1997)); North (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406, 228-256) (2011)); or IMGT (International Immunogenetics Database, accessed at www.imgt.org; see Lefranc et al., Nucleic Acids Res. (1999); 27:209-212).

[0070] Exemplary embodiments of the antibodies disclosed herein also include antibody fragments or antigen-binding fragments comprising at least a portion of an antibody that retains the ability to specifically interact with an antigen, such as Fab, Fab', F(ab')2, Fv fragments, scFv, scFab, disulfide-linked Fvs(sdFv), Fd fragments, and linear antibodies.

[0071] As used herein, the term "anti-IL-13 antibody" refers to an antibody that specifically binds to human IL-13. In some embodiments, the anti-IL-13 antibody binds to human IL-13 with a dissociation constant (KD) ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, or ≤ 0.01 nM (e.g., 10 nM). -8 M or smaller, or 10 -9 M or smaller).

[0072] As used herein, the term “baseline” means before or at the time of administration of the first dose of anti-IL-13 antibody or a pharmaceutical composition containing anti-IL-13 antibody (week 0).

[0073] Unless otherwise stated, the term "binding" and its grammatical variations as used herein refer to the ability of one protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, such interaction causing the two proteins or molecules to come close to each other (as determined by conventional methods known in the art).

[0074] The "effective amount" of a drug agent refers to the amount that, within the necessary dosage and time period, is sufficient to achieve the desired therapeutic effect.

[0075] Unless otherwise stated, the term “IL-13” as used herein refers to any interleukin-13 isoform derived from humans. This term includes “full-length”, unprocessed IL-13, and any form of IL-13 produced by cell processing. It also includes naturally occurring IL-13 variants, such as splice variants or allelic variants. Exemplary amino acid sequences of human IL-13 are known, for example, NCBI accessions NP_002179.2, NP_001341920.1, NP_001341921.1, NP_001341922.1; UniProtKB accession number P35225.

[0076] The term "loading dose" refers to the dose of medication given at the start of treatment that is higher than the doses given subsequently and at each subsequent dose during the remainder of treatment.

[0077] "Maintenance dose" refers to the subsequent dose of medication given to a patient in order to maintain or prolong the expected therapeutic effect.

[0078] As used in this article, the term "patient" refers to a human patient.

[0079] As used herein, “treatment” and its grammatical variations refer to all processes aimed at slowing, controlling, delaying, or stopping the progression of the symptoms or disease disclosed herein, or improving the symptoms or disease of the condition, but this does not necessarily mean the complete elimination of all symptoms or disease of the condition. Treatment includes the administration of proteins, nucleic acids, carriers, or compositions to treat a patient’s (particularly human) disease or condition.

[0080] Example

[0081] Example 1. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluating the efficacy and safety of lerechizumab in subjects with chronic sinusitis and nasal polyps who were receiving background treatment with intranasal corticosteroids.

[0082] This is a phase III, multinational, multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial designed to evaluate the efficacy and safety of lerechizumab in patients with chronic rhinosinusitis (CRS) and bilateral nasal polyps (NP) who were receiving background treatment with intranasal corticosteroids (INCS).

[0083] Approximately 510 adult subjects (≥18 years old) with CRS and bilateral nasal polyps were enrolled.

[0084] This study has four phases: a screening period (maximum 30 days), an induction period (4 weeks), a randomized treatment period (56 weeks, including an induction period (24 weeks; week 0 to week 24) and a maintenance period (32 weeks; week 24 to week 56)), and a safety follow-up period (SFU, 8 weeks, starting after the week 56 visit). The longest planned duration of participation for each participant in this study is approximately 72 weeks.

[0085] Goals and endpoints: The primary, secondary, and exploratory objectives and endpoints of this study are shown in Table 2.

[0086] Table 2 Goals and Endpoints

[0087] patient group

[0088] The inclusion and exclusion criteria for subjects enrolled in this study are described in the following sections.

[0089] Inclusion criteria Each participant must meet all of the following criteria to be enrolled in this study: 1. Adult subjects were ≥18 years old when signing the informed consent form (ICF), and adolescent subjects were ≥12 to <18 years old and weighed ≥40 kg at the first visit.

[0090] 2. CRS diagnosed by physician with bilateral NP.

[0091] 3. Within the past two years, the patient has received SCS treatment for CRS or CRSwNP (or has medical contraindications or intolerance to systemic corticosteroids), has undergone nasal polyp surgery, or both.

[0092] 4. Bilateral endoscopic NPS scores performed during the screening period (first visit) and the baseline period (third visit) must have a total score of at least 5 points (out of 8), with a minimum score of 2 points for each nasal cavity.

[0093] 5. Symptoms that persisted for at least 8 weeks prior to entering the study (screening period [first visit]), including: a. Having moderate to severe nasal congestion symptoms (score 2 or 3) during the screening period (first visit) (first visit is a single-day assessment), and having a weekly mean severity score of at least 1 (range 0 to 3) at randomization (average of the 14 days prior to baseline at the third visit), and b. At least one other symptom, such as, but not limited to, partial loss of smell (hypopnea), complete loss of smell (anosmia), or anterior or posterior nasal discharge.

[0094] 6. Subjects with comorbid asthma must have been on permitted routine asthma treatment and have stable conditions for 3 months prior to screening.

[0095] 7. Subjects must complete at least 4 out of 7 days of eDiary within 2 weeks prior to the randomized group visit (3rd visit [baseline]).

[0096] 8. Women of childbearing potential (WOCBP) must use at least one highly effective method of contraception, or a combination of two effective methods of contraception that comply with local regulations regarding contraceptive methods for clinical trial participants.

[0097] 9. Parents / legal guardians of adult or adolescent subjects must understand the nature of this study and sign a written informed consent form approved by the Institutional Ethics Committee (IEC) / Institutional Review Board (IRB) before undergoing any study-related procedures. Adolescent subjects must also understand the nature of the study and sign an informed consent form in accordance with local regulations before undergoing any study-related procedures.

[0098] 10. Willing and able to comply with all clinical visits, research-related procedures and questionnaires, especially including receiving the required background treatment and completing the eDiary daily.

[0099] Exclusion criteriaParticipants meeting any of the following criteria will be excluded from this study: 1. Previously received Regizumab.

[0100] 2. Currently enrolling any other clinical study involving the investigational drug, or any other type of medical investigator deemed scientifically or medically incompatible with this study.

[0101] 3. Individuals who received the study drug within 8 weeks prior to randomization or within 5 half-lives (whichever is longer).

[0102] 4. Patients with known hypersensitivity to levothyroxine or its excipients.

[0103] 5. Those with contraindications or intolerance to mometasone furoate.

[0104] 6. Individuals who have received leukotriene receptor antagonist treatment within 4 weeks prior to the screening period (first visit).

[0105] 7. Individuals who have received any rescue treatment medication and / or require nasal polyp surgery during the screening and / or induction period.

[0106] 8. Allergen immunotherapy (subcutaneous immunotherapy [SCIT] / sublingual immunotherapy [SLIT]) started within 6 months prior to screening, and is not at a stable dose (3 months prior to screening [first visit]) or may require dose adjustment during the study.

[0107] 9. Individuals who have previously or currently received biologic therapy for CRSwNP and / or asthma and / or AD, including but not limited to omalizumab, dupilumab, mepolizumab, relizumab, and benalizumab.

[0108] 10. Prior to the baseline visit (3rd visit; randomization), the patient had received any biologics or systemic immunosuppressants for inflammatory or autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis).

[0109] a. Use of B-cell depleting biologics, including rituximab, within the past 6 months.

[0110] b. Other biological agents used within 5 half-lives (if known) or 8 weeks (whichever is longer).

[0111] c. Use of systemic immunosuppressants within 4 weeks prior to the baseline period (3rd visit).

[0112] 11. Have undergone any sinus or intranasal surgery (including nasal polyp removal) within 6 months prior to the screening period (first visit).

[0113] 12. Previous sinus surgery (including sinus surgery that alters the lateral wall structure of the nasal cavity) makes it difficult to assess endoscopic NPS.

[0114] 13. History of severe acute asthma exacerbation within the past year and a record of using SCS for asthma within the past 12 months.

[0115] 14. Any of the following circumstances that may affect the endpoint assessment exist during the screening period (first visit) or the baseline period (third visit): a. Nasal septum deviation causes obstruction of at least one nostril.

[0116] b. Posterior nasal polyps of the sinuses.

[0117] c. Acute sinusitis, acute nasal infection, or acute upper respiratory tract infection.

[0118] d. Persistent drug-induced rhinitis.

[0119] e. Another diagnosis associated with nasal polyps exists (i.e., eosinophilic granulomatous polyangiitis, granulomatous polyangiitis, Young's syndrome, primary ciliary dyskinesia, cystic fibrosis).

[0120] f. Nasal cavity tumors (malignant or benign).

[0121] g. Evidence of fungal sinusitis.

[0122] 15. Received any live or attenuated live vaccine (including BCG vaccination or treatment) within 4 weeks prior to baseline (3rd visit), or plan to receive an attenuated live vaccine (or BCG treatment) during the study period and within 4 weeks of the last administration of the investigational drug (IP). The following are not considered live vaccines: messenger RNA vaccines, vaccines containing inactivated virus components, and / or non-replicating viral vector vaccines. Researchers should assess whether adolescent subjects' immunization status meets local vaccination guidelines before enrollment in the study. For adolescents with unmet vaccination targets, researchers should document the benefit / risk basis for enrolling them in the study.

[0123] 16. History of HIV infection or positive HIV serology.

[0124] 17. Currently has active or chronic HBV infection (i.e., positive for hepatitis B surface antigen [HBsAg] and / or positive for polymerase chain reaction).

[0125] 18. Currently infected with hepatitis C virus (HCV) (HCV RNA positive).

[0126] 19. Known to have cirrhosis and / or chronic hepatitis of any cause.

[0127] 20. Be diagnosed with an active endoparasitic infection, or be at high risk of such an infection.

[0128] 21. A known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, Pneumocystis pneumonia, and aspergillosis), even if the infection has been cured; or, in the investigator's judgment, a history of unusually frequent, recurrent, or persistent infections.

[0129] 22. Any of the following types of infection occurred within 3 months prior to screening, or occurred during the screening or introduction period: a. Severe infection (requiring hospitalization and / or treatment with IV or equivalent oral antibiotics).

[0130] b. Opportunistic infections.

[0131] c. Individuals with symptomatic herpes zoster infection that has not yet healed during the screening period. Note: Herpes zoster is considered to be in an active and persistent state until all blisters have dried and crusted over.

[0132] d. Chronic (symptoms, signs, and / or treatment lasting 6 weeks or longer)

[0133] e. Recurrent (including but not limited to recurrent cellulitis, chronic osteomyelitis). Note: Subjects with only recurrent, mild, and uncomplicated oral herpes and / or genital herpes may be admitted with the discretion of the medical monitor.

[0134] 23. Subjects with an active or acute infection requiring systemic antibiotics, antiviral drugs, antiparasitic drugs, antiprotozoal drugs, or antifungal drugs within two weeks prior to baseline (third visit). Note: Subjects may be screened again after infection resolution. Subjects with vaginal or oral candidiasis who are receiving only symptomatic treatment and do not require systemic anti-infective medication may be considered for inclusion in the study, provided they meet other study inclusion criteria. Inclusion of subjects with other uncomplicated localized infections should be discussed with the sponsor-designated medical monitor.

[0135] 24. History of malignant tumors within 5 years prior to screening (exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has received adequate treatment, and cervical carcinoma in situ).

[0136] 25. Having any other medical or psychological condition that, in the researcher's opinion, may suggest the presence of a new and / or not yet fully understood disease, may pose an unreasonable risk to the participant's participation in this clinical study, may lead to unreliable participation, or may interfere with the study evaluation.

[0137] 26. Suffering from serious comorbidities that researchers believe would adversely affect participation in the study.

[0138] 27. Loss of smell due to COVID or any cause other than CRSwNP.

[0139] 28. Subjects who have recently undergone nasal perforation that has not yet fully healed, who may experience nasal symptoms during the screening period (first visit), or who plan to undergo a new nasal perforation during the study period.

[0140] 29. Subjects whose FEV1 is less than or equal to 50% of the predicted normal value during the screening period (first visit).

[0141] 30. Subjects whose laboratory test results are clinically significant and abnormal at the screening period (first visit) or baseline period (third visit) are considered by the researchers to be abnormal.

[0142] 31. Female subjects who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study period.

[0143] 32. Eli Lilly employees, family members of Eli Lilly employees, or employees of any third-party organization involved in this study who need to be excluded.

[0144] 33. Research center staff members directly subordinate to this study and their immediate family members, where immediate family members are defined as spouses, parents, children, or siblings (whether biological or legally adopted).

[0145] 34. The subject or caregiver is unable or unwilling to remain engaged throughout the study, or is unwilling to comply with study restrictions and procedures (including subcutaneous administration of study drugs).

[0146] 35. Individuals with a history of chronic alcoholism, intravenous drug abuse, or other illicit drug abuse within the two years prior to screening.

[0147] 36. Based on the researcher's judgment, other aspects are unsuitable for inclusion in this study.

[0148] Research drugs:

[0149] The pharmaceutical composition containing 125 mg / mL lerechizumab or placebo is provided in the form of a sterile pre-filled syringe equipped with a pre-loaded needle safety device (PFS-NSD) for subcutaneous administration to patients. The lerechizumab sequence is provided in Table 1. The placebo solution is identical in appearance and volume to the active solution, except that it does not contain lerechizumab.

[0150] INCS mometasone furoate nasal spray is administered at a dose of 200 μg (2 sprays per nostril) twice daily.

[0151] Research Design: The research design of this experiment is as follows: Figure 1 As shown.

[0152] Subjects meeting the inclusion and exclusion criteria were randomly assigned to the following treatment groups in a 1:1:1 ratio at the baseline visit (3rd visit): Lerechizumab Q2W / Q4W group: Lerechizumab 500 mg loading dose was administered in weeks 0 and 2, followed by 250 mg Q2W until week 24 (induction period), and then 250 mg Q4W until week 56 (maintenance period).

[0153] Lerechizumab Q2W / Q8W group: Lerechizumab 500 mg loading dose was administered in weeks 0 and 2, followed by 250 mg Q2W until week 24 (induction period), and then 250 mg Q8W until week 56 (maintenance period).

[0154] PBO group: placebo Q2W to week 24 (induction period), then placebo Q4W to week 56 (maintenance period).

[0155] Adolescent subjects were enrolled using an open-label approach, and all adolescents were assigned to the lericizumab Q2W / Q4W treatment group.

[0156] Adult subjects were randomized using a fixed-block randomization method and stratified according to the following factors: asthma and / or aspirin-induced respiratory disease (AERD) versus no asthma / no ARD; history of nasal polyp surgery versus no history of nasal polyp surgery; geographic region (North America, Europe, other parts of the world).

[0157] The treatment groups were completely blinded by the participants, researchers, and research center staff.

[0158] All participants received intranasal mometasone furoate treatment at the start of the 4-week introduction period and throughout the randomized treatment period (week 0 to week 56). During the safety follow-up (SFU) period, investigators may decide whether participants should continue using mometasone furoate.

[0159] Statistical analysis was performed on primary, secondary, and exploratory endpoints.

Claims

1. A method for treating chronic sinusitis with nasal polyps in a patient in need, the method comprising administering a therapeutically effective amount of an anti-IL-13 antibody to the patient, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

2. A method for treating chronic sinusitis with nasal polyps, the method comprising: Select patients with chronic sinusitis and nasal polyps, and The patient is given a therapeutically effective amount of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and the VL comprises LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO:

6.

3. The method according to claim 1 or 2, wherein the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO:

8.

4. The method according to any one of claims 1-3, wherein the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO:9 and a light chain as shown in SEQ ID NO:

10.

5. The method according to any one of claims 1-4, wherein the anti-IL-13 antibody is lerechizumab.

6. The method according to any one of claims 1-5, wherein the anti-IL-13 antibody is administered subcutaneously to the patient.

7. The method according to any one of claims 1-6, wherein the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg.

8. The method according to any one of claims 1-7, wherein the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks.

9. The method of claim 8, wherein the patient further receives a loading dose of the anti-IL-13 antibody of 500 mg.

10. The method of claim 9, wherein the loading dose is administered to the patient in week 0 and week 2.

11. The method according to any one of claims 1-10, wherein the patient receives treatment with the anti-IL-13 antibody for approximately 24 weeks.

12. The method according to any one of claims 1-11, wherein the patient further receives maintenance therapy for approximately 32 weeks.

13. The method of claim 12, wherein during the maintenance period, the patient receives a maintenance dose of 250 mg of anti-IL-13 antibody every 4 weeks.

14. The method of claim 12, wherein during the maintenance period, the patient receives a maintenance dose of 250 mg of anti-IL-13 antibody every 8 weeks.

15. The method according to any one of claims 1-14, further comprising determining the severity score of the patient's nasal congestion symptoms (NCS) before, during and after the treatment.

16. The method according to any one of claims 1-14, further comprising determining the endoscopic nasal polyp score (NPS) of the patient before, during and after the treatment.

17. The method according to any one of claims 1-16, wherein the anti-IL-13 antibody is administered to the patient using a subcutaneous administration device.

18. The method of claim 17, wherein the subcutaneous application device is selected from a pre-filled syringe, a disposable pen injection device, a microneedle device, a micro-infusion device, a needle-free injection device, or an auto-injector device.

19. The method according to any one of claims 1-18, further comprising administering an intranasal corticosteroid to the patient.

20. The method of claim 19, wherein the intranasal corticosteroid is mometasone furoate.

21. The method of claim 19 or 20, wherein the intranasal corticosteroid and the anti-IL-13 antibody are administered simultaneously, in parallel, or sequentially.

22. The method according to any one of claims 1-21, wherein the patient has bilateral nasal polyps.

23. The method according to any one of claims 1-22, wherein the patient has a bilateral NPS score of at least 5 points (out of 8) under endoscopy before treatment, and the score of each nasal cavity is not less than 2 points.

24. The method according to any one of claims 1-23, wherein the patient suffers from nasal congestion and is accompanied by at least one other symptom selected from hyposmia, anosmia, anterior nasal discharge, or posterior nasal discharge.

25. The method according to any one of claims 1-24, wherein the patient is 18 years of age or older.

26. An anti-IL-13 antibody for treating chronic sinusitis with nasal polyps, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

27. A pharmaceutical composition comprising an anti-IL-13 antibody for treating chronic sinusitis with nasal polyps, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

28. Use of an anti-IL-13 antibody in the preparation of a medicament for treating chronic sinusitis with nasal polyps, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

29. An anti-IL-13 antibody for the use of claim 26, wherein the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO:

8.

30. An anti-IL-13 antibody for the use of claim 26 or 29, wherein the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO:

10.

31. An anti-IL-13 antibody for use as described in claim 26, 29 or 30, wherein the anti-IL-13 antibody is lerechizumab.

32. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-31, wherein the anti-IL-13 antibody is administered subcutaneously.

33. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-32, wherein the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg.

34. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-33, wherein the anti-IL-13 antibody is administered subcutaneously at a dose of 250 mg every two weeks.

35. An anti-IL-13 antibody for use as claimed in any one of claims 34, wherein the anti-IL-13 antibody is further administered at a loading dose of 500 mg.

36. An anti-IL-13 antibody for use as claimed in claim 35, wherein the loading dose is administered at week 0 and week 2.

37. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-36, wherein the anti-IL-13 antibody is administered for a period of approximately 24 weeks.

38. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-37, wherein the anti-IL-13 antibody is further administered for a maintenance period of approximately 32 weeks.

39. An anti-IL-13 antibody for use as claimed in claim 38, wherein the anti-IL-13 antibody is administered at a dose of 250 mg of the anti-IL-13 antibody every 4 weeks during the maintenance period.

40. An anti-IL-13 antibody for use as claimed in claim 38, wherein the anti-IL-13 antibody is administered at a dose of 250 mg of the anti-IL-13 antibody every 8 weeks during the maintenance period.

41. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-40, further comprising determining the severity score of the patient’s nasal congestion symptoms (NCS) before, during and after treatment.

42. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-41, further comprising determining the endoscopic nasal polyp score (NPS) of the patient before, during and after treatment.

43. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-42, wherein the anti-IL-13 antibody is administered using a subcutaneous administration device.

44. An anti-IL-13 antibody for the use of claim 43, wherein the subcutaneous administration device is selected from a prefilled syringe, a disposable pen injection device, a microneedle device, a microinfusion device, a needle-free injection device, or an auto-injector device.

45. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-44, further comprising administration of an intranasal corticosteroid.

46. ​​An anti-IL-13 antibody for use as claimed in claim 45, wherein the intranasal corticosteroid is mometasone furoate.

47. An anti-IL-13 antibody for use as claimed in claim 45 or 46, wherein the intranasal corticosteroid and the anti-IL-13 antibody are administered simultaneously, in parallel, or sequentially.

48. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-47, wherein the patient has bilateral nasal polyps.

49. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-48, wherein the patient has a bilateral NPS score of at least 5 (out of 8) on endoscopy prior to treatment, and a score of not less than 2 for each nasal cavity.

50. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-49, wherein the patient suffers from nasal congestion and is accompanied by at least one other symptom selected from hyposmia, anosmia, anterior nasal discharge, or posterior nasal discharge.

51. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-49, wherein the patient is 18 years of age or older.

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