TW202544035A - Il-13 antibodies for the treatment of perennial allergic rhinitis - Google Patents

Abstract

Provided herein are methods and uses of antibodies that specifically bind human IL-13 (“anti-IL-13 antibodies”) for treating perennial allergic rhinitis.

Description

IL-13 antibodies used to treat perennial allergic rhinitis

This invention relates to a method and use of an antibody that specifically binds to human interleukin (IL)-13 ("anti-IL-13 antibody") for the treatment of perennial allergic rhinitis (PAR).

Allergic rhinitis perennial (PAR) is a type 2 inflammatory mediated disease (Giavina-Bianchi P et al., United airway disease: current perspectives. J Asthma Allergy. 2016;9:93-100). Studies using samples collected from patients with allergic rhinitis (AR) have shown that IL-13 levels in the nasal mucosa and nasal secretions increase after allergen exposure (Baumann, R. et al., The release of IL-31 and IL-13 after nasal allergen challenge and their relation to nasal symptoms. Clin Transl Allergy. 2012;2(1):13). Another study found that, compared with non-allergic controls, AR patients had higher levels of serum Th2 intercytokine transcripts, especially IL-13 and IL-13RA1 (Nur Husna S.M. et al., IL-4/IL-13 axis in allergic rhinitis: elevated serum cytokines levels and inverse association with tight junction molecules expression. Front Mol Biosci. (2022); 9:819772).

Symptoms of PAR include nasal congestion, nasal itching, and sleep disturbances. Diagnosis is usually based on the presence of characteristic PAR symptoms, risk factors, and physical examination, and can be supported by skin testing for specific IgE from airborne allergens (Dykewicz, M.S. et al., Rhinitis 2020: a practice parameter update. J Allergy Clin Immunol. (2020); 146(4):721-67).

The primary treatment options for PAR are nasal endothelial steroids (INCS), along with other options including antihistamines (oral and intranasal), mast cell stabilizers, leukotriene modulators, and allergen immunotherapy (AIT) (Dykewicz et al., 2020). However, these therapies have limitations and may not adequately treat daily symptoms in some patients. Although INCS is the most effective treatment for most PAR patients, it often causes bothersome local side effects such as nosebleeds, raises concerns about potential growth restriction in children, and causes unpleasant aftertaste and throat discomfort, which can affect patient preference and compliance (Seidman, M.D. et al., Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg. (2015); 152(1 Supplement):S1-43; Mener, D.J. et al., Topical intranasal corticosteroids and growth velocity in children: a meta-analysis. Int Forum Allergy Rhinol. (2015); 5(2):95-103; Meltzer, E.O., Formulation considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. (2007); 98(1):12-21). Although AIT is an option for patients with symptom-refractory disease, it does not indicate that AIT is suitable for all patients, and non-compliance rates have been reported to be as high as 90%, with most patients only completing one year of the recommended three to five-year course of treatment required for long-term efficacy (Roberts, G. et al., EAACI guidelines on allergen immunotherapy: allergic rhinoconjunctivitis. Allergy. (2018); 73(4):765-98; Mao J et al., Cost of subcutaneous immunotherapy in a large insured population in the United States. Curr Med Res Opin. (2019); 35(2):351-8.). Although existing treatments are available, many patients with PAR do not achieve adequate control with standard care, resulting in a significant residual economic burden (Hellings, P.W. et al., A common language to assess allergic rhinitis control: results from a survey conducted during EAACI 2013 Congress. Clin Transl Allergy. (2015); 5:36; Dykewicz et al., 2020).

There is still a need for alternative and effective therapies for treating PAR. There is also a need to provide patients with more tolerable, convenient, and lower-risk treatment and medication regimens to improve patient compliance and satisfaction.

This article provides information on the methods and uses of anti-IL-13 antibodies, such as lebrikizumab (i.e., antibodies that specifically bind to human IL-13), or pharmaceutical compositions containing anti-IL-13 antibodies, for the treatment of perennial allergic rhinitis.

In one embodiment, this article provides methods for treating perennial allergic rhinitis in patients in need, methods comprising administering a therapeutically effective dose of anti-IL-13 antibodies to the patient. In some embodiments, this article provides methods for treating perennial allergic rhinitis, methods comprising: selecting a patient suffering from perennial allergic rhinitis and administering a therapeutically effective dose of anti-IL-13 antibodies to the patient.

In another embodiment, this article provides an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for the treatment of perennial allergic rhinitis. This article also provides the use of the anti-IL-13 antibody in the manufacture of a medicament for the treatment of perennial allergic rhinitis.

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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises: VH comprising SEQ ID NO: 7 and VL comprising SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises: VH comprising SEQ ID NO: 11 and VL comprising SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises: a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14. In some embodiments, the anti-IL-13 antibody is a levozomonab. In some embodiments, the anti-IL-13 antibody comprises the VH sequence described in SEQ ID NO: 11, the VL sequence described in SEQ ID NO: 12, and the human IgG sequence described in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises the VH sequence described in SEQ ID NO: 11, the VL sequence described in SEQ ID NO: 12, the human IgG sequence described in SEQ ID NO: 15, and the constant light chain sequence described in SEQ ID NO: 16.

In some practices, anti-IL-13 antibodies are administered subcutaneously to patients. In some practices, anti-IL-13 antibodies are administered at doses ranging from 250 mg to 500 mg. In some practices, anti-IL-13 antibodies are administered subcutaneously to patients at a dose of 250 mg every two weeks. In some practices, patients are further treated with a loading dose of 500 mg anti-IL-13 antibodies. In some practices, patients are given one or two loading doses. In some practices, patients are given loading doses at week 0 (baseline) and week 2. In some practices, patients are treated with anti-IL-13 antibodies for approximately 16 weeks.

In some practices, patients are further treated for a maintenance period of approximately 40 weeks. In some practices, patients are treated with a maintenance dose of 250 mg anti-IL-13 antibody every four weeks during the maintenance period. In some practices, patients are treated with a maintenance dose of 250 mg anti-IL-13 antibody every eight weeks during the maintenance period.

In some practices, patients were treated with a 500 mg anti-IL-13 antibody load at week 0 (baseline) and week 2, followed by a 250 mg dose every two weeks for 16 weeks, and then a 250 mg maintenance dose every four weeks for 40 weeks.

In some embodiments, the methods and uses described herein further include determining the Total Nasal Symptom Score (TNSS) of patients before, during, and after treatment. In some embodiments, the methods and uses described herein further include determining the Standardized Version of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) score of patients before, during, and after treatment. In some embodiments, the methods and uses described herein further include determining the postnasal drip score of patients before, during, and after treatment.

In some embodiments, the methods and uses described herein further include administering nasal endothelial steroids to the patient. In some embodiments, the nasal endothelial steroid is mometasone furoate. In some embodiments, nasal endothelial steroids and anti-IL-13 antibodies are administered simultaneously, concurrently, or sequentially.

In some practices, patients had a history of inadequate response to nasal endothelial steroids prior to treatment. In some practices, patients had moderate to severe nasal symptoms with a TNSS score ≥8 prior to treatment. In some practices, patients were 18 years of age or older. In some practices, patients were 12 to 18 years of age and weighed at least 40 kg.

This application claims the rights under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63/610,089, filed December 14, 2023, and U.S. Provisional Application No. 63/648,940, filed May 17, 2024, the disclosures of which are incorporated herein by reference. Sequence List

This application is filed together with a sequence list in ST.26 XML format. The sequence list is provided as a file created on December 11, 2024, entitled "30944_WO_000 Sequence Listing ST26", and is 20 kilobytes in size. The ST.26 XML sequence list information is incorporated herein by reference in its entirety.

This article provides methods and uses for the treatment of perennial allergic rhinitis using anti-IL-13 antibodies (such as lerejuzab) or pharmaceutical compositions containing anti-IL-13 antibodies (such as lerejuzab).

In one embodiment, this article provides methods for treating perennial allergic rhinitis in patients in need, methods comprising administering a therapeutically effective dose of anti-IL-13 antibodies to the patient. In some embodiments, this article provides methods for treating perennial allergic rhinitis, methods comprising: selecting a patient suffering from perennial allergic rhinitis and administering a therapeutically effective dose of anti-IL-13 antibodies to the patient.

In another embodiment, this article provides for anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies for the treatment of perennial allergic rhinitis. This article also provides for the use of anti-IL-13 antibodies in the manufacture of medicaments for the treatment of perennial allergic rhinitis.

In some embodiments, the methods and uses described herein further include determining the Total Nasal Symptom Score (TNSS) of patients before, during, and after treatment. In some embodiments, the methods and uses described herein further include determining the Standardized Version of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) score of patients before, during, and after treatment. In some embodiments, the methods and uses described herein further include determining the postnasal drip score of patients before, during, and after treatment.

In some embodiments, the methods and uses described herein further include administering nasal endothelial steroids to a patient. In some embodiments, the nasal endothelial steroid is mometasone furoate. In some embodiments, nasal endothelial steroids and anti-IL-13 antibodies are administered simultaneously, concurrently, or sequentially.

In some practices, patients had a history of inadequate response to nasal endothelial steroids prior to treatment. In some practices, patients had moderate to severe nasal symptoms with a TNSS score ≥8 prior to treatment. In some practices, patients were 18 years of age or older. In some practices, patients were 12 to 18 years of age and weighed at least 40 kg.

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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises: VH comprising SEQ ID NO: 7 and VL comprising SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises: VH comprising SEQ ID NO: 11 and VL comprising SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises: a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises the VH sequence described in SEQ ID NO: 11, the VL sequence described in SEQ ID NO: 12, and the human IgG sequence described in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises the VH sequence described in SEQ ID NO: 11, the VL sequence described in SEQ ID NO: 12, the human Fc region comprising the human IgG sequence described in SEQ ID NO: 15, and the constant light chain sequence described in SEQ ID NO: 16. In some embodiments, the anti-IL-13 antibody is levozostatin (CAS No. 953400-68-5). Lerezim antibody is a humanized monoclonal IgG4 antibody that binds specifically to IL-13 with high affinity and blocks signal transduction through the active IL-4Rα/IL-13Rα1 heterodimer. The amino acid sequence of lerezim antibody is provided in Table 1. C-terminal cleavage of the IgG antibody may 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, it can be cleaved or removed from the heavy chain. The penultimate glycine (G) can also be cleaved or removed from the heavy chain. N-terminal amino acids of IgG can also be modified. For example, an N-terminal glutamic acid (Q) or glutamic acid (E) can spontaneously cyclize to pyroglutamic acid (pE). SEQ ID NO: 9 reflects these potential modifications to the levozomba heavy chain. Similarly, SEQ ID NO: 11, 13 and 15 reflect these potential modifications to the levozomba VH variant, the levozomba HC variant and the human IgG1 Fc region, respectively. Table 1. Anti- IL-13 antibody sequences SEQ ID NO: describe sequence 1 Lerui monoclonal antibody HCDR1 AYSVN 2 Lerui monoclonal antibody HCDR2 MIWGDGKIVYNSALKS 3 Lerui monoclonal antibody HCDR3 DGYYPYAMDN 4 Lerui monoclonal antibody LCDR1 RASKSVDSYGNSFMH 5 Lerui monoclonal antibody LCDR2 LASNLES 6 Lerui monoclonal antibody LCDR3 QQNNEDPRT 7 Levofloxacin monoclonal antibody heavy chain variable region (VH) VTLRESGPALVKPTQTLTLTCTVSGFSLSAYSVNWIRQPPGKALEWLAMIWGDGKIVYNSALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCAGDGYYPYAMDNWGQGSLVTVSS 8 Levozo monoclonal antibody light chain variable region (VL) DIVMTQSPDSLSVSLGERATINCRASKSVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDPRTFGGGTKVEIK 9 Levitra monoclonal antibody heavy chain (HC) Xaa1VTLRESGPALVKPTQTLTLTCTVSGFSLSAYSVNWIRQPPGKALEWLAMIWGDGKIVYNSALKSRLTISKDTSKNQVVLTTMTNMDPVDTATYYCAGDGYYPYAMDNWGQ GSLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLXaa2Xaa3 where Xaa1 is Q, pE, or does not exist; Xaa2 is G or does not exist; Xaa3 is K or does not exist. 10 Levitra monoclonal antibody light chain (LC) DIVMTQSPDSLSVSLGERATINCRASKSVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDPRTFGGGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 11 Levozo monoclonal antibody variant heavy chain variable region (VH) Xaa1VQLQESGPGLVKPSETLSLTCTVSGFSLNAYSVNWIRQPPGKGLEWLGMIWGDGKIVYNSALKSRLTISKDSSKNQVSLKLSSVTAADTAVYYCAGDGYYPYAMDNWGQGTTVTVSS where Xaa1 is E, pE, or does not exist. 12 Levozo monoclonal antibody variant with variable light chain region (VL) DIQLTQSPSSSLSASVGDRVTITCRASKSVDSYGNSFMHWYQQKPGKAPKLLIYLASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNNEDPRTFGGGTKVEIK 13 Levozo monoclonal antibody variant heavy chain (HC) Xaa1VQLQESGPGLVKPSETLSLTCTVSGFSLNAYSVNWIRQPPGKGLEWLGMIWGDGKIVYNSALKSRLTISKDSSKNQVSLKLSSVTAADTAVYYCAGDGYYPYA MDNWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTUSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSXaa2Xaa3 Where Xaa1 is E, pE, or does not exist; Xaa2 is P or does not exist; Xaa3 is G or does not exist. 14 Levozo monoclonal antibody variant light chain (LC) DIQLTQSPSSSLSASVGDRVTITCRASKSVDSYGNSFMHWYQQKPGKAPKLLIYLASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNNEDPRTFGGGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 15 hlgGI-LALA-YTE HC constant domain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTUSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSXaa1Xaa2 where Xaa1 is P or does not exist; Xaa2 is G or does not exist 16 LC Human κ LC RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

In some embodiments, the anti-IL-13 antibody is a variant of lerezomonab containing the same HCDR and LCDR sequences as lerezomonab. In some embodiments, the anti-IL-13 antibody is a variant of lerezomonab 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 lerezomonab variants are also provided in Table 1.

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 IL-13 inhibitors are disclosed in, for example, 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 trororubumab. In some embodiments, the anti-IL-13 antibody is sendazumab.

Anti-IL-13 antibodies can be formulated with suitable carriers or excipients into pharmaceutical consumables suitable for administration to patients. For example, an anti-IL-13 antibody, such as lerizobactam, can be formulated into a pharmaceutical consumable as described in WO 2013/066866. The pharmaceutical consumable 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 consumable contains 250 mg to 500 mg of anti-IL-13 antibody. In some embodiments, the concentration of the anti-IL-13 antibody in the pharmaceutical composition is between 100 mg/mL and 150 mg/mL, for example, 125 mg/mL. The pharmaceutical composition may also contain a buffer, such as a 5 mM to 40 mM histidine acetate buffer, with a pH of 5.4 to 6.0. In some embodiments, the pharmaceutical composition further comprises a polyol (e.g., a sugar) at a concentration between 100 mM and 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., lerizumab), 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 a substance for inhibiting IL-13 and a pharmaceutically acceptable carrier or excipient.

In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to the patient. The administration frequency may be approximately once a week, 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, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to the patient once every two weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 250 mg once every two weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 250 mg every four weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 250 mg every eight weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered to the patient every eight weeks, every twelve weeks, every twenty-four weeks, every 36 weeks, or every 52 weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered to patients approximately every eight weeks, approximately every twelve weeks, approximately every twenty-four weeks, approximately every 36 weeks, or approximately every 52 weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to patients at a dose of 360 mg every eight weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to patients at a dose of 360 mg every twelve weeks. In some embodiments, anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies are administered subcutaneously to patients at a dose of 360 mg every twenty-four weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every thirty-six weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every fifty-two weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every eight weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every twelve weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every 24 weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every 36 weeks. In some embodiments, anti-IL-13 antibodies or a pharmaceutical combination containing anti-IL-13 antibodies are administered subcutaneously to the patient at a dose of 360 mg every 52 weeks.

In some practices, patients are treated with anti-IL-13 antibodies or drug combinations containing anti-IL-13 antibodies for approximately 16 weeks or longer. In some practices, patients are further treated for a maintenance period of approximately 40 weeks or longer. In some embodiments, patients are treated with anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies for approximately 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 weeks. In some embodiments, patients are treated with anti-IL-13 antibodies or pharmaceutical combinations containing anti-IL-13 antibodies for approximately 16 weeks. In some embodiments, patients are further treated with anti-IL-13 antibodies or drug combinations containing anti-IL-13 antibodies for approximately 40 weeks of maintenance therapy. In some embodiments, patients are treated with anti-IL-13 antibodies or drug combinations containing anti-IL-13 antibodies for approximately 56 weeks.

In some practices, patients are treated with a loading dose of anti-IL-13 antibodies, such as 500 mg. Several loading doses may be administered at the start of treatment. For example, a 500 mg loading dose of anti-IL-13 antibodies may be administered at week 0 (baseline) and week 2. Following the loading dose, patients may be administered anti-IL-13 antibodies at doses of 250 mg every two weeks, 250 mg every four weeks, and 250 mg every eight weeks.

In some practices, patients were treated with a loading dose of 500 mg of anti-IL-13 antibody at week 0 (baseline) and week 2, followed by a dose of 250 mg every two weeks for 16 weeks, and then a maintenance dose of 250 mg every four weeks for 40 weeks.

In some practices, patients were treated with a loading dose of 500 mg of anti-IL-13 antibody at week 0 (baseline) and week 2, followed by a dose of 250 mg every two weeks for 16 weeks, and then a maintenance dose of 250 mg every eight weeks for 40 weeks.

In some practices, patients were treated with a loading dose of 720 mg of anti-IL-13 antibody in weeks 0 and 2, followed by a dose of 360 mg of anti-IL-13 antibody in weeks 4 and 12, and then a maintenance dose of 360 mg of anti-IL-13 antibody every 12 weeks for 40 weeks.

In some practices, patients were treated with a loading dose of 720 mg of anti-IL-13 antibody in weeks 0 and 2, followed by a dose of 360 mg of anti-IL-13 antibody in weeks 4 and 12, and then a maintenance dose of 360 mg of anti-IL-13 antibody every 24 weeks for 40 weeks.

In some embodiments, a subcutaneous delivery device is used to deliver anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies to a patient. The subcutaneous delivery device may be selected from pre-filled syringes, disposable pen-type injection devices, microneedle devices, microinfusion sets, needle-free injection devices, or auto-injector devices. Various subcutaneous delivery devices (including auto-injector devices) are known and commercially available in this art. Exemplary devices include (but are not limited to) pre-filled syringes (such as BD HYPAK SCF®, READYFILL ^™ and STERIFILL SCF ^™ from Becton Dickinson; CLEARSHOT ^™ copolymer pre-filled syringes from Baxter; and Daikyo Seiko CRYSTAL ZENITH® pre-filled syringes available from West Pharmaceutical Services); disposable pen-type injection devices (such as BD Pen from Becton Dickinson); ultra-sharp and microneedle devices (such as INJECT-EASE ^™ and microinfusion sets from Becton Dickinson; and H-PATCH ^™ available from Valeritas). ), and needle-free injection devices (such as BIOJECTOR® and IJECT® available from Bioject; and SOF-SERTER® and patch devices available from Medtronic). In some embodiments, the subcutaneous delivery device is an auto-injector device described in WO 2008/112472, WO 2011/109205, WO 2014/062488 or WO 2016/089864.

Before, during, and after treatment, patients can be evaluated based on one or more characteristics that define certain signs, symptoms, features, or parameters associated with perennial allergic rhinitis and can be quantitatively or qualitatively assessed. These characteristics include (but are not limited to) TNSS, RQLQ(S), postnasal drip score, VAS for allergic rhinitis control, NPIF, _FEV1 , TOSS, SNOT-22, ACQ-6, EQ-5D-5L, WPAI+CIQ:AS, PROMIS Anxiety Summary v1.0-Anxiety 8a, PROMIS Depression Summary v1.0-Depression 8a, PGI-S, and PGI-C.

The Total Nasal Symptom Score (TNSS) is a clinical outcome assessment that measures the severity of four symptoms reported by participants, including the following (Downie, S.R. et al., Symptoms of persistent allergic rhinitis during a full calendar year in house dust mite-sensitive subjects. Allergy. (2004); 59(4):406-14): rhinorrhea (runny nose); nasal congestion; nasal itching; and sneezing. Participants assessed the severity of each individual symptom daily (over the past 24 hours) using a scale of 0 to 3 (0 = asymptomatic, 3 = severe symptoms), and recorded the results in an electronic diary outside the study site. The individual scores for the four symptoms were then summed to obtain a total score ranging from 0 to 12.

The subjective impact of PAR on participants' health-related quality of life can be assessed using the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) (Juniper, E.F. et al., Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol. (1996); 98(4):843-5). The RQLQ(S) contains 28 items, divided into 7 domains: nasal symptoms (4 items); eye symptoms (4 items); activity limitation (3 items); sleep impairment (3 items); non-nasal/eye symptoms (7 items); practical problems (3 items); and emotional functioning (4 items). Participants were asked to recall health-related quality of life impairments experienced in the past week, answering questions on a 7-point scale (0 to 6), and their responses were recorded on a tablet at the study location. The overall mean RQLQ(S) score was calculated, with a maximum severity score of 6. A change of at least 0.5 points in the overall RQLQ(S) score was considered a minimally clinically significant change, and a change of at least 1.0 points was considered a moderately significant change (Juniper et al., 1996). The three sleep impairment domains of the RQLQ(S) were used to assess the degree of disturbance participants experienced from various sleep problems caused by nasal/eye symptoms in the previous week. The RQLQ(S) Sleep Disorders domain consists of three items, copied verbatim from the corresponding RQLQ(S) items. The questions asked are: difficulty falling asleep, waking up during the night, and lack of quality nighttime sleep. The response method is consistent with the RQLQ(S), with options ranging from 0 (no disturbance) to 6 (extremely disturbing). Scores are calculated using the same method as the overall average score.

Postnasal drip refers to the flow of mucus into the throat as part of allergic rhinitis. Participants rated their postnasal drip using a 4-point scale, where 0 corresponds to no symptoms and 3 corresponds to severe symptoms. Participants were asked to record the severity of their postnasal drip over the past 24 hours. This assessment was collected from participants' electronic diaries.

The Visual Analogue Scale (VAS) for allergic rhinitis control can be assessed as follows. Allergic rhinitis control can be assessed using a single-item VAS scale from 0 to 100 mm, with the two ends anchored by the terms "completely undisturbed" and "extremely disturbed," corresponding to the question "How disturbed have your allergic rhinitis symptoms been in the past 7 days?", thereby assessing the degree of disturbance of allergic symptoms. On the 0 to 100 mm scale, well-controlled AR is defined as a VAS score of 20 or lower (Bousquet, J. et al., MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis. J Allergy Clin Immunol. 2016 Aug;138(2):367-374.e2).

Peak nasal inspiratory flow (NPIF) was measured as the maximum inspiratory flow rate through both nostrils during inspiration, expressed in L/min. Participants with an NPIF >120 L/min were considered to have no 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, using the highest of three readings. NPIF measurements were performed by trained and qualified personnel.

Vital capacity measurement is used to measure physiological airflow during the forced expiratory volume in one second ( _FEV1 ). A normal _FEV1 value is typically ≥80% (Barriero, TJ, An approach to interpreting spirometry. Am Fam Physician. (2004); 69(5):1107-14). Lower _FEV1 values may indicate more severe asthma or other causes of airway restriction or obstruction. FEV1 was measured only in study participants with a current history of asthma at designated visits, and was performed using a study-supplied spirometer that conformed to the recommendations of the American Thoracic Society/European Respiratory Society, at least 6 hours after discontinuation of the last short-acting bronchodilator. Percentage predictors are based on the Global Lung Function Initiative (Quanjer, PH et al., Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. (2012); 40(6):1324-43). Vital capacity measurements were performed by trained and qualified personnel according to the procedures specified in the research reference manual. A minimum of three and a maximum of eight measurements were required at each time point. Vital capacity measurements were reviewed by a central reviewer who confirmed the highest FEV1 and FVC values at each time point. Vital capacity measurements should be performed at the study site whenever possible within ±1 hour of the baseline values.

The Total Ocular Symptom Score (TOSS) is a clinical outcome assessment that measures the severity of two reported ocular symptoms: itching/redness and tearing. Participants assessed the severity of individual symptoms daily (within the past 24 hours) in an electronic diary using an integer scale of 0-3 (0 = absent to 3 = severe) outside the study site (Pfaar, O. et al., Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI position paper. Allergy. (2014); 69(7):854-67). The individual scores for the two symptoms were then summed to obtain a total score ranging from 0 to 6.

The Nasal Sinus Outcomes Test (SNOT-22) is a validated participant-reported questionnaire that assesses the impact on health-related quality of life. It consists of 22 questions that assess nasal, 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 from 0 (no problem) to 5 (extremely severe problem). The scores for each question are summed to obtain a total score ranging from 0 (no disease) to 110 (most severe disease). Lower scores indicate a smaller impact, and the recall period is the past two weeks. A change of 8.9 points was 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.).

The Asthma Control Questionnaire-6 (ACQ-6) is a 6-question participant report questionnaire that assesses the most common asthma symptoms and was collected on a tablet computer at the study site only from participants with asthma. Questions included: waking up due to asthma; symptoms upon waking; limited mobility; shortness of breath; wheezing; and inhalation frequency/use of inhalers. Participants with a history of asthma were asked to recall their asthma episodes over the past week and answer the questions on a 7-point scale, where 0 corresponds to no impairment and 6 corresponds to maximum impairment. The ACQ-6 score was calculated as the average of the scores and represents a total control score of 6, where 0 corresponds to complete asthma control and 6 corresponds to severe asthma out of control. The minimum clinically significant difference in ACQ-6 is defined as a change of 0.5 points (Juniper, E.F. et al., Development and validation of a questionnaire to measure asthma control. Eur Respir J. (1999); 14(4):902-7; Juniper, E.F. et al., Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. (2005); 99(5):553-8).

The European Quality of Life 5 Dimensions-5 Levels (EQ-5D-5L) is a universal questionnaire that assesses health status and collects data on tablets at research sites. It consists of a descriptive system comprising five dimensions (mobility, self-care, daily activities, pain/discomfort, and anxiety/depression), each with five levels: no problem, minor problem, moderate problem, severe problem, and very severe problem. The questionnaire also includes the VAS scale, in which respondents rate their health status on a vertical VAS with "the best health you can imagine" and "the worst health you can imagine" at the two ends (EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 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, A.K. et al., The EQ-5D: a new tool for studying clinical outcomes in chronic rhinosinusitis. Laryngoscope. (2015); 125(1):7-15).

Work Performance and Activity Impairment Plus Classroom Impairment Questionnaire: The Allergy-Specific Questionnaire (WPAI+CIQ:AS) is a patient-reported tool used to assess impairment in work, classroom, and routine activities for patients with allergies (AR); data was also collected on a tablet at the study site. It contains nine items measuring the following: employment status; actual working hours; working hours missed due to allergies; the impact of allergies on work performance; attendance at academic settings; school/class hours; class hours missed due to allergies; the impact of allergies on performance under classroom settings; and the impact of allergies on routine daily activities. WPAI+CIS:AS yields four sub-scores: Absence (missed work or class time); Presenteeism (impairment in work or class/reduced on-the-job productivity); Work productivity impairment (total work or class impairment/absence plus presenteeism); and Activity impairment. The scores are calculated as percentages of impairment (Reilly, M.C., Zbrozek, A.S., Dukes, E.M. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. (1993); 4(5):353-65), with higher values indicating greater impairment and lower efficiency, i.e., a worse outcome.

The PROMIS Anxiety Scale v1.0 - Anxiety 8a is suitable for the general population and individuals with chronic symptoms. The PROMIS Anxiety Item Scale assesses self-reported fears (fear, panic), anxiety distress (worry, apprehension), hyperarousal (tension, restlessness, irritability), and arousal-related physical symptoms (rapid heartbeat, dizziness). The PROMIS Anxiety Scale 8a (v1.0) includes 8 questions assessing participants' symptoms over the past 7 days. The corresponding options range from 1 = Never; 2 = Rarely; 3 = Sometimes; 4 = Often; 5 = Always. The total raw score was converted into a T-score, where a higher score indicates a greater level of anxiety (PROMIS Anxiety 2019, published March 1, 2019. Accessed March 8, 2021. Available at https://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Anxiety_Scoring_Manual.pdf).

The PROMIS Depression Summary Form v1.0-Depression 8a is suitable for the general population and individuals with chronic symptoms. The PROMIS Depression Item Scale assesses self-reported negative emotions (sadness, guilt), self-perception (self-criticism, feelings of worthlessness), social cognition (loneliness, social alienation), and decreased positive affect and engagement (loss of interest, meaning, and purpose). The PROMIS Depression Summary Form 8a (v1.0) includes eight questions assessing participants' symptoms over the past seven days. The corresponding options range from 1 = Never; 2 = Rarely; 3 = Sometimes; 4 = Often; 5 = Always. The total raw score was converted into a T-score, where a higher score indicates a greater degree of depression (PROMIS Depression 2019, released February 28, 2019. Accessed March 8, 2021. Available at https://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Depression_Scoring_Manual.pdf).

The Patient Overall Impression Severity (PGI-S) and Patient Overall Impression Change (PGI-C) scales are used to facilitate the assessment of whether changes in patients’ TNSS, postnasal drip, and RQLQ(S) are clinically significant.

PGI-S: TNSS requires participants to rate the overall severity of nasal symptoms (nasal congestion, itching, sneezing, runny nose) caused by AR in the past 14 days. The corresponding options are: asymptomatic, mild, moderate, severe, and very severe.

PGI-S: Postnasal drip requires participants to rate the overall severity of postnasal drip caused by AR in the past 14 days. The corresponding options are: asymptomatic, mild, moderate, severe, and very severe.

PGI-S: RQLQ(S) requires participants to rate the overall severity of activity restrictions (routine activities at home, at work or school, social or outdoor activities) caused by AR in the past 7 days, with corresponding options: asymptomatic, mild, moderate, severe, and very severe.

PGI-C: TNSS requires participants to describe the overall changes in their nasal symptoms (nasal congestion, nasal itching, sneezing, runny nose) caused by AR since they started using a new medication. The corresponding options are: much better, better, slightly better, no change, slightly worse, worse, and much worse.

PGI-C: Postnasal drip requires participants to describe the overall change in their postnasal drip caused by AR since the start of using a new medication. The corresponding options are: much better, better, slightly better, no change, slightly worse, worse, and much worse.

PGI-C: RQLQ(S) requires participants to describe the overall change in their activity limitations caused by AR since they started using a new drug. The corresponding options are: much better, better, slightly better, no change, slightly worse, worse, and much worse.

The described characteristics can be measured at one or more time points after baseline and administration of anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies. For example, it can be measured at the end of week 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 starting treatment with anti-IL-13 antibodies or a combination of medicines containing anti-IL-13 antibodies. The difference between the values at specific time points after the start of treatment and the baseline values is used to determine whether these characteristics have improved (e.g., been alleviated).

In another embodiment, this article provides for anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies for the treatment of perennial allergic rhinitis. This article also provides for the use of anti-IL-13 antibodies in the manufacture of medicaments for the treatment of perennial allergic rhinitis.

As used herein, unless otherwise indicated 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 interpreted to cover both the singular and the plural.

As used herein, the term “about” means within a reasonable approximation of the value, such as by adding or subtracting 10% of the value.

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

An exemplary antibody is an immunoglobulin G (IgG) antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) cross-linked by inter-chain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains includes a variable region primarily responsible for antigen recognition, containing approximately 100 to 125 or more amino acids. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for the therapeutic effect. 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 subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

The VH and VL regions can be further subdivided into hypervariable regions called complementary determinant regions (CDRs), interspersed with more conserved regions called framework regions (FRs). CDRs are exposed on the protein surface and are important for the antigen-binding specificity of the antibody. Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: 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," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain most of the residues that form specific interactions with the antigen. Assigning amino acid residues to the CDR can be done according to well-known protocols, including those described in the following: Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (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. (The international ImMunoGeneTics database is available at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

The exemplary embodiments of antibodies disclosed herein also include antibody fragments or antigen-binding fragments that contain at least a portion of the ability of the antibody to retain and interact with antigen specificity, such as Fab, Fab', F(ab') ₂ , Fv fragments, scFv, scFab, disulfide-linked Fv (sdFv), Fd fragments, and linear antibodies.

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

As used in this article, the term "baseline" means before or at the time of administration of the first dose of an anti-IL-13 antibody or a pharmaceutical combination containing an anti-IL-13 antibody (week 0).

Unless otherwise indicated, the terms “bind” or “binds” as used herein are intended to mean the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, as determined by commonly known methods in this art, which causes the two proteins or molecules to approach each other.

The "effective dose" of a drug refers to the amount that effectively achieves the desired therapeutic effect at the necessary dose and within the necessary time period.

As used herein, unless otherwise specified, the term "IL-13" refers to any human interleukin-13 isoform. The term encompasses "full-length," untreated IL-13, and any form of IL-13 produced by treatment in cells. The term also encompasses naturally occurring IL-13 variants, such as splice variants or paired gene variants. Exemplary human IL-13 amino acid sequences are known, for example, NCBI accessions NP_002179.2, NP_001341920.1, NP_001341921.1, NP_001341922.1; UniProtKB accession P35225.

The term "load dose" refers to the dose of drug administered at the beginning of treatment, which is higher than the doses subsequently administered and the doses administered during the remainder of treatment.

The term "maintenance dose" refers to the follow-up dose of medication administered to a patient to maintain or sustain the desired therapeutic effect.

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

The term "allergic rhinitis perennial (PAR)" is well-known in this field and is generally considered a type 2 inflammation-mediated disease (Giavina-Bianchi P et al., United airway disease: current perspectives. J Asthma Allergy. (2016); 9:93-100). As used herein, PAR is intended to refer to diseases or symptoms known in this field that are the same as or substantially the same as allergic rhinitis caused by perennial allergens.

As used herein, "treatment" refers to any method that can slow, control, delay, or stop the progression of the symptoms or diseases described herein, or improve the symptoms or symptoms of the symptoms or diseases, but does not necessarily indicate the complete elimination of all symptoms or diseases. Treatment includes the administration of proteins or nucleic acids or vectors or compounds to treat the disease or condition in patients (especially humans). Example 1. A phase 3 , multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluating the efficacy and safety of levozomonab in adult participants with perennial allergic rhinitis .

This is a phase 3, multinational, multicenter, double-blind, PBO-controlled, parallel-group, randomized clinical study evaluating the efficacy and safety of levozomab in approximately 450 adult (>18 years) participants with PAR whose disease is not adequately controlled by standard care (INCS in combination with or without OAH, INAH, or AHs eye drops, and/or mast cell stabilizers, or having both of these properties to treat allergic symptoms).

This study has four phases: screening (up to 30 days); run-in (4 weeks); randomized controlled trials (56 weeks), which includes an induction phase (16 weeks; week 0 to week 16) and a maintenance phase (40 weeks; week 16 to week 56); and safety follow-up (SFU) (8 weeks), beginning with a site visit in week 56. The maximum duration of participation for each participant is approximately 72 weeks.

Goals and End Points:

The primary, secondary, and exploratory objectives and endpoints of this study are presented in Table 2. Table 2. Objectives and Endpoints Target Finish line Primary objective: ● To evaluate the efficacy of levofloxacin 250 mg Q2W compared to PBO for the treatment of total nasal symptoms up to week 16. Key endpoint: ● Mean total nasal symptom score (TNSS) change from baseline up to week 16 (CFBL) Key secondary objectives: ● Evaluate the efficacy of levetiracetamab 250 mg Q2W compared to PBO up to week 16. ● Evaluate the efficacy of levetiracetamab 250 mg Q2W up to week 56, compared to PBO. Key secondary endpoints: ● Average RQLQ(S) CFBL up to week 16 ● Average RQLQ(S) CFBL up to week 56 ● Average TNSS score CFBL up to week 4 ● Average TNSS score CFBL up to week 56 ● Average postnasal drip score CFBL up to week 16 Other secondary objectives: ● To compare the efficacy of levozobactam and PBO through clinical evaluation, participant-reported results, and quality of life measurement results. Other secondary endpoints: ● Percentage of participants requiring emergency medication during visits ● Average CFBL of RQLQ(S) sleep domain during visits ● Average CFBL of TNSS and its four components during visits ● Percentage of participants with a 50% reduction in TNSS during visits ● Percentage of participants with an ≥1.0 improvement in RQLQ(S) during visits ● Average CFBL of RQLQ(S) during visits ● Average CFBL of postnasal drip score during visits ● Average CFBL of NPIF during visits ● Average CFBL of _FEV1 during visits ● Average CFBL of TOSS during visits ● Average CFBL of SNOT-22 during visits ● The following are the average CFBL (Current Functional Level) results obtained through interviews: ● Average CFBL of the AR-controlled VAS (Version Scale) ● Average CFBL of the PROMIS Anxiety Scale ● Average CFBL of the PROMIS Depression Scale ● Average CFBL of the ACQ-6 (Version Scale) ● Average CFBL of the WPAI+CIQ:AS (Version Scale) ● Average CFBL of the EQ-5D-5L (Version Scale) ● Average CFBL of the PGI-S (Version Scale) ● Average CFBL of the PGI-C (Version Scale) ● Average CFBL of the PGI-C (Version Scale) ● Average CFBL of the PGI-S ...S (Version Scale) ● Average CFBL of the PGI-S (Version Scale) ● Average CFBL of the PGI-C (Version Scale) ● Average CFBL of the PGI-S (Version Scale) ● Average CFBL of the PGI Safety objectives: ● Describe the safety and tolerability of Levozo monoclonal antibody. Safety endpoints : ● Incidence of adverse events and serious adverse events ● Baseline values and changes over time in clinical laboratory assessments ● Baseline values and changes over time in vital signs Exploratory objectives: ● Characterize the pharmacokinetics of the levofloxacin monoclonal antibody during the study. ● Characterize changes in immunogenicity and exploratory biomarkers during the study. ● Characterize changes in SPT response and/or antigen-specific IgE with treatment. ● Analyze genetic variations related to drug response (optional). Exploratory endpoints: ● Serum concentration of the monoclonal antibody at the designated visit ● Immunogenicity (antidrug-resistant antibody), total immunoglobulin E (IgE), and nasal and blood biomarkers at the designated visit ● Changes in SPT response/antigen-specific IgE self-screening at week 56 ● Pharmacogenomic analysis The inclusion and exclusion criteria for the patients included in this study are described in the following sections.

Inclusion Criteria : Participants must meet all of the following criteria to be included in this study: 1. Adult participants must be ≥18 years of age at the time of signing the informed consent form (ICF). 2. Participants must be diagnosed with PAR by a physician and require treatment for most days of more than 12 weeks per year for at least two consecutive years to control persistent symptoms. Regardless of whether background therapy is used regularly or continuously, participants must have a history of inadequate response to INCS, i.e., having a TNSS score ≥8 for moderate or severe nasal symptoms at screening (first visit) and randomization (third visit) (mean of the score within the two weeks prior to randomization [third visit], measured at least 4 days per week). 3. During screening, participants must be positive for indoor allergens via skin prick test (SPT) using a validated analytical method (central laboratory) (mean wheal diameter at least 5 mm larger than negative controls) and/or positive for antigen-specific serum IgE (≥0.70 kU/L) for indoor allergens (e.g., pets, fungi, dust mites, cockroaches, horses). In addition, one of the following must also be met: a. Participants must be allergic to at least one dust mite species, or b. During the study period, participants must be exposed to at least one other (non-dust mite) year-round allergen that elicits positive SPT and/or positive antigen-specific serum IgE. (Note: Participants who test positive for fungi are not eligible), or c. Participants must have clinical symptoms associated with a year-round allergen that is positive when tested by SPT or a positive antigen-specific serological test. 4. Participants with a known history of dermatographia or diagnosed with dermatographia during SPT are eligible to participate in this study if their serum IgE test is positive. 5. Participants with asthma must maintain stable asthma using permitted routine treatment for 3 months prior to screening. 6. For women of childbearing potential (WOCBP), highly effective contraception should be used in accordance with local regulations regarding contraception methods for clinical trial participants. Women with non-fertility risk (WNOCBP) and women without fertility risk (WOCBP) are eligible to participate in this study. 7. Participants 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. 8. Participants must be willing and able to comply with all clinic visits, study-related procedures, and questionnaires, including, importantly, the use of necessary background medications and completion of daily electronic journaling. 9. Participants must complete their electronic journaling for four out of seven days each week for two weeks prior to the randomized group visit (the third visit [baseline]).

Exclusion Criteria : Participants meeting any of the following criteria will be excluded from the study: 1. Having received a dose of lerezab. 2. Currently enrolled in any other clinical study involving the investigational drug or any other type of medical study deemed scientifically or medically incompatible with this study. 3. Having received treatment with the investigational drug within 8 weeks prior to randomization or within 5 half-lives (if known), whichever is longer. 4. Known allergy to any component of lerezab or its excipients. 5. Contraindications or intolerance to mometasone furoate or any background medication used during the study. 6. Currently receiving allergen immunotherapy (subcutaneous or sublingual immunotherapy [SCIT/SLIT]). However, individuals who discontinued SCIT/SLIT ≥3 years prior to randomization are eligible if they did not receive a maintenance AIT regimen. 7. Received any emergency medication during the screening and pilot period. 8. Received any biologic or systemic immunosuppressant treatment for inflammatory or autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) prior to baseline (3rd visit; randomization), including the following: ● Use of a B-cell scavenging biologic, including rituximab, within 6 months. ● Use of other biologics within 5 half-lives (if known) or 8 weeks (whichever is longer). ● Use of systemic immunosuppressants within 4 weeks prior to baseline (3rd visit). 9. Participants with a history of seasonal exacerbations of AR were excluded if a seasonal exacerbation was expected to occur during the 4-week trial period, the first 16 weeks after randomization (induction period), or the last 4 weeks of the maintenance period (weeks 52 to 56). 10. Significant changes in daily environmental exposure were expected for more than 2 consecutive weeks within 2 weeks prior to week 16 or 4 weeks prior to week 56. 11. A known history of recurrent acute or chronic sinusitis, defined as requiring more than 4 sessions of systemic antibiotic treatment within 3 months prior to screening or within 2 years prior to screening. 12. Known history of ≥2 severe asthma exacerbations within the past year. A severe asthma exacerbation is defined as any asthma flare requiring at least 3 days of systemic corticosteroids and/or hospitalization. A single non-intestinal dose of corticosteroids used for an asthma exacerbation will also be considered a severe exacerbation. 13. History of nasal polyps or presence of nasal polyps at screening (first visit). 14. Moderate to severe nasal septum deviation. 15. Underwent any sinus/nasal surgery within 12 months prior to screening (first visit), or is scheduled to undergo surgery during the study period. 16. Known history of rhinitis of other causes (e.g., drug-induced rhinitis, vasomotor rhinitis). 17. Has received any live or attenuated live vaccine (including BCG or treatment) within 4 weeks of baseline (3rd visit), or intends to receive a live or attenuated live vaccine (or BCG treatment) during the study or within 4 weeks of receiving the last dose of IP. Note: The following vaccines are not considered live vaccines: messenger RNA vaccines, vaccines containing inactive viral components, and/or non-replicating viral vector vaccines. 18. Known history of HIV infection or HIV serological positivity. 19. Currently infected or chronically infected with hepatitis B virus (HBV) (i.e., positive for hepatitis B surface antigen (HBsAg) and/or positive for polymerase chain reaction). 20. Currently infected with hepatitis C virus (HCV) (HCV RNA positive). 21. Known to have cirrhosis and/or chronic hepatitis of any cause. 22. Diagnosed with an active intraparasitic infection or at high risk of such infection. 23. Known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., tuberculosis [TB], histopathic infection, listeriosis, coccidioidomycosis, pneumocystis infection, and aspergillosis), despite remission; or, as researchers believe, an unusually frequent, recurrent, or long-term infection. 24. Having any of the following types of infection within 3 months of screening or developing any of these infections during the screening or pilot period: a. Severe infection (requiring hospitalization and/or IV or equivalent oral antibiotic treatment). b. Opportunistic infections [as defined in Winthrop KL, Novosad SA, Baddley JW et al., Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 2015; 74(12):2107-16]. c. Symptomatic herpes zoster infection that has not subsided at screening. Note: Herpes zoster is considered active and persistent until all blisters have dried and crusted over. d. Chronic infection (symptoms, signs, and/or treatment lasting 6 weeks or longer). e. Recurrent infection (including (but not limited to) recurrent cellulitis, chronic osteomyelitis). Participants with only recurrent, mild, and uncomplicated herpes labialis and/or genital herpes may be admitted at the discretion of the medical monitor. 25. Active or acute infection requiring treatment with systemic antibiotics, antiviral agents, antiparasitic agents, antiprotozoal agents, or antifungal agents within 2 weeks prior to baseline (3rd visit). Note: Participants may be re-screened after infection resolution. Participants with vaginal or oral candidiasis who are receiving only symptomatic treatment and do not require systemic anti-infective agents may be considered for admission if they meet other study eligibility criteria. Admission of participants with other uncomplicated localized infections should be discussed with the client-designated medical monitor. 26. History of malignant tumors within 5 years prior to screening (first visit; exceptions include adequately treated basal cell or squamous cell carcinoma, cervical carcinoma in situ). 27. Any other medical or psychological condition that researchers believe may indicate a new and/or poorly understood illness, may pose an unreasonable risk to the study participant, may render participation unreliable, or may interfere with study evaluation. 28. Having a severe comorbidity that researchers believe will adversely affect participation in the study. 29. A chemical or hematological test result that researchers considered clinically significant at screening (first visit) or baseline (third visit). 30. A female participant who is pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study. 31. A female participant who, at screening (first visit), has a recent, incompletely healed nasal perforation that could cause nasal symptoms, or who plans to undergo a new nasal perforation during participation in the study. 32. An employee of Lilly, a relative of an Lilly employee, or an employee of any third party requesting exclusion of their employee from the study. 33. Research staff directly subordinate to the researchers at the research site, and/or their immediate family members, defined as spouses, parents, children, or siblings, whether biologically or legally adopted. 34. Participants or caregivers who are unable or unwilling to cooperate during the study period, or who are unwilling to comply with research restrictions and procedures, including subcutaneous administration of the investigational drug. 35. A history of chronic alcohol abuse, intravenous drug abuse, or other prohibited drug abuse within the two years prior to screening. 36. Other reasons deemed unsuitable for inclusion in the study by the researchers. Investigational Drug:

The pharmaceutical conjugate containing 125 mg/mL lerezab or placebo is provided in a sterile prefilled syringe with a pre-assembled needle safety device (PFS-NSD) for subcutaneous administration to patients. The lerezab 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 lerezab.

INCS Mometasone Furoate Nasal Spray, 100 μg daily (50 μg sprayed twice in each nostril). Study Design:

The research design for this experiment is shown in Figure 1.

Following the screening and trial period, at baseline (third visit), individuals meeting the inclusion and exclusion criteria were randomly assigned in a 1:1:1 ratio to the following treatment arms using an interactive online response system: ● Lerezazumab Q2W/Q4W arm: Lerezazumab 500 mg load dose was administered at weeks 0 and 2, followed by 250 mg Q2W until week 16 (induction period), and then 250 mg Q4W until week 56 (maintenance period). ● Lerezab Q2W/Q8W Arm: Lerezab 500 mg loading dose was administered at weeks 0 and 2, followed by 250 mg Q2W until week 16 (induction phase), and then 250 mg Q8W until week 56 (maintenance phase). To maintain blinding, participants received PBO doses every 8 weeks starting four weeks after the week 16 dose. ● PBO Arm: PBO Q2W until week 16 (induction phase) and PBO Q4W until week 56 (maintenance phase).

Randomization was stratified based on the following factors: ● Allergic rhinitis classification (PAR, PAR + seasonal AR [defined as positive for one perennial allergen and one seasonal allergen]). Allergic rhinitis classification was based on SPT and/or serum IgE at the start of the study. PAR: Participants sensitive to indoor allergens and insensitive to seasonal allergens; PAR + seasonal AR: Participants sensitive to indoor allergens and sensitive to at least one seasonal allergen; ● Region (North America, Europe, other parts of the world); and ● Baseline use of oral antihistamines (OAH)/intranasal antihistamines (INAH) (INAH used, OAH used but not INAH used, neither OAH nor INAH used).

The participants, researchers, and staff at the research site were completely blind to the treatment arm.

Intranasal mometasone furoate will be used as a background medication during the 4-week pilot period and throughout the randomized controlled trial (weeks 0 to 56). Additional background medication may also be provided throughout the study, starting from the pilot period. During the safety follow-up period, participants may continue to use background medications (including mometasone furoate) as determined by the medical monitor.

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

Figure 1 is a schematic diagram of the phase 3 study design described in Example 1. Abbreviations: TBSS = Total Nasal Symptom Score; CFBL = Change from Baseline; INCS = Nasal Intracorticosteroid; Lebri = Lebri monoclonal antibody; PBO = Placebo; Q2W = Every 2 weeks; Q4W = Every 4 weeks; Q8W = Every 8 weeks.

TW202544035A_113148730_SEQL.xml

Claims (51)

A method for treating year-round allergic rhinitis in patients in need, the method comprising administering to the patient 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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6. A method for treating perennial allergic rhinitis, the method comprising: selecting a patient suffering from perennial allergic rhinitis and administering to the patient 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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2 and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5 and LCDR3 comprising SEQ ID NO: 6. The method of claim 1 or 2, wherein the anti-IL-13 antibody comprises: VH comprising SEQ ID NO: 7 and VL comprising SEQ ID NO: 8. The method of any one of claims 1 to 3, wherein the anti-IL-13 antibody comprises: a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. The method of any of claims 1 to 4, wherein the anti-IL-13 antibody is lebrikizumab. The method of any of claims 1 to 5, wherein the anti-IL-13 antibody is administered subcutaneously to the patient. The method of any one of claims 1 to 6, wherein the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg. The method described in any of claims 1 to 7, wherein the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks. The method of claim 8, wherein the patient is further treated with a loading dose of 500 mg of the anti-IL-13 antibody. The method described in claim 9, wherein the load is administered to the patient in week 0 and week 2. The method described in any of claims 1 to 10, wherein the patient is treated with the anti-IL-13 antibody for approximately 16 weeks. The method described in any of the requests 1 to 11, wherein the patient is further treated for a maintenance period of approximately 40 weeks. The method of claim 12, wherein during the maintenance period, the patient is treated with a maintenance dose of 250 mg of the anti-IL-13 antibody every four weeks. The method of claim 12, wherein during the maintenance period, the patient is treated with a maintenance dose of 250 mg of anti-IL-13 antibody every eight weeks. The method described in any of the requests 1 to 14 further includes determining the patient’s Total Nasal Symptom Score (TNSS) before, during and after the treatment. The method described in any of the requests 1 to 14 further includes determining the patient’s RQLQ(S) score before, during and after the treatment. The method described in any of claims 1 to 14 further includes determining the patient’s postnasal drip score before, during and after the treatment. The method of any of claims 1 to 17, wherein the anti-IL-13 antibody is administered to the patient using a subcutaneous delivery device. The method of claim 18, wherein the subcutaneous delivery device is selected from a pre-filled syringe, a disposable pen-type injection device, a microneedle device, a micro infusion device, a needle-free injection device, or an automatic syringe device. The method of any of claims 1 to 19 further includes administering nasal endothelial steroids to the patient. The method of claim 20, wherein the nasal endothelial steroid is mometasone furoate. The method of claim 20 or 21, wherein the nasal endothelial steroid and the anti-IL-13 antibody are administered simultaneously, concurrently or sequentially. The method of any of claims 1 to 22, wherein the patient has a history of inadequate response to nasal endothelial steroids prior to the treatment. The method described in any of the requests 1 to 23, wherein the patient had moderate or severe nasal symptoms with a TNSS score ≥8 prior to the treatment. The method described in any of the requests 1 to 24, wherein the patient is 18 years of age or older. An anti-IL-13 antibody for treating perennial allergic rhinitis, 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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2 and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5 and LCDR3 comprising SEQ ID NO: 6. A pharmaceutical composition comprising an anti-IL-13 antibody for the treatment of perennial allergic rhinitis, 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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2 and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5 and LCDR3 comprising SEQ ID NO: 6. The anti-IL-13 antibody is intended for use in the manufacture of a medicament for the treatment of perennial allergic rhinitis, 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 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2 and HCDR3 comprising SEQ ID NO: 3, and the VL comprises: LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5 and LCDR3 comprising SEQ ID NO: 6. The anti-IL-13 antibody used in claim 26, wherein the anti-IL-13 antibody comprises: VH comprising SEQ ID NO: 7 and VL comprising SEQ ID NO: 8. The anti-IL-13 antibody used in claims 26 or 29, wherein the anti-IL-13 antibody comprises: a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. The anti-IL-13 antibody used in any of the requests 26, 29 or 30 is a levozo monoclonal antibody. The anti-IL-13 antibody used in any of claims 26 or 29 to 31, wherein the anti-IL-13 antibody is administered subcutaneously to the patient. The anti-IL-13 antibody used in any of claims 26 or 29 to 32 is administered at a dose of 250 mg to 500 mg. The anti-IL-13 antibody used in any of claims 26 or 29 to 33 is administered subcutaneously at a dose of 250 mg every two weeks. The anti-IL-13 antibody used in claim 34 is further administered at a loading dose of 500 mg. The anti-IL-13 antibody used in Request 35 is administered at doses in weeks 0 and 2. The anti-IL-13 antibody used in any of claims 26 or 29 to 36, wherein the anti-IL-13 antibody is administered for a period of approximately 16 weeks. The anti-IL-13 antibody used in any of claims 26 or 29 to 37, wherein the anti-IL-13 antibody is further administered for a maintenance period of approximately 40 weeks. The anti-IL-13 antibody used in claim 38, wherein during the maintenance period, the anti-IL-13 antibody is administered at a dose of 250 mg every four weeks. The anti-IL-13 antibody used in claim 38, wherein during the maintenance period, the anti-IL-13 antibody is administered at a dose of 250 mg every eight weeks. If the anti-IL-13 antibody used in any of the requests 26 or 29 to 40 is further included in determining the patient’s Total Nasal Symptom Score (TNSS) before, during and after the treatment. If the anti-IL-13 antibody used in any of the requests 26 or 29 to 41 is further included in determining the patient’s Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) score before, during and after the treatment. If the anti-IL-13 antibody used in any of the requests 26 or 29 to 41 is further included in determining the patient’s postnasal drip score before, during and after the treatment. The anti-IL-13 antibody used in any of claims 26 or 29 to 43 is administered using a subcutaneous delivery device. The anti-IL-13 antibody used in claim 44, wherein the subcutaneous delivery device is selected from a pre-filled syringe, a disposable pen injection device, a microneedle device, a micro infusion set device, a needle-free injection device, or an automatic syringe device. The anti-IL-13 antibody used in any of claims 26 or 29 to 45 further includes administration of nasal endothelial steroids. The anti-IL-13 antibody used in claim 46, wherein the nasal endothelial steroid is mometasone furoate. The anti-IL-13 antibody used in claims 46 or 47, wherein the nasal endothelial steroid and the anti-IL-13 antibody are administered simultaneously, concurrently, or sequentially. If the anti-IL-13 antibody used in any of the requests 26 or 29 to 48 is used, the patient has a history of inadequate response to nasal endothelial steroids prior to the treatment. If the anti-IL-13 antibody is used in any of the requests 26 or 29 to 49, the patient had moderate or severe nasal symptoms with a TNSS score ≥8 prior to the treatment. The anti-IL-13 antibody used in any of requests 26 or 29 to 50, wherein the patient is 18 years of age or older.