Treatment of headache disorders using NK3 modulators

Abstract

The present invention relates to a method for treating or preventing a headache disorder selected from the group consisting of migraine, headache due to drug overuse, cluster headache, general headache, trigeminal neuralgia, and oral and facial pain, comprising administering a therapeutically effective amount of a therapeutic agent that modulates the activity of the neurokinin receptor 3 ('NK3') protein or modulates the expression of the TACR3 gene.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 334,308, filed on April 25, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] Migraine is a painful and debilitating neurological disorder of the trigeminovascular system with a high prevalence in the general population, affecting approximately 15% of individuals, making it the second leading cause of disability worldwide. Migraine is characterized by recurrent throbbing headaches of moderate to severe pain intensity that are sensitive to movement, visual, auditory, and other sensory input and can last from 4 to 72 hours.

[0004] Although several classes of oral medications are approved for the treatment of migraine, many of the currently used drugs are associated with severe side effects, leading to frequent discontinuation and switching of drug classes, with poor efficacy. Antibody therapies and small molecules targeting the CGRP receptor have reported fewer side effects, but less than one-third of migraine patients respond to these treatments. Therefore, novel therapies are urgently needed to treat migraine and other disorders of the trigeminovascular system, such as cluster headache and medication overuse headache and trigeminal neuralgia. Summary of the invention

[0005] In some aspects, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutic agent that modulates the activity of a neurokinin receptor 3 ("NK3") protein or modulates the expression of a TACR3 gene, wherein the disease or condition is selected from migraine, cluster headache, general headache, medication overuse headache, trigeminal neuralgia, and orofacial pain.

[0006] In another aspect, the present disclosure provides a NK3 modulator for treating or preventing a disease or condition selected from migraine, cluster headache, general headache, medication overuse headache, trigeminal neuralgia and orofacial pain, wherein the NK3 modulator is a therapeutic agent that modulates the activity of NK3 protein or modulates the expression of TACR3 gene.

[0007] In some embodiments, the disease or condition is selected from the group consisting of migraine, medication overuse headache, cluster headache, and headache in general. In some embodiments, the disease or condition is migraine.

[0008] In some embodiments, the therapeutic agent modulates the activity of the NK3 protein. In some embodiments, the therapeutic agent is a NK3 antagonist. In some embodiments, the therapeutic agent modulates the expression of the TACR3 gene. In some embodiments, the therapeutic agent reduces the expression of the TACR3 gene.

[0009] In some embodiments, the administration of the therapeutic agent does not reduce luteinizing hormone in the subject (e.g., when the therapeutic agent is administered at a therapeutically effective dose). In some embodiments, the administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of at least 10 to 1. In some embodiments, the administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of at least 100 to 1. In some embodiments, the administration of the therapeutic agent selectively regulates the activity of NK3 protein in peripheral tissues or the expression of TACR3 genes compared to the central nervous system. In some embodiments, the administration of the therapeutic agent selectively regulates the activity of NK3 protein in the peripheral nervous system or the expression of TACR3 genes compared to the central nervous system.

[0010] In some embodiments, the therapeutic agent is a small molecule, a protein, or a nucleic acid. In some embodiments, the therapeutic agent is a small molecule.

[0011] In some embodiments, wherein the therapeutic agent is disclosed in EP0673928, WO1995032948, WO1997010211, WO1997019928, WO1997019927, WO1997021680, WO1998018785, WO1998057972, WO1999026924, WO1999001451, WO2000021931, WO2000064877, WO2000039114, WO2002013825, WO2002094821, WO2002083645, WO2002038547, WO2002038548, W O2002044154, WO2002043734, WO2002044165, WO2004066951, WO2004066950, WO2005014575, WO2005061462, WO2005016884, WO2005110987, US2005148 601. WO2006050989, WO2006050991, WO2006050992, WO2006130080, WO2006137789, WO2007086799, WO2007018465, WO2007018469, WO200700396, WO200 W O2008131779, WO2008148688, WO2008148689, WO2008151969, WO2008081012, WO2009130240, WO2009156339, WO2009033995, WO2009019163, WO2009024 502. WO2009072643, WO2010106081, WO2010045948, WO2010028655, WO2010 086259, WO2010015626, WO2020101017, JP201081888, WO2011110183, WO201 1121137、WO2012039718、WO2012009227、WO2012004207、WO2013050424、WO 2014154895, WO2014154896, WO2014089019, WO2015200594, WO2015033163,WO2019210327, WO2019074081 or WO2021030335.

[0012] In some embodiments, the small molecule is selected from fezolinetant, pavinetant, talnetant, osanetant, elinzanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, PD161182, SCH206272, GSK256471, and SB48968. In some embodiments, the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, and PD161182. In some embodiments, the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653, and MLE-301.

[0013] In some embodiments, the therapeutic agent is a protein. In some embodiments, the therapeutic agent is an antibody or a functional fragment thereof that selectively binds to NK3 or neurokinin B. In some embodiments, the therapeutic agent is an antibody or a functional fragment thereof that selectively binds to NK3 disclosed in WO2012020162A1. In some embodiments, the therapeutic agent is an antibody or a functional fragment thereof that selectively binds to neurokinin B disclosed in WO2003102136 or WO2020101017. In some embodiments, the therapeutic agent is a fusion protein.

[0014] In some embodiments, the therapeutic agent is a nucleic acid. In some embodiments, the therapeutic agent is an RNAi molecule. In some embodiments, the RNAi molecule is shRNA, siRNA, microRNA or asymmetric interfering RNA. In some embodiments, the therapeutic agent is an antisense molecule, lhRNA, shRNA embedded in miRNA or a small internally segmented RNA. In some embodiments, the therapeutic agent is administered by a viral vector.

[0015] In some embodiments, the subject is a human.

[0016] In another aspect, the present disclosure provides a NK3 modulator for use in treating or preventing a disease or condition selected from migraine, cluster headache, general headache, medication overuse headache, trigeminal neuralgia, and orofacial pain, wherein the NK3 modulator is a therapeutic agent that modulates NK3 protein activity or modulates TACR3 gene expression. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description and accompanying drawings (also referred to herein as "figures" and "FIG.") which set forth illustrative embodiments in which the principles of the present invention are utilized, in which:

[0018] Figure 1A-1B The brain-penetrant NK3 antagonist fezonetant ( Figure 1A ) and the peripherally restricted NK3 antagonist SB235375 ( Figure 1B ) Effects on periorbital thresholds after nitroglycerin (hereinafter referred to as "GTN") exposure in an in vivo migraine model using rats with inflammatory soup-sensitized trigeminal ganglia.

[0019] Figure 2 Shown are the effects of NK3 antagonists on luteinizing hormone (LH) levels at 30, 90 and 150 minutes after dosing with fezonetant or SB 235375 in adult castrated rats.

[0020] Incorporation by reference

[0021] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0022] Neurokinin receptor 3 ("NK3") (also referred to as tachykinin receptor 3) is encoded by the TACR3 gene (also referred to herein as the "NK3 gene"). NK3 modulators are provided herein for the treatment of headache disorders and diseases (such as cluster headaches and migraines). Such NK3 modulators include agents that modulate NK3 protein activity (e.g., agents that bind to and / or modulate NK3 protein activity) and agents that modulate TACR3 gene expression (e.g., agents that modulate NK3 protein levels by changing the expression level of the TACR3 gene encoding the NK3 protein). The present disclosure demonstrates the efficacy of NK3 modulators in well-known migraine models. In addition, in some embodiments of the present disclosure, NK3 modulators are subject to peripheral restrictions (e.g., hardly penetrate into the central nervous system ("CNS"), so that NK3 modulators only produce pharmacological effects on peripheral tissues (including, for example, tissues of the peripheral nervous system)). Such peripherally restricted NK3 modulators have the additional advantage of minimizing unnecessary side effects caused by NK3 regulation in the CNS, such as unnecessary changes in hormone levels, including luteinizing hormone (LH).

[0023] definition

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated by reference.

[0025] As used in the specification and claims, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0026] As used herein, the term "about" or "approximately" when referring to a measurable value (such as amount or concentration, etc.) is intended to cover a change of 20%, 10%, 5%, 1%, 0.5% or even 0.1% of a specified amount. For example, according to the practice of this area, "about" can mean plus or minus 10%. Alternatively, "about" can mean a range of plus or minus 20%, plus or minus 10%, plus or minus 5% or plus or minus 1% of a given value. Alternatively, particularly for biological systems or processes, the term can mean within an order of magnitude, up to 5 times or up to 2 times of a value. When a specific value can be described in the application and claims, unless otherwise stated, it can be assumed that the term "about" covers an acceptable error range for the specific value. In addition, when a range, subrange or both of a value can be provided, the range or subrange can include the endpoints of the range or subrange.

[0027] When values ​​are described as ranges, it is understood that such disclosure includes disclosure of all possible sub-ranges within such ranges, as well as specific values ​​falling within such ranges, regardless of whether a specific value or specific sub-range is explicitly stated.

[0028] The terms "comprises," "having," and "includes" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," are also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, and also encompasses other unlisted steps.

[0029] As used herein, the term "antibody or antigen-binding fragment thereof" is intended to encompass polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies, including mutant proteins and variants thereof; antibody fragments such as Fab fragments, F(ab') fragments, single-chain FvFc, single-chain Fv; and derivatives thereof, including Fc fusions and other modifications, and any other immunologically active molecules, as long as they exhibit the desired biological activity (i.e., antigen association or binding). In addition, unless the context dictates otherwise, the term also includes antibodies of all classes (i.e., IgA, IgD, IgE, IgG, and IgM) and all isotypes (i.e., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) and variants thereof.

[0030] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0031] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0032] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable", i.e., compatible with the other ingredients of the formulation and not harmful to the patient.

[0033] The term "preventing" is art-recognized and well understood in the art when used in connection with a condition such as headache, and includes administering a composition that reduces the frequency of symptoms of, or delays the onset of, a medical condition in a subject relative to a subject not receiving the composition. Thus, preventing a headache includes, for example, reducing the number of patients suffering from a headache in a population of patients receiving prophylactic treatment relative to a control population not receiving treatment. Preventing a headache condition also includes, for example, reducing the number of diagnoses of a headache condition in a population receiving treatment relative to a control population not receiving treatment, and / or delaying the onset of symptoms of a headache condition in a population receiving treatment relative to a control population not receiving treatment.

[0034] As used herein, the phrase "therapeutically effective amount" means the amount of a compound that, when administered to a patient to treat a disease, is sufficient to treat a disease or condition. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism and excretion of the patient to be treated.

[0035] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result for a disease, disorder, or medical condition, including but not limited to a therapeutic benefit. In certain embodiments, treatment or therapy involves administering a compound or composition disclosed herein to a subject. Therapeutic benefit may include eradication or amelioration of the underlying disorder being treated.

[0036] As used herein, "RNAi" refers to interfering RNA or RNA interference. RNAi refers to the means of selective post-transcriptional gene silencing by destroying specific mRNA by binding and inhibiting molecules processed by mRNA, such as inhibiting mRNA translation or causing mRNA degradation. As used herein, the term "RNAi" refers to any type of interfering RNA, including but not limited to siRNAi, shRNAi, endogenous microRNA, artificial microRNA or asymmetric interfering RNA. For example, it includes sequences previously identified as siRNA, regardless of the downstream processing mechanism of RNA.

[0037] As used herein, "regulation" refers to the presence of a composition, relative to comparable conditions in the absence of a composition, changes in the activity or expression of a target protein / gene. As used herein, the term "regulation" can be up-regulated (e.g., activated or stimulated) or down-regulated (e.g., inhibited or contained). For example, regulation can lead to changes in the cellular level of a target protein or target gene expression, protein stability, enzymatic modification (e.g., phosphorylation) of a target protein, binding characteristics (e.g., binding to a target transcriptional regulatory element) or any other biological, functional or immunological properties of a target protein. Activity changes can be caused by, for example, an increase or decrease in target gene expression, stability of the mRNA encoding the target protein, translation efficiency or other biological activity changes of a target protein transcription factor (e.g., regulating the expression of a target protein response gene). The mode of action of a target gene / protein regulator can be direct, such as by binding to a target protein or to a gene encoding a target protein. Changes can also be indirect, such as by binding to and / or modifying (e.g., enzymatically) another molecule that otherwise regulates a target gene / protein (e.g., a kinase that specifically phosphorylates a target protein).

[0038] As used herein, the terms "administer," "administered," "administration," or "to administer" refer to the step of giving (i.e., administering) a pharmaceutical composition to a subject, or alternatively, to the step of a subject receiving a pharmaceutical composition. The pharmaceutical compositions disclosed herein can be topically administered by various methods. For example, intramuscular, intradermal, subcutaneous administration, intrathecal administration, intraperitoneal administration, topical (transdermal), instillation, and implantation (e.g., slow release devices such as polymer implants or micro-osmotic pumps) can all be appropriate routes of administration.

[0039] As used herein, the term "nucleic acid" refers to ribonucleic acid or deoxyribonucleic acid or its analogs, including nucleic acid analytes in any form; for example, siRNA or microRNA. Nucleic acid can be single-stranded or double-stranded, or can contain parts of both double-stranded and single-stranded sequences. Nucleic acid can be DNA, genome and cDNA, RNA or hybrid, wherein the nucleic acid can contain a combination of deoxyribonucleotides and ribonucleotides, and a base combination including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine, hypoxanthine, isocytosine and isoguanine. Nucleic acid can be synthesized as a single-stranded molecule or expressed in a cell (in vitro or in vivo) using a synthetic gene. Nucleic acid can be obtained by chemical synthesis methods or by recombinant methods. The description of a single strand also defines the sequence of the complementary strand. Therefore, nucleic acid also encompasses the complementary strand of the described single strand. Many variants of nucleic acid can be used for the same purpose as a given nucleic acid. Therefore, nucleic acid also encompasses substantially identical nucleic acids and their complements.

[0040] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cattle, ungulates, lagomorphs, rodents, etc.). In various embodiments, a subject may be a person (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a boy, a girl) who is receiving care from a physician or other health worker in a hospital, as an outpatient, or in other clinical settings. In certain embodiments, a subject may not be under the care or prescription of a physician or other health worker.

[0041] As used herein, the phrase "a subject in need thereof" refers to a subject suffering from or at risk of a pathology that is being treated prophylactically or therapeutically with a therapeutic protein described herein, as described below.

[0042] As used herein, the term "specificity" refers to the ability of a protein binding domain, particularly an immunoglobulin or immunoglobulin fragment (such as a nanobody), to preferentially bind to one antigen over a different antigen, and does not necessarily mean high affinity.

[0043] Treatment of headache disorders

[0044] Provided herein is a method for treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a therapeutic agent that modulates the activity of a neurokinin receptor 3 ("NK3") protein or modulates the expression of a TACR3 gene. In some embodiments, the disease or condition is a headache disorder. In some embodiments, the disease or condition is selected from migraine, medication overuse headache, cluster headache, general headache, tension headache, caffeine headache, hormonal headache, persistent migraine, hypertensive headache, rebound headache, post-traumatic headache, exertion headache, spinal headache, thunderclap headache, ice pick headache, trigeminal neuralgia, oral-facial pain (e.g., chronic oral-facial pain), or a combination of two or more of these diseases or conditions. Non-limiting examples of the combination include migraine and general headache, general headache and trigeminal neuralgia, and cluster headache and oral-facial pain. In some embodiments, the disease or condition is selected from: migraine, medication overuse headache, cluster headache, general headache, trigeminal neuralgia, and oral-facial pain. In further embodiments, the disease or condition is migraine.In some embodiments, the subject is a mammal.In some embodiments, the subject is a human.

[0045] In some embodiments, the therapeutic agents described herein are used in the preparation of a medicament for preventing or treating a disease or condition. In some embodiments, the therapeutic agents described herein are used in the preparation of a medicament for preventing or treating a headache disorder. In some embodiments, the therapeutic agents described herein are used in the preparation of a medicament for preventing or treating a disease or condition selected from migraine, medication overuse headache, cluster headache, general headache, tension headache, caffeine headache, hormonal headache, continuous migraine, hypertensive headache, rebound headache, post-traumatic headache, exertion headache, spinal headache, thunderclap headache, ice pick headache, trigeminal neuralgia, orofacial pain, or a combination of two or more of these diseases or conditions.

[0046] In some embodiments, described herein are NK3 modulators for use in treating or preventing a disease or condition. In some embodiments, described herein are NK3 modulators for use in treating or preventing a headache disorder. In some embodiments, the disclosure provides NK3 modulators for use in treating or preventing a disease or condition selected from the group consisting of migraine, medication overuse headache, cluster headache, general headache, trigeminal neuralgia, and orofacial pain, wherein the NK3 modulator is a therapeutic agent that modulates NK3 protein activity or modulates TACR3 gene expression.

[0047] In some embodiments, compositions comprising therapeutic agents of the present disclosure are administered for prophylactic and / or therapeutic treatment. In some embodiments, NK3 modulators are administered to a patient already suffering from a headache disorder in an amount sufficient to cure or at least partially arrest one or more symptoms of the headache disorder. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to medications, and the judgment of the treating physician.

[0048] In some embodiments, administration of a therapeutic agent of the present disclosure results in cessation or reduction of one or more symptoms of a headache disorder. In some embodiments, administration of a therapeutic agent of the present disclosure results in cessation or reduction of one or more symptoms of a disease or condition selected from migraine, medication overuse headache, cluster headache, general headache, trigeminal neuralgia, and orofacial pain. In some embodiments, administration of a therapeutic agent of the present disclosure results in cessation or reduction of one or more symptoms selected from pain, sensitivity to light, sensitivity to sound, sensitivity to smell, aura, nausea, vomiting, restlessness, vertigo, dizziness, muscle stiffness, muscle cramps, swelling, numbness, scalp tenderness, and nasal congestion. In some embodiments, administration of a therapeutic agent of the present disclosure results in cessation or reduction of one or more symptoms selected from pain, sensitivity to light, sensitivity to sound, nausea, and vomiting. In some embodiments, administration of a therapeutic agent of the present disclosure results in cessation or reduction of pain (e.g., pain associated with a headache disorder). In some embodiments, administration of a therapeutic agent of the present disclosure results in the disappearance of pain.

[0049] In preventive applications, compositions containing the therapeutic agents described herein are administered to a patient susceptible to a disorder or condition (e.g., a headache disorder) or at risk of another disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, etc. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0050] The therapeutic agents of the present disclosure can be administered to a subject using various routes of administration, including oral, transmucosal, topical, transdermal, inhalation, intravenous, subcutaneous, intradermal, intramuscular, intraarticular, perineural, intraventricular, intravenous, intraperitoneal, intranasal, and intraocular.

[0051] NK3 signaling has a unique function in the CNS where its regulation of KNDy (kisspeptin, NKB, dynorphin) neurons in the hypothalamus modulates gonadotropin-releasing hormone (GnRH), ultimately controlling pulsatile pituitary secretion of LH. See Uenoyama, Y., Nagae, M., Tsuchida, H., Inoue, N. & Tsukamura, H., Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as aGnRH Pulse Generator Controlling Mammalian Reproduction. 12 FRONT. ENDOCRINOL. 724632 (2021); Depypere, H., Lademacher, C., Siddiqui, E. & Fraser, GL Fezolinetant in the treatment of vasomotor symptoms associated with menopause, 30 EXPERTOPIN. INVESTIG. DRUGS 681–694 (2021) (hereinafter “Depypere 2021”). In order to avoid unnecessary side effects associated with affecting the secretion of these gonadotropins, in some embodiments, the therapeutic agent selectively regulates NK3 in peripheral tissues rather than NK3 in the CNS. In some embodiments, the therapeutic agent selectively modulates NK3 in the peripheral nervous system, but not in the CNS.

[0052] In some embodiments, the therapeutic agent is a peripherally restricted NK3 regulator. In some embodiments, the therapeutic agent is a peripherally restricted NK3 regulator (e.g., not accumulated in the brain to a clinically significant concentration). In some embodiments, the use of peripherally restricted NK3 regulators minimizes or avoids unnecessary side effects associated with NK3 regulation in the CNS (e.g., changes in gonadotropin levels such as LH). Such side effects include thermoregulatory dysfunction, changes in bone density, paresthesia, thrombophlebitis, and changes in one or more gonadotropin levels. In some embodiments, the administration of NK3 regulators disclosed herein lacks one or more of the following side effects: changes in bone density, paresthesia, thrombophlebitis, infertility, changes in libido, abnormal menstrual cycles (e.g., delayed or blocked ovulation), changes in testosterone levels, testicular atrophy, and changes in gonadotropin levels (e.g., luteinizing hormone). In some embodiments, the administration of NK3 regulators disclosed herein does not reduce LH levels in the subject.

[0053] In some embodiments, administration of a therapeutic agent in a therapeutically effective amount does not reduce luteinizing hormone in a subject. In some embodiments, administration of a therapeutically effective amount of a therapeutic agent reduces luteinizing hormone in a subject, e.g., by less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 11%, less than 12%, less than 13%, less than 14%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50%. In some embodiments, administration of a therapeutically effective amount of a therapeutic agent reduces the concentration of luteinizing hormone in a sample obtained from a subject, for example, by less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 11%, less than 12%, less than 13%, less than 14%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50%. In some embodiments, administration of a therapeutic agent at a therapeutic level reduces luteinizing hormone in a subject by less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5%. In some embodiments, the sample includes, for example, blood, plasma, urine, mucus, or saliva.The foregoing examples are exemplary only and are not intended to limit the scope of the present disclosure.

[0054] NK3 modulators

[0055] In some embodiments, the therapeutic agent modulates the activity of neurokinin receptor 3 ("NK3") protein or modulates the expression of the TACR3 gene. In some embodiments, the therapeutic agent modulates the activity of the NK3 protein. In some embodiments, the therapeutic agent is a NK3 modulator. In some embodiments, the therapeutic agent is a NK3 antagonist. In some embodiments, the therapeutic agent is a NK3 agonist. In some embodiments, the therapeutic agent binds to the NK3 protein to prevent endogenous ligands from binding to the NK3 protein. The method of the present disclosure includes administering a therapeutic agent that can modulate the activity of the NK3 protein. The therapeutic agent can enhance or weaken the activity of the NK3 protein. In some embodiments, at a therapeutically effective concentration, the therapeutic agent modulates the activity of the NK3 protein by at least about 0.01%, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% relative to the activity of the NK3 protein in the standard.

[0056] In some embodiments, the therapeutic agent regulates the expression of the TACR3 gene. In some embodiments, the therapeutic agent inhibits the expression of the TACR3 gene. In some embodiments, the therapeutic agent downregulates the expression of the TACR3 gene. In some embodiments, the therapeutic agent increases the expression of the TACR3 gene. In some embodiments, the therapeutic agent upregulates the expression of the TACR3 gene.

[0057] In some embodiments, relative to the central nervous system, the administration of therapeutic agents selectively regulates the activity of NK3 proteins in peripheral tissues or the expression of TACR3 genes. In some embodiments, relative to the central nervous system, the administration of therapeutic agents selectively regulates the activity of NK3 proteins in peripheral nervous systems or the expression of TACR3 genes. In some embodiments, the administration of therapeutic agents does not cause one or more pharmacological effects associated with NK3 regulation in CNS. In some embodiments, the administration of therapeutic agents does not cause one or more pharmacological effects selected from thermoregulatory dysfunction, bone mineral density, paresthesia, thrombophlebitis and gonadotropin levels (e.g., luteinizing hormone) changes.

[0058] In some embodiments, the therapeutic agent is confined to peripheral tissues. In some embodiments, the therapeutic agent is confined to the peripheral nervous system. In some embodiments, the therapeutic agent does not substantially cross the blood-brain barrier. In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of, for example, at least about 2: 1, at least about 3: 1, at least about 4: 1, at least about 5: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25: 1, at least about 50: 1, at least about 75: 1, at least about 100: 1, at least about 150: 1, at least about 200: 1, at least about 250: 1, at least about 300: 1, at least about 350: 1, at least about 400: 1, at least about 450: 1, at least about 500: 1, or at least about 1000: 1. In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of at least about 10: 1. In further embodiments, administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of at least about 100:1.

[0059] In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in a subject of, e.g., about 2:1 to about 1000:1, about 2:1 to about 500:1, about 2:1 to about 250:1, about 2:1 to about 100:1, about 2:1 to about 75:1, about 2:1 to about 50:1, about 2:1 to about 25:1, about 2:1 to about 20:1, about 2:1 to about 15:1, about 2:1 to about 10:1, about 2:1 to about 5:1, about 2:1 to about 4:1, or about 2:1 to about 3:1. In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in a subject of, e.g., about 4:1 to about 1000:1, about 4:1 to about 500:1, about 4:1 to about 250:1, about 4:1 to about 100:1, about 4:1 to about 75:1, about 4:1 to about 50:1, about 4:1 to about 25:1, about 4:1 to about 20:1, about 4:1 to about 15:1, about 4:1 to about 10:1, or about 4:1 to about 5:1. In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration in a subject to brain tissue concentration of, e.g., about 10: 1 to about 1000: 1, about 10: 1 to about 500: 1, about 10: 1 to about 250: 1, about 10: 1 to about 100: 1, about 10: 1 to about 75: 1, about 10: 1 to about 50: 1, about 10: 1 to about 25: 1, about 10: 1 to about 20: 1, or about 10: 1 to about 15: 1. In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration in a subject to brain tissue concentration of, e.g., about 2: 1 to about 20: 1.

[0060] In some embodiments, the therapeutic agent contemplated herein is a small molecule, a protein, or a nucleic acid. In some embodiments, the therapeutic agent is a small molecule. Non-limiting examples of small molecule therapeutic agents include those disclosed in the following documents: EP0673928, WO1995032948, WO1997010211, WO1997019928, WO1997019927, WO1997021680, WO1998018785, WO1998057972, WO1999026924, WO1999001451, WO2000021931, WO2000064877, WO2000039114, WO2002013825, WO2002094821, WO2002083645, WO2002083646, WO2002083650 002038547, WO2002038548, WO2002044154, WO2002043734, WO2002044165, WO2004066951, WO2004066950, WO2005014575, WO2005061462, WO20 05016884, WO2005110987, US2005148601, WO2006050989, WO2006050991, WO2006050992, WO2006130080, WO2006137789, WO2007086799, WO200 7018465, WO2007018469, WO200700396, WO2007035157, WO2007018466, WO2007035156, WO2007035158, WO2007069977, WO2007012900, WO20070 28654, US20070219214, EP1829556, WO2008115140, WO2008131779, WO2008148688, WO2008148689, WO2008151969, WO2008081012, WO20091302 40. WO2009156339, WO2009033995, WO2009019163, WO2009024502, WO2009072643, WO2010106081, WO2010045948, WO2010028655, WO201008625 9. WO2010015626, WO2020101017, JP201081888, WO2011110183, WO2011121137, WO2012039718, WO2012009227, WO2012004207, WO2013050424,WO2014154895, WO2014154896, WO2014089019, WO2015200594, WO2015033163, WO2019210327, WO2019074081, and WO2021030335.

[0061] In some embodiments, the small molecule therapeutic agent is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, PD161182, SCH206272, GSK 256471, and SB48968. In some embodiments, the small molecule therapeutic agent is selected from the group consisting of fizonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, and PD161182. In some embodiments, the small molecule therapeutic agent is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653. In some embodiments, the small molecule therapeutic agent is selected from the group consisting of 2-diphenylquinoline-4-carbohydrazide, PD161182, SR142801, CS-003 and MLE-301.

[0062] In some embodiments, the therapeutic agent is a protein. In some embodiments, the protein therapeutic agent is selected from antibodies, enzymes, hormone proteins, signaling proteins, and fusion proteins or functional fragments thereof. In some embodiments, the therapeutic agent is an antibody or functional fragment thereof that selectively binds to NK3 or neurokinin B. Non-limiting examples of antibodies or functional fragments thereof that selectively bind to NK3 include those disclosed in WO2012020162A1. Non-limiting examples of antibodies or functional fragments thereof that selectively bind to neurokinin B include those disclosed in WO2003102136 or WO2020101017. In some embodiments, the therapeutic agent is a fusion protein that selectively binds to NK3 or neurokinin B. In some embodiments, the protein therapeutic agent is a NK3 activator. Non-limiting examples of protein therapeutic agents that activate NK3 are selected from neurokinin B, neurokinin A, hemokinin 1, substance P, [Pro 7 ]Neurokinin B, [MePhe 7 ]-neurokinin B and its derivatives (see Misu et al., Med. Chem. 2014, 57, 20, 8646-8651), senktide and its derivatives (see Misu et al., Med. Chem. 2014, 57, 20, 8646-8651), kassinin, eledoisin, NK3R-A1, NK3R-A2, Senktide analogs and Scyliorhinin II. In other embodiments, the protein therapeutic agent is an NK3 inhibitor. Non-limiting examples of protein therapeutic agents that activate NK3 are selected from [Trp 7 ,β-Ala 8 ] neurokinin A and [MePhe 7 β-Ala 8 ] neurokinin A (see Drapeau et al., Regulatory Peptides, Volume 31, Issue 2, 15 November 1990), FK 224, GR138676, substance P (1-7) (Arg-Pro-Lys-Pro-Gln-Gln-Phe) and GR 94800 TFA (Bz-AA-{D-Trp}-F-{D-Pro}-P-{Nle}-NH2).

[0063] In a further embodiment, the protein therapeutic comprises one or more CDRs from the following antibodies: NB300-102 and NBP1-82561 from Novus Biologicals, ABIN500361 and ABIN725735 from antibodies-online, GTX31316 and GTX70489 from GeneTex, A04916 and A30848 from Boster Biological Technology, PAB13001 and PAB27695 from Abnova Corporation, TA306441 and AP01273PU-N from OriGene, LS-C34712 and LS-C120754 from LifeSpan BioSciences., Inc., and LS-C120755 from Invitrogen. Antibodies, bs-0166R and bs-0914R from Bioss, orb74850 and orb339175 from Biorbyt, AP30602PU-N and AP05734PU-N from Acris Antibodies GmbH, CSB-PA003454 and CSB-PA023070ESR2HU from Cusabio Biotech Co., Ltd, OAAF05000 and ARP64678_P050 from Aviva Systems Biology, APS10550 and AP14222b from Abgent, DF4997 from Affinity Biosciences, 4255 from ProSci, FNab08472 from Wuhan FineBiotech Co., Ltd, and FNab08472 from Bioworld Technology, Inc. BS2736, Proteintech Group 22334-1-AP, NovoPro Bioscience Inc. 115972 and 129584, St John's Laboratory STJ29300 and STJ94498, Abbkine Scientific Co. Ltd.ABP51965 and ABP57531 from MilliporeSigma / Merck KGaA, SAB3500368 and HPA009418 from MyBioSource, HPA009418 from Atlas Antibodies, 250776 and 250777 from Abbiotec, 868901 and 868902 from BioLegend, abx217136 and abx006440 from Abbexa, AMM06701G and APR13683G from Leading Biology, 224546 and 224546-AP from United States Biological, and 224546-AP from Creative Biotechnology. CPBT-66754RT and DPABH-02783 from Diagnostics, 119-10140 and 119-10172 from RayBiotech, Inc., 18-461-10149 and 18-461-10183 from GenWay, and 600-401-DC1 from Rockland Immunochemicals, Inc.

[0064] In other embodiments, the therapeutic agent is a nucleic acid, such as an RNA molecule, such as an interfering RNA (RNAi) molecule. RNA interference is a biological process in which RNA molecules participate in the sequence-specific inhibition of gene expression by double-stranded RNA through translation or transcription inhibition. In some embodiments, the therapeutic agent is an asymmetric interfering RNA complementary to a part of a human TACR3 gene (NCBI gene ID: 6870), or any combination thereof. In some embodiments, the therapeutic agent is an antisense molecule, an lhRNA, an miRNA-embedded shRNA, a small internal segment RNA, which is complementary to a part of a human TACR3 gene (NCBI gene ID: 6870) or any combination thereof. In some embodiments, the therapeutic agent is administered by a viral vector.

[0065] Pharmaceutical preparations

[0066] In some aspects, the present disclosure provides a pharmaceutical composition comprising a NK3 modulator and at least one pharmaceutically acceptable excipient.

[0067] NK3 modulators can be formulated into any suitable pharmaceutical formulation. The pharmaceutical formulations disclosed herein generally contain an active ingredient (e.g., NK3 modulator) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, antioxidants, solubilizers and adjuvants. The preparation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999).

[0068] The formulation method of therapeutic protein can include any therapeutic protein of the present disclosure and one or more inert, pharmaceutically acceptable excipients or carriers to form a semisolid or liquid composition. These pharmaceutical compositions can include at least one active ingredient (e.g., therapeutic agent of the present disclosure). Such compositions can also include non-toxic auxiliary substances, such as solvents, buffers or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, the therapeutic protein of the present disclosure can be lyophilized or in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0069] The amount of a therapeutic agent of the present disclosure will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the therapeutic protein and the judgment of the prescribing physician.

[0070] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Those skilled in the art will now appreciate that many variations, changes and substitutions are possible without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used to practice the present invention. The following claims are intended to define the scope of the present invention, and thus encompass methods and structures and their equivalents within the scope of these claims.

[0071] Example

[0072] The following examples are illustrative and do not limit the scope of the compositions, devices, uses and methods disclosed herein.

[0073] Example 1: In vivo migraine model

[0074] The surgery was performed as previously described in Oshinsky, ML & Gomonchareonsiri, S., Episodic dural stimulation in awake rats: a model for recurrent headache, 47 HEADACHE 1026–1036 (2007). Adult male Sprague-Dawley rats were accustomed to the operation for 1-2 weeks before the dural cannulation surgery under isoflurane anesthesia. Care was taken not to disturb the dura mater. A custom flange guide cannula (22GA, Plastics One) was inserted. The cannula was fixed to the bone with a small screw and dental cement.

[0075] After 1-2 weeks of recovery from surgery, animals received an epidural infusion of an inflammatory soup containing 2 mM histamine, bradykinin, serotonin, 0.2 mM prostaglandin E2 for 5 consecutive days (1 time / day) (i.e., a 5-day sensitization period) under brief isoflurane anesthesia (1.5-3%). If rats did not show signs of facial sensitivity after the final infusion, they were removed from the study.

[0076] After a 5-day sensitization period, rats had a one-week washout period before receiving nitroglycerin challenge (GTN, 0.1 mg / kg, IP) and fezonetant (30 or 100 mg / kg, PO), SB 235375 (30 or 100 mg / kg, PO) or vehicle (0.5% methylcellulose in sterile water for fezonetant, sterile water for SB 235375, PO). The design was that the same animals received multiple treatments in a crossover manner within the subject with at least a one-week washout period between each treatment. Evoked sensory testing for mechanical allodynia was performed by the von Frey periorbital threshold test. Sensory testing was performed during the day using von Frey filaments with reproducible calibrated flexion forces ranging from 0.4 to 10 g and an up-and-down method. See Dixon, WJ, The Up-and-Down Method for Small Samples, 60 J. AM. STAT. ASSOC., 967–978 (1965); Chaplan, SR, Bach, FW, Pogrel, JW, Chung, JM & Yaksh, TL, Quantitative assessment of tactile allodynia in the rat paw, 53 J. NEUROSCI. METHODS 55–63 (1994) (hereinafter “Chaplan 1994”). Based on the response pattern and the force of the final filament, the periorbital threshold (g) is calculated according to the prior art methods described below, for example, Chaplan 1994 and Bonin, RP, Bories, C. & De Koninck, Y., A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments, 10 MOL. PAIN 26 (2014). Blinded investigators tested periorbital sensitivity before drug administration and 45 min and 1.5 h after drug administration.Studies were conducted with n=13-22.

[0077] Results from the in vivo migraine model Figure 1A-1B Specifically, Figure 1A-1B The brain-penetrant NK3 antagonist fezonetant ( Figure 1A ) and the peripherally restricted NK3 antagonist SB 235375 ( Figure 1B) on the periorbital threshold of rats with inflammatory decoction-sensitized trigeminal ganglion after exposure to GTN. There were no significant differences in baseline withdrawal threshold between the groups (baseline measurements were obtained from Figure 1A-1B ).like Figure 1A As shown, at the 90-min time point, the paw withdrawal threshold of rats receiving GTN and 30 mg / kg fezonetant was significantly higher than that of rats receiving either control group (normal saline + vehicle or GTN + vehicle). Compared with each control group, the paw withdrawal threshold of rats receiving GTN and 100 mg / kg fezonetant was significantly higher at both time points, indicating that both doses had NK3-dependent analgesic effects (2-factor ANOVA, vs GTN / veh). In addition, Figure 1A A dose-dependent increase in the periorbital threshold was demonstrated for fezonetant treatment, as a 100 mg / kg dose of fezonetant produced a higher paw withdrawal threshold than a 30 mg / kg dose of fezonetant.

[0078] Figure 1B The effectiveness of SB 235375 (NK3 antagonist with minimal brain penetration) in an in vivo migraine model of the same sensitization was shown. See Hay, DWP et al., Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs, 300 J. PHARMACOL. EXP. THER. 314–323 (2002). Similar to rats treated with fezonetant, rats co-administered with GTN and SB 235375 showed higher pain thresholds than rats treated with GTN and vehicle at both doses (30 and 100 mg / kg) and time points (45, 90 minutes) (see Figure 1B ). Therefore, if Figure 1A-1B As shown, two NK3 antagonists, including the CNS-penetrant fezonetant and the peripherally restricted SB 235375, showed efficacy in treating migraine.

[0079] Example 2: Luteinizing Hormone (LH) Suppression Study

[0080] LH measurement studies were performed in castrated male Sprague-Dawley rats. Animals were castrated by midline scrotal incision under 50% anesthesia. Surgery was performed at least 15 days before compound testing.

[0081] Serum was collected at baseline and then every 15 minutes starting from 30 minutes after PO (periorbital) administration with vehicle, fezonetant (30 mg / kg) or SB 235375 (30 and 100 mg / kg). Blood was collected from the jugular vein, transferred to a 1.5 mL centrifuge tube, and centrifuged at 8000 g for 15 minutes to separate serum. Serum LH levels were determined using a rat luteinizing hormone ELISA kit (colorimetric, Novus). The assay was performed according to the manufacturer's protocol. For the vehicle and SB 235375 groups, the group size was n=10, and for the fezonetant group, the group size was n=4.

[0082] The results of LH suppression studies are Figure 2 Available in. Figure 2 The data shown in demonstrate that brain exposure of SB235375 at doses used to treat migraines is insufficient to cause significant CNS-dependent effects. Both fenazolinitan (30 mg / kg) and SB 235375 (30 and 100 mg / kg) were tested for their ability to suppress the high LH levels reported in castrated rats. See Depypere 2021; Modi, M. & Dhillo, WS, Neurokinin 3 Receptor Antagonism: A Novel Treatment for Menopausal Hot Flushes, 109 NEUROENDOCRINOLOGY, 242–248 (2019). Rats treated with fenazolinitan (30 mg / kg) showed significantly reduced serum LH concentrations at all measured time points (30, 90 and 150 min). In contrast, there was no significant difference in LH levels in animals treated with SB 235375 compared to the vehicle-treated group (see Figure 2 ).

[0083] Figure 2 The mean LH values ​​on which the data provided are based are provided in Table 1 below.

[0084] Table 1

[0085]

[0086] As shown in Table 1, at 150 minutes after administration, LH values ​​for vehicle, 30 mg / kg dose of SB 235375, and 100 mg / kg dose of SB 235375 were substantially the same (29.3 ng / mL, 30.4 ng / mL, and 31.1 ng / mL, respectively), while fezonetant resulted in a significant decrease in LH levels (5.5 ng / mL). Thus, fezonetant resulted in an approximately 85% decrease in LH levels compared to vehicle treatment, while minimal changes were observed at the SB 235375 doses tested at 150 minutes after treatment (approximately 4% and 10% decreases for the 30 mg / kg and 100 mg / kg doses, respectively). Similarly, at 30 and 90 minutes post-treatment, fezonetant resulted in a more significant decrease in LH levels (approximately 60% and 85% decreases compared to vehicle, respectively) compared to the same 30 mg / kg dose of SB 235375 (approximately +4% and +13% increases, respectively) and 100 mg / kg dose of SB 235375 (approximately 26% and 14% decreases, respectively).

[0087] Figure 1A-1B and Figure 2 The foregoing data presented in show that NK3 modulators are effective in treating headaches (e.g., migraines), and this efficacy is retained when the NK3 modulators are peripherally restricted (e.g., not accumulated to clinically significant concentrations in the brain). In addition, the data show that the use of peripherally restricted NK3 modulators provides the additional advantage of avoiding unnecessary side effects associated with NK3 regulation in the CNS (e.g., changes in gonadotropin levels such as LH). The foregoing examples are exemplary only and are not intended to limit the scope of the present disclosure.

Claims

1. A method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutic agent that modulates the activity of a neurokinin receptor 3 ("NK3") protein or modulates the expression of a TACR3 gene, wherein the disease or condition is selected from the group consisting of migraine, medication overuse headache, cluster headache, general headache, trigeminal neuralgia, and orofacial pain.

2. The method of claim 1, wherein the disease or condition is selected from the group consisting of migraine, medication overuse headache, cluster headache, and general headache.

3. The method of claim 1, wherein the disease or condition is migraine.

4. The method according to any one of claims 1 to 3, wherein the therapeutic agent modulates the activity of NK3 protein.

5. The method of claim 4, wherein the therapeutic agent is a NK3 antagonist.

6. The method according to any one of claims 1 to 3, wherein the therapeutic agent modulates the expression of the TACR3 gene.

7. The method of claim 6, wherein the therapeutic agent reduces expression of the TACR3 gene.

8. The method of any one of claims 1 to 7, wherein said administration of said therapeutically effective amount of said therapeutic agent does not reduce luteinizing hormone in said subject.

9. The method of any one of claims 1 to 8, wherein the administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of at least 10 to 1.

10. The method of claim 9, wherein the administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in the subject of at least 100 to 1. 11 . The method according to any one of claims 1 to 10 , wherein the administration of the therapeutic agent modulates the activity of the NK3 protein or the expression of the TACR3 gene in peripheral tissues.

12. The method of claim 11, wherein the administration of the therapeutic agent selectively modulates the activity of the NK3 protein or the expression of the TACR3 gene in peripheral tissues as compared to in the central nervous system.

13. The method of any one of claims 1 to 12, wherein the therapeutic agent is a small molecule, a protein, or a nucleic acid.

14. The method of claim 13, wherein the therapeutic agent is a small molecule.

15. The method of claim 14, wherein the therapeutic agent is disclosed in EP0673928, WO1995032948, WO1997010211, WO1997019928, WO1997019927, WO1997021680, WO1998018785, WO1998057972, WO1999026924, WO1999001451, WO2000021931, WO2000064877, WO2000039114, WO2002013825, WO2002094821, WO2002083645, WO2002038547, WO2 002038548, WO2002044154, WO2002043734, WO2002044165, WO2004066951, WO2004066950, WO2005014575, WO2005061462, WO2005016884, WO20051109 87. US2005148601, WO2006050989, WO2006050991, WO2006050992, WO2006130080, WO2006137789, WO2007086799, WO2007018465, WO2007018469, WO200 700396, WO2007035157, WO2007018466, WO2007035156, WO2007035158, WO2007069977, WO2007012900, WO2007028654, US20070219214, EP1829556, WO 2008115140, WO2008131779, WO2008148688, WO2008148689, WO2008151969 , WO2008081012, WO2009130240, WO2009156339, WO2009033995, WO20090191 63. WO2009024502, WO2009072643, WO2010106081, WO2010045948, WO2010028655, WO2010086259, WO2010015626, WO2020101017, JP201081888, WO201 1110183、WO2011121137、WO2012039718、WO2012009227、WO2012004207、WO 2013050424, WO2014154895, WO2014154896, WO2014089019, WO2015200594,WO2015033163, WO2019210327, WO2019074081 or WO2021030335.

16. The method of claim 14, wherein the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, PD161182, SCH206272, GSK 256471, and SB48968.

17. The method of claim 16, wherein the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, and PD161182.

18. The method of claim 16, wherein the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653, and MLE-301.

19. The method of claim 13, wherein the therapeutic agent is a protein.

20. The method of claim 19, wherein the therapeutic agent is an antibody or a functional fragment thereof that selectively binds to NK3 or neurokinin B.

21. The method according to claim 20, wherein the therapeutic agent is an antibody or a functional fragment thereof that selectively binds to NK3 disclosed in WO2012020162A1.

22. The method according to claim 20, wherein the therapeutic agent is an antibody or a functional fragment thereof that selectively binds to neurokinin B disclosed in WO2003102136 or WO2020101017.

23. The method of claim 19, wherein the therapeutic agent is a fusion protein.

24. The method of claim 13, wherein the therapeutic agent is a nucleic acid.

25. The method of claim 24, wherein the therapeutic agent is an RNAi molecule.

26. The method of claim 25, wherein the RNAi molecule is shRNA, siRNA, microRNA, or asymmetric interfering RNA.

27. The method of claim 24, wherein the therapeutic agent is an antisense molecule, an lhRNA, a miRNA-intercalated shRNA, or a small internal segment RNA.

28. The method of any one of claims 1 to 27, wherein the therapeutic agent is administered via a viral vector.

29. The method of any one of claims 1 to 28, wherein the subject is a human.

30. A NK3 modulator for use in treating or preventing a disease or condition in a subject in need thereof, wherein the disease or condition is selected from: migraine, cluster headache, general headache, trigeminal neuralgia and orofacial pain; and wherein the NK3 modulator is a therapeutic agent that modulates NK3 protein activity or modulates TACR3 gene expression.

31. The NK3 modulator for use according to claim 30, wherein the disease or condition is selected from the group consisting of migraine, medication overuse headache, cluster headache and headache in general.

32. A NK3 modulator for use according to claim 30 or claim 31 wherein the disease or condition is migraine.

33. A NK3 modulator for use according to any one of claims 30 to 32, wherein the NK3 modulator modulates the activity of a NK3 protein.

34. A NK3 modulator for use according to any one of claims 30 to 33, wherein the NK3 modulator is a NK3 antagonist.

35. A NK3 modulator for use according to any one of claims 30 to 34, wherein the NK3 modulator modulates the expression of the TACR3 gene.

36. A NK3 modulator for use according to any one of claims 30 to 35, wherein the therapeutic agent reduces expression of the TACR3 gene.

37. A NK3 modulator for use according to any one of claims 30 to 36, wherein administration of the therapeutically effective amount of the NK3 modulator to the subject does not decrease luteinizing hormone in the subject.

38. A NK3 modulator for use according to any one of claims 30 to 37, wherein administration of the NK3 modulator to the subject results in a ratio of plasma concentration to brain tissue concentration in the subject of at least 10 to 1.

39. The NK3 modulator for use according to claim 38, wherein administration of the NK3 modulator to the subject results in a ratio of plasma concentration to brain tissue concentration in the subject of at least 100 to 1.

40. The NK3 modulator for use according to any one of claims 30 to 39, wherein the NK3 modulator modulates the activity of the NK3 protein or the expression of the TACR3 gene in peripheral tissues.

41. The NK3 modulator for use according to claim 40, wherein the NK3 modulator selectively modulates the activity of the NK3 protein or the expression of the TACR3 gene in peripheral tissues as compared to in the central nervous system.

42. A NK3 modulator for use according to any one of claims 30 to 41, wherein the NK3 modulator is a small molecule, a protein or a nucleic acid.

43. A NK3 modulator for use according to any one of claims 30 to 42, wherein the NK3 modulator is a small molecule.

44. The NK3 modulator for use according to claim 43, wherein the small molecule is disclosed in EP0673928, WO1995032948, WO1997010211, WO1997019928, WO1997019927, WO1997021680, WO1998018785, WO1998057972, WO1999026924, WO1999001451, WO2000021931, WO2000064877, WO2000039114, WO2002013825, WO2002094821, WO2002083645, WO2002038547 , WO2002038548, WO2002044154, WO2002043734, WO2002044165, WO2004066951, WO2004066950, WO2005014575, WO2005061462, WO2005016884, WO20051 10987, US2005148601, WO2006050989, WO2006050991, WO2006050992, WO2006130080, WO2006137789, WO2007086799, WO2007018465, WO2007018469, WO 200700396, WO2007035157, WO2007018466, WO2007035156, WO2007035158, WO2007069977, WO2007012900, WO2007028654, US20070219214, EP1829556, WO2008115140, WO2008131779, WO2008148688, WO2008148689, WO2008151969, WO2008081012, WO2009130240, WO2009156339, WO2009033995, WO200901 9163, WO2009024502, WO2009072643, WO2010106081, WO2010045948, WO201 0028655, WO2010086259, WO2010015626, WO2020101017, JP201081888, WO20 11110183、WO2011121137、WO2012039718、WO2012009227、WO2012004207、WO 2013050424, WO2014154895, WO2014154896, WO2014089019, WO2015200594,WO2015033163, WO2019210327, WO2019074081 or WO2021030335.

45. The NK3 modulator for use according to claim 43 or claim 44, wherein the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, PD161182, SCH206272, GSK 256471 and SB48968.

46. ​​The NK3 modulator for use according to any one of claims 43 to 45, wherein the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946 and PD161182.

47. The NK3 modulator for use according to any one of claims 43 to 46, wherein the small molecule is selected from the group consisting of fezonetant, parvenetant, talnetant, osanetant, elinanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653 and MLE-301.

48. The NK3 modulator for use according to claim 42, wherein the NK3 modulator is a protein.

49. The NK3 modulator for use according to claim 48, wherein the NK3 modulator is an antibody or a functional fragment thereof that selectively binds to NK3 or neurokinin B.

50. The NK3 modulator for use according to claim 49, wherein the NK3 modulator is an antibody or a functional fragment thereof that selectively binds to NK3 as disclosed in WO2012020162A1.

51. The NK3 modulator for use according to claim 50, wherein the NK3 modulator is an antibody or a functional fragment thereof that selectively binds to neurokinin B disclosed in WO2003102136 or WO2020101017.

52. The NK3 modulator for use according to claim 48, wherein the NK3 modulator is a fusion protein.

53. The NK3 modulator for use according to claim 42, wherein the NK3 modulator is a nucleic acid.

54. The NK3 modulator for use according to claim 53, wherein the NK3 modulator is an RNAi molecule.

55. The NK3 modulator for use according to claim 54, wherein the RNAi molecule is shRNA, siRNA, microRNA or asymmetric interfering RNA.

56. The NK3 modulator for use according to claim 55, wherein the NK3 modulator is an antisense molecule, an lhRNA, a miRNA-embedded shRNA or a small internal segment RNA.

57. A NK3 modulator for use according to any one of claims 30 to 56, wherein the NK3 modulator is administered via a viral vector.

58. A NK3 modulator for use according to any one of claims 30 to 57, wherein the subject is a human.

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