Treatment of headache disorders with NK3 modulators

Abstract

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

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 334,308, filed April 25, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Migraine is a painful and debilitating trigeminovascular neurological disorder with high prevalence in the general population, affecting approximately 15% of individuals and representing the second leading cause of disability worldwide. Migraine is characterized by recurrent, pulsating headache attacks of moderate to severe pain intensity accompanied by sensitivity to movement, vision, hearing, and other sensory inputs that can last from 4 to 72 hours.

[0003] Although several classes of oral medications have been approved for the treatment of migraine, many currently in use are associated with significant side effects, leading to frequent discontinuations and class changes with poor outcomes. Antibody therapies and small molecules targeting the CGRP receptor have fewer reported side effects, but fewer than one-third of migraine patients respond to these treatments. Thus, there is a great need for novel therapies to treat migraine and other disorders of the trigeminovascular system, such as cluster headaches and medication-overuse headaches and trigeminal neuralgia. Summary of the Invention

[0004] In some aspects, the disclosure provides a method for treating or preventing 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 neurokinin receptor 3 ("NK3") protein or modulates expression of the TACR3 gene, wherein the disease or condition is selected from the group consisting of migraine, cluster headache, general headache, medication-overuse headache, trigeminal neuralgia, and orofacial pain.

[0005] In another aspect, the disclosure provides an NK3 modulator for use in the treatment or prevention of a disease or condition selected from the group consisting of 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 the TACR3 gene.

[0006] In some embodiments, the disease or condition is selected from the group consisting of migraine, medication overuse headache, cluster headache, and general headache. In some embodiments, the disease or condition is migraine.

[0007] In some embodiments, the therapeutic agent modulates the activity of NK3 protein. In some embodiments, the therapeutic agent is an NK3 antagonist. In some embodiments, the therapeutic agent modulates the expression of TACR3 gene. In some embodiments, the therapeutic agent reduces the expression of TACR3 gene.

[0008] In some embodiments, administration of the therapeutic agent does not decrease luteinizing hormone in the subject (e.g., when the therapeutic agent is administered in a therapeutically effective amount). 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 10 to 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 100 to 1. In some embodiments, administration of the therapeutic agent selectively regulates the activity of NK3 protein or the expression of TACR3 gene in peripheral tissue compared to the central nervous system. In some embodiments, administration of the therapeutic agent selectively regulates the activity of NK3 protein or the expression of TACR3 gene in the peripheral nervous system compared to the central nervous system.

[0009] 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.

[0010] In some embodiments, the therapeutic agent is a therapeutic agent as described in EP 0673928, WO 1995032948, WO 1997010211, WO 1997019928, WO 1997019927, WO 1997021680, WO 1998018785, WO 1998057972, WO 1999026924, WO 1999001451, WO 2000021931, WO 2000064877, WO 2000039114, WO 20020138 25, International Publication No. 2002094821, International Publication No. 2002083645, International Publication No. 2002038547, International Publication No. 2002038548, International Publication No. 2002044154, International Publication No. 2002043734, International Publication No. 2002044165, International Publication No. 2004066951, International Publication No. 2004066950, International Publication No. 2005014575, International Publication No. 2005061462, International Publication No. 2005016884, International Publication No. 2005110987, U.S. Patent Application Publication No. 2005148601, International Publication No. 2006050989, International Publication No. 2006050991, International Publication No. 2006050992, International Publication No. 2006130080, International Publication No. 2006137789, International Publication No. 2007086799, International Publication No. 2007018465, International Publication No. 2007018469, International Publication No. 200700396, International Publication No. 2007035157, International Publication No. 2007018466, International Publication No. 2007035156, International Publication No. 2007035158, International Publication No. 2007069977, International Publication No. 20070 12900, International Publication No. 2007028654, U.S. Patent Application Publication No. 20070219214, European Patent No. 1829556, International Publication No. 2008115140, International Publication No. 2008131779, International Publication No. 2008148688, International Publication No. 2008148689, International Publication No. 2008151969, International Publication No. 2008081012, International Publication No. 2009130240, International Publication No. 2009156339, International Publication No. 2009033995, International Publication No. 2009019163, International Publication No. 2009024502,International Publication No. 2009072643, International Publication No. 2010106081, International Publication No. 2010045948, International Publication No. 2010028655, International Publication No. 2010086259, International Publication No. 2010015626, International Publication No. 2020101017, JP201081888, International Publication No. 2011110183, International Publication No. 2011121137, International Publication No. 2012039718, International Publication No. 2012039718, International Publication No. 20120201020101017, JP201081888, International Publication No. 2011110183, International Publication No. 2011121137 ...101017, JP201081888, International Publication No. 2011110183, International Publication No. 2011121137, International Publication No. 2012039718, International Publication No. 20120201010101010101010101010101010101010101010101010101010101010101010 The present invention is disclosed in International Publication No. 12009227, International Publication No. 2012004207, International Publication No. 2013050424, International Publication No. 2014154895, International Publication No. 2014154896, International Publication No. 2014089019, International Publication No. 2015200594, International Publication No. 2015033163, International Publication No. 2019210327, International Publication No. 2019074081, or International Publication No. 2021030335.

[0011] In some embodiments, the small molecule is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, 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 fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, 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 fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653, and MLE-301.

[0012] In some embodiments, the therapeutic agent is a protein. In some embodiments, the therapeutic agent is an antibody or functional fragment thereof that selectively binds to NK3 or neurokinin B. In some embodiments, the therapeutic agent is an antibody or functional fragment thereof that selectively binds to NK3 as disclosed in WO2012020162A1. In some embodiments, the therapeutic agent is an antibody or functional fragment thereof that selectively binds to neurokinin B as disclosed in WO2003102136 or WO2020101017. In some embodiments, the therapeutic agent is a fusion protein.

[0013] 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 an shRNA, an siRNA, a microRNA, or an asymmetric interfering RNA. In some embodiments, the therapeutic agent is an antisense molecule, an lhRNA, an miRNA-embedded shRNA, or an internally segmented small RNA. In some embodiments, the therapeutic agent is administered by a viral vector.

[0014] In some embodiments, the subject is a human.

[0015] In another aspect, the disclosure provides an NK3 modulator for use in the treatment or prevention of a disease or condition selected from the group consisting of 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 the TACR3 gene. [Brief description of the drawings]

[0016] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "figures" and drawings ("FIGs")). [Figure 1A] Figure 1A shows the effect of the brain-penetrant NK3 antagonist fezolinethant (Figure 1A) and the peripherally restricted NK3 antagonist SB 235375 (Figure 1B) on periorbital thresholds following nitroglycerin (GTN) exposure in an in vivo migraine model using rats with trigeminal ganglia sensitized to inflammatory soup. [Figure 1B]Figure 1A shows the effect of the brain-penetrant NK3 antagonist fezolinethant (Figure 1A) and the peripherally restricted NK3 antagonist SB 235375 (Figure 1B) on periorbital thresholds following nitroglycerin (GTN) exposure in an in vivo migraine model using rats with trigeminal ganglia sensitized to inflammatory soup. [Diagram 2] FIG. 1 shows the effect of NK3 antagonists on luteinizing hormone (LH) levels in adult castrated rats 30, 90, and 150 minutes after administration of fezolinethant or SB 235375.

[0017] Incorporation by Reference 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 OF THE PREFERRED EMBODIMENTS

[0018] Neurokinin receptor 3 ("NK3") (also known as tachykinin receptor 3) is encoded by the TACR3 gene (also referred to herein as the "NK3 gene"). Provided herein are NK3 modulators for treating headache disorders and diseases, such as cluster headaches and migraines. Such NK3 modulators include both agents that modulate the activity of the NK3 protein (e.g., agents that bind to and / or modulate the activity of the NK3 protein) and agents that modulate the expression of the TACR3 gene (e.g., agents that modulate the level of the NK3 protein by changing the expression level of the TACR3 gene that encodes the NK3 protein). The present disclosure demonstrates the efficacy of NK3 modulators in well-known migraine models. Furthermore, in some embodiments of the present disclosure, the NK3 modulators are peripherally restricted (e.g., have little or no penetration into the central nervous system ("CNS")) so as to have a pharmacological effect only on peripheral tissues (e.g., including tissues of the peripheral nervous system). Such peripherally restricted NK3 modulators have the added advantage of minimizing undesirable side effects caused by modulation of NK3 in the CNS, such as undesirable changes in hormone levels, including luteinizing hormone (LH).

[0019] definition Unless otherwise defined, 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 mentioned herein are incorporated by reference.

[0020] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0021] As used herein, the term "about" or "approximately," when referring to a measurable value, such as an amount or concentration, is meant to encompass a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. For example, "about" may mean ±10%, as per the practice in the art. Alternatively, "about" may mean a range of ±20%, ±10%, ±5%, or ±1% of a given value. Alternatively, particularly with respect to biological systems and processes, the term may mean within an order of magnitude, up to 5-fold, or up to 2-fold of a value. Where particular values ​​may be described in the present application and claims, unless otherwise stated, the term "about" may be assumed to encompass an acceptable range of error for the particular value. Also, where a range, subrange, or both of values ​​may be provided, the range or subrange may include the endpoints of the range or subrange.

[0022] When numerical values ​​are described as ranges, whether or not a specific numerical value or a specific subrange is explicitly recited, such disclosure can be understood to include disclosure of not only the specific numerical values ​​that fall within such ranges, but also all subranges that can exist within such ranges.

[0023] The terms "comprise," "have," and "include" are open-ended linking verbs. Any conjugation 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, but also encompasses other unlisted steps.

[0024] As used herein, the term "antibody or antigen-binding fragment thereof" is intended to encompass polyclonal, multiclonal, monoclonal, chimeric, humanized and primatized antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies including muteins 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, as well as any other immunologically active molecule so long as it exhibits the desired biological activity (i.e., antigen association, or antigen binding). Moreover, unless otherwise indicated by context, the term further includes all classes of antibodies (i.e., IgA, IgD, IgE, IgG, and IgM), and all isotypes (i.e., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), and variations thereof.

[0025] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of 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.

[0026] The phrase "pharmacologically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that 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.

[0027] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0028] The term "preventing" is art-recognized and, when used in relation to a disease such as headache, is well understood in the art and includes administration of a composition that reduces the frequency or delays the onset of symptoms of a medical condition in a subject relative to a subject not receiving the composition. Thus, preventing headaches includes, for example, reducing the number of sufferers of headaches in a population of patients receiving a prophylactic treatment compared to an untreated control population. Preventing headache diseases also includes, for example, reducing the number of diagnoses of headache diseases in a treated population relative to an untreated control population and / or delaying the onset of symptoms of headache diseases in a treated population relative to an untreated control population.

[0029] As used herein, a "therapeutically effective amount" means an amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the 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, excretion, etc., of the patient being treated.

[0030] As used herein, "treatment" or "treating" refers to an approach for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, therapeutic benefit. In certain embodiments, treating or treating includes administering to a subject a compound or composition disclosed herein. A "therapeutic benefit" can include eradication or amelioration of the underlying disease being treated.

[0031] As used herein, "RNAi" refers to interfering RNA or RNA interference. RNAi refers to a method of selective post-transcriptional gene silencing by destroying specific mRNA by a molecule that binds to and inhibits the processing of mRNA, for example by 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 the sequence previously identified as siRNA, regardless of the mechanism of downstream processing of RNA.

[0032] As used herein, "modulate" refers to altering the activity or expression of a target protein / gene in the presence of a composition relative to comparable conditions in the absence of the composition. As used herein, the term "modulate" can be upregulation (e.g., activation or stimulation) or downregulation (e.g., inhibition or suppression). For example, modulation can cause a change in the cellular level of a target protein, or a change in the expression of a target gene, protein stability, enzymatic modification of a target protein (e.g., phosphorylation), binding properties (e.g., binding to a target transcriptional control element), or any other biological, functional, or immunological property of a target protein. A change in activity can result, for example, from an increase or decrease in expression of a target gene, stability, translation efficiency of an mRNA encoding a target protein, or from a change in other biological activity of a target protein transcription factor (e.g., modulation of expression of a target protein-responsive gene). The mode of action of a target gene / protein modulator can be direct, for example, via binding to a target protein or a gene encoding a target protein. The change can also be indirect, for example, by binding to and / or (e.g., enzymatic) modification of another molecule that differentially regulates the target gene / protein (e.g., a kinase that specifically phosphorylates the target protein).

[0033] As used herein, the terms "administer", "administered", "administration" or "administering" refer to the process of giving (i.e., administering) a pharmaceutical composition to a subject, or alternatively, to a subject receiving a pharmaceutical composition. The pharmaceutical compositions disclosed herein can be administered locally by a variety of methods. For example, intramuscular administration, intradermal administration, subcutaneous administration, intrathecal administration, intraperitoneal administration, topical administration (transdermal administration), instillation, and implantation (e.g., of a polymeric implant or a sustained release device such as a mini-osmotic pump) can all be suitable routes of administration.

[0034] As used herein, the term "nucleic acid" refers to ribonucleic acid or deoxyribonucleic acid or analogs thereof, including nucleic acid analytes presented in any context, such as siRNA or microRNA. Nucleic acids may be single-stranded or double-stranded, or may contain portions of both double-stranded and single-stranded sequences. Nucleic acids may be DNA, both genomic and cDNA, RNA, or hybrids, and may contain combinations of deoxyribonucleotides and ribonucleotides, as well as combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine, and isoguanine. Nucleic acids may be synthesized as single-stranded molecules or expressed in cells (in vitro or in vivo) using synthetic genes. Nucleic acids may be obtained by chemical synthesis or recombinant methods. The depiction of a single strand also defines the sequence of the complementary strand. Thus, a nucleic acid also encompasses the complementary strand of the depicted single strand. Many variants of a nucleic acid can be used for the same purpose as a given nucleic acid. Thus, a nucleic acid also encompasses substantially identical nucleic acids and their complementary strands.

[0035] 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, cows, ungulates, rabbits, mice, etc.). In various embodiments, a subject may be a human (e.g., an adult male, adult female, adolescent male, adolescent female, boy, girl) under the care of a physician or other medical practitioner as an outpatient in a hospital or other clinical setting. In certain embodiments, a subject may not be under the care or prescription of a physician or other medical practitioner.

[0036] As used herein, the phrase "a subject in need" refers to a subject, as described below, suffering from or at risk of a condition to be treated prophylactically or therapeutically with a therapeutic protein described herein.

[0037] As used herein, the term "specificity" refers to the ability of a protein binding domain, particularly an immunoglobulin or a fragment of an immunoglobulin such as a nanobody, to preferentially bind to one antigen relative to different antigens, and does not necessarily imply high affinity.

[0038] Treatment of Headache Disorders 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 neurokinin receptor 3 ("NK3") protein or modulates the expression of the 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, hemicrania continua, hypertension headache, rebound headache, post-traumatic headache, exertion headache, spinal headache, thunderclap headache, ice pick headache, trigeminal neuralgia, orofacial pain (e.g., chronic orofacial pain), or a combination of two or more of these diseases or conditions. Non-limiting examples of the above combinations include migraine and general headache, general headache and trigeminal neuralgia, and cluster headache and orofacial pain. In some embodiments, the disease or condition is selected from the group consisting of migraine, medication overuse headache, cluster headache, general headache, trigeminal neuralgia, and orofacial 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.

[0039] 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, hemicrania continua, hypertensive headache, rebound headache, post-traumatic headache, severe headache, spinal headache, thunderclap headache, ice pick headache, trigeminal neuralgia, orofacial pain, or a combination of two or more of these diseases or conditions.

[0040] In some embodiments, the present disclosure provides an NK3 modulator for use in treating or preventing a disease or condition.In some embodiments, the present disclosure provides an NK3 modulator 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, the NK3 modulator being a therapeutic agent that regulates the activity of NK3 protein or regulates the expression of TACR3 gene.

[0041] In some embodiments, compositions containing the therapeutic agents of the present disclosure are administered for prophylactic and / or therapeutic treatment.In some embodiments, NK3 modulators are administered to patients already suffering from headache disorders in an amount sufficient to cure or at least partially suppress one or more symptoms of headache disorders.Amounts effective for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician.

[0042] In some embodiments, administration of a therapeutic agent of the present disclosure results in the 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 the 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 the cessation or reduction of one or more symptoms selected from pain, sensitivity to light, sensitivity to sound, sensitivity to smell, aura, nausea, vomiting, agitation, dizziness, lightheadedness, muscle stiffness, muscle spasms, swelling, numbness, scalp tenderness, and stuffy nose. In some embodiments, administration of a therapeutic agent of the present disclosure results in the 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 the cessation or reduction of pain (e.g., pain associated with a headache disorder). In some embodiments, administration of the therapeutic agents of the present disclosure provides relief from pain.

[0043] In prophylactic applications, compositions containing the therapeutic agents described herein are administered to a patient susceptible to or otherwise at risk of a disorder or disease (e.g., headache disorder). Such an amount is defined as a "prophylactically effective amount or dose." In this use, the exact amount will also vary depending on the patient's health condition, weight, and the like. 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 treatments, the patient's health condition and response to the drug, and the judgment of the treating physician.

[0044] The therapeutic agents of the present disclosure may be administered to a subject using different routes of administration, including oral, transmucosal, topical, transdermal, inhalation, intravenous, subcutaneous, intradermal, intramuscular, intraarticular, perineural, intraventricular, intravenous, intraperitoneal, intranasal, and intraocular.

[0045] NK3 signaling has distinct functions in the CNS, where it regulates KNDy (kisspeptin, NKB, dynorphin) neurons in the hypothalamus, thereby controlling gonadotropin-releasing hormone (GnRH) and ultimately 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 a GnRH Pulse Generator Controlling Mammalian Reproduction. 12 FRONT.ENDOCRINOL.724632 (2021); Depypere, H., Lademacher, C., Siddiqui, E. & Fraser, GLFezolinetant in the treatment of vasomotor symptoms associated with menopause, 30 EXPERT OPIN.INVESTIG.DRUGS 681-694 (2021) (hereinafter "Depypere 2021"). To avoid undesirable side effects associated with affecting the secretion of these gonadotropins, in some embodiments, the therapeutic agent selectively modulates NK3 in peripheral tissues over NK3 in the CNS. In some embodiments, the Therapeutic Agent selectively modulates NK3 in the peripheral nervous system over NK3 in the CNS.

[0046] In some embodiments, the therapeutic agent is a peripherally restricted NK3 modulator. In some embodiments, the therapeutic agent is a peripherally restricted NK3 modulator (e.g., does not accumulate in the brain to clinically significant concentrations). In some embodiments, the use of a peripherally restricted NK3 modulator minimizes or avoids undesirable side effects associated with NK3 modulation in the CNS (e.g., changes in gonadotropin levels, such as LH). Such side effects include thermoregulatory dysfunction, changes in bone mineral density, paresthesia, thrombophlebitis, and changes in one or more gonadotropin levels. In some embodiments, administration of the NK3 modulators disclosed herein is free of one or more of the following side effects: changes in bone density, paresthesia, thrombophlebitis, infertility, changes in libido, menstrual cycle abnormalities (e.g., delayed or blocked ovulation), changes in testosterone levels, testicular shrinkage, and changes in gonadotropin levels (e.g., luteinizing hormone). In some embodiments, administration of the NK3 modulators disclosed herein does not reduce LH levels in a subject.

[0047] 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 therapeutic agent in a therapeutically effective amount reduces luteinizing hormone in a subject by, for example, 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 the subject by, for example, 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 therapeutic levels of the therapeutic agent reduces luteinizing hormone in the 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 above examples are merely illustrative and are not intended to limit the scope of the present disclosure.

[0048] NK3 Modulator In some embodiments, the therapeutic agent is a therapeutic agent that 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 an NK3 modulator. In some embodiments, the therapeutic agent is an NK3 antagonist. In some embodiments, the therapeutic agent is an NK3 agonist. In some embodiments, the therapeutic agent binds to the NK3 protein, thereby preventing the binding of endogenous ligands to the NK3 protein. The methods of the present disclosure include administration of a therapeutic agent that can modulate the activity of the NK3 protein. The therapeutic agent can enhance or decrease the activity of the NK3 protein. In some embodiments, at a therapeutically effective concentration, a therapeutic agent modulates NK3 protein activity 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 a standard NK3 protein.

[0049] In some embodiments, the therapeutic agent modulates expression of the TACR3 gene. In some embodiments, the therapeutic agent inhibits expression of the TACR3 gene. In some embodiments, the therapeutic agent downregulates expression of the TACR3 gene. In some embodiments, the therapeutic agent increases expression of the TACR3 gene. In some embodiments, the therapeutic agent upregulates expression of the TACR3 gene.

[0050] In some embodiments, the administration of the therapeutic agent selectively regulates the activity of NK3 protein or the expression of TACR3 gene in peripheral tissues relative to the central nervous system. In some embodiments, the administration of the therapeutic agent selectively regulates the activity of NK3 protein or the expression of TACR3 gene in peripheral nervous system relative to the central nervous system. In some embodiments, the administration of the therapeutic agent does not cause one or more pharmacological effects associated with NK3 regulation in the CNS. In some embodiments, the administration of the therapeutic agent does not cause one or more pharmacological effects selected from thermoregulatory dysfunction, bone density, paresthesia, thrombophlebitis, and changes in gonadotropin levels (e.g., luteinizing hormone).

[0051] In some embodiments, the therapeutic agent is restricted to peripheral tissues. In some embodiments, the therapeutic agent is restricted 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 that is, 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 that is at least about 10:1. In a further embodiment, 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.

[0052] In some embodiments, administration of the therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in a subject that is, for example, 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 that is, for example, 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 to brain tissue concentration in the subject of, for example, 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 to brain tissue concentration in the subject of, for example, about 2:1 to about 20:1.

[0053] In some embodiments, the therapeutic agent contemplated herein is a small molecule, protein, or nucleic acid.In some embodiments, the therapeutic agent is a small molecule.Non-limiting examples of small molecule therapeutic agents include EP0673928, WO1995032948, WO1997010211, WO1997019928, WO1997019927, WO1997021680, WO1998018785, WO1998057972, WO1999026924, WO1999001451, WO2000021931, WO2000064877, WO200003 9114, International Publication No. 2002013825, International Publication No. 2002094821, International Publication No. 2002083645, International Publication No. 2002038547, International Publication No. 2002038548, International Publication No. 2002044154, International Publication No. 2002043734, International Publication No. 2002044165, International Publication No. 2004066951, International Publication No. 2004066950, International Publication No. 2005014575, International Publication No. 2005061462, International Publication No. 2005016884, International Publication No. US Patent Publication No. 2005110987, US Patent Publication No. 2005148601, International Publication No. 2006050989, International Publication No. 2006050991, International Publication No. 2006050992, International Publication No. 2006130080, International Publication No. 2006137789, International Publication No. 2007086799, International Publication No. 2007018465, International Publication No. 2007018469, International Publication No. 200700396, International Publication No. 2007035157, International Publication No. 2007018466, International Publication No. 2007 035156, International Publication No. 2007035158, International Publication No. 2007069977, International Publication No. 2007012900, International Publication No. 2007028654, U.S. Patent Application Publication No. 20070219214, European Patent No. 1829556, International Publication No. 2008115140, International Publication No. 2008131779, International Publication No. 2008148688, International Publication No. 2008148689, International Publication No. 2008151969, International Publication No. 2008081012, International Publication No. 2009130240,International Publication No. 2009156339, International Publication No. 2009033995, International Publication No. 2009019163, International Publication No. 2009024502, International Publication No. 2009072643, International Publication No. 2010106081, International Publication No. 2010045948, International Publication No. 2010028655, International Publication No. 2010086259, International Publication No. 2010015626, International Publication No. 2020101017, JP201081888, International Publication No. 2011110183, International Publication No. 201112 1137, International Publication No. 2012039718, International Publication No. 2012009227, International Publication No. 2012004207, International Publication No. 2013050424, International Publication No. 2014154895, International Publication No. 2014154896, International Publication No. 2014089019, International Publication No. 2015200594, International Publication No. 2015033163, International Publication No. 2019210327, International Publication No. 2019074081, and International Publication No. 2021030335.

[0054] In some embodiments, the small molecule therapeutic is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, PD161182, SCH206272, GSK 256471, SB48968. In some embodiments, the small molecule therapeutic is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, 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 fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653. In some embodiments, the small molecule therapeutic agent is selected from 2-diphenylquinoline-4-carbohydrazide, PD161182, SR142801, CS-003, and MLE-301.

[0055] In some embodiments, the therapeutic agent is a protein. In some embodiments, the protein therapeutic agent is selected from an antibody, an enzyme, a hormone protein, a signaling protein, and a fusion protein, or a functional fragment thereof. In some embodiments, the therapeutic agent is an antibody that selectively binds to NK3 or neurokinin B, or a functional fragment thereof. 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 an NK3 activator. Non-limiting examples of protein therapeutic agents that activate NK3 include 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 is an NK3 inhibitor. Non-limiting examples of protein therapeutics that activate NK3 include [Trp 7 ,β-Ala 8 ]Neurokinin A, and [MePhe 7 β-Ala 8] selected from neurokinin A (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 (see Bz-AA-{D-Trp}-F-{D-Pro}-P-{Nle}-NH2).

[0056] In further embodiments, the protein therapeutic is selected from the group consisting of 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., Invitrogen PA5-20392 and PA5-102108 from 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 Fine Biotech Co.,Ltd., BS2736 from Bioworld Technology,Inc, 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 MilliporeSigma / Merck KGaA, MBS150256 and MBS9126076 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 Creative Biosciences. and one or more CDRs from GenWay Diagnostics, CPBT-66754RT and DPABH-02783, RayBiotech, Inc., 119-10140 and 119-10172, GenWay, 18-461-10149 and 18-461-10183, and Rockland Immunochemicals, Inc., 600-401-DC1.

[0057] 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 are involved in sequence-specific suppression of gene expression by double-stranded RNA through translational or transcriptional repression. In some embodiments, the therapeutic agent is an shRNA, siRNA, microRNA, asymmetric interfering RNA, or combinations thereof, that is complementary to a portion of the human TACR3 gene (NCBI Gene ID: 6870). In some embodiments, the therapeutic agent is an antisense molecule, lhRNA, miRNA-embedded shRNA, internally segmented small RNA, or any combination thereof, that is complementary to a portion of the human TACR3 gene (NCBI Gene ID: 6870). In some embodiments, the therapeutic agent is administered by a viral vector.

[0058] Pharmaceutical preparations In some aspects, the present disclosure provides a pharmaceutical composition comprising an NK3 modulator and at least one pharma- ceutically acceptable excipient.

[0059] NK3 modulator can be formulated into any suitable pharmaceutical formulation.The pharmaceutical formulation of the present disclosure typically comprises active ingredient (e.g., NK3 modulator) and one or more pharma- ceutically 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, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, NY, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0060] Methods for formulating therapeutic proteins may include formulating any of the therapeutic proteins of the present disclosure with one or more inert and pharma- ceutically acceptable excipients or carriers to form semi-solid or liquid compositions. These pharmaceutical compositions may include at least one active ingredient (e.g., a therapeutic agent of the present disclosure). Such compositions may further contain non-toxic auxiliary substances, such as solvents, buffers, or emulsifiers, pH buffers, and other pharma-ceutically acceptable additives. Alternatively, the therapeutic proteins of the present disclosure may be lyophilized or in powder form for reconstitution with a suitable vehicle, such as pyrogen-free sterile water, before use.

[0061] The amount of therapeutic agent of the disclosure will vary depending on the mammal being treated, the severity of the disorder or disease, the rate of administration, the nature of the therapeutic protein, and the discretion of the prescribing physician.

[0062] While 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. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. It is understood that various alternatives to the embodiments of the present invention described herein may be employed in carrying out the present invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents are protected thereby. EXAMPLES

[0063] The following examples are illustrative and do not limit the scope of the compositions, devices, uses, and methods disclosed herein.

[0064] Example 1: In vivo migraine model 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). Male adult Sprague-Dawley rats were habituated to handling for 1-2 weeks before undergoing dural cannulation surgery under isoflurane anesthesia. Care was taken not to damage the dura. A custom-made flange guide cannula (22GA, Plastics One) was inserted. The cannula was fixed to the bone by small screws and dental cement.

[0065] After 1-2 weeks of recovery from surgery, animals were given supradural infusions of an inflammatory soup containing 2 mM histamine, bradykinin, serotonin, and 0.2 mM prostaglandin E2 under brief isoflurane anesthesia (1.5-3%) for 5 consecutive days (one per day) (i.e., 5-day sensitization period). If rats did not show signs of facial sensitivity after the final infusion, they were excluded from the study.

[0066] After a 5-day sensitization period and a 1-week washout period, rats were challenged with nitroglycerin (GTN, 0.1 mg / kg, IP) and either fezolinethant (30 or 100 mg / kg, PO), SB 235375 (30 or 100 mg / kg, PO), or vehicle (0.5% methylcellulose in sterile water for fezolinethant, and sterile water, PO for SB 235375). The design was within-subjects, with the same animals receiving multiple treatments in a crossover fashion with at least a 1-week washout between each treatment. Sensory provocation testing for mechanical allodynia was performed by von Frey periorbital threshold testing. Sensory testing was performed during the day using a light-raising and lowering technique with von Frey filaments with reproducible calibrated buckling forces varying from 0.4 to 10 g. 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) was calculated according to the prior art methods described, for example, in 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). A blinded investigator examined periorbital sensitivity before drug administration and at 45 minutes and 1.5 hours after drug administration. Studies were performed in n=13-22 subjects.

[0067] The results of the in vivo migraine model are shown in Figure 1A-1B. Specifically, Figure 1A-1B show the effect of the brain-penetrant NK3 antagonist fezolinethant (Figure 1A), and the peripherally restricted NK3 antagonist SB 235375 (Figure 1B) on periorbital thresholds after GTN exposure in rats with trigeminal ganglia sensitized to inflammatory soup. The baseline withdrawal thresholds were not significantly different between groups (baseline measurements in Figure 1A-1B). As shown in Figure 1A, the withdrawal thresholds of rats administered GTN and 30 mg / kg fezolinethant were significantly higher than those of rats administered either the control groups (saline + vehicle or GTN + vehicle) at 90 min. Withdrawal thresholds in rats treated with GTN and 100 mg / kg fezorinetant were significantly higher at all time points compared to the respective control groups, demonstrating NK3-dependent analgesic effects at both doses (2-way ANOVA, vs. GTN / veh). Furthermore, Figure 1A shows a dose-dependent increase in periorbital thresholds with fezorinetant treatment, as the 100 mg / kg dose of fezorinetant produced higher withdrawal thresholds than the 30 mg / kg dose of fezorinetant.

[0068] Figure 1B shows the efficacy of SB 235375, an NK3 antagonist with minimal brain penetration, in the same sensitized in vivo migraine model. 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 administered fezolinethant, rats co-administered with GTN and SB 235375 showed higher pain thresholds at both doses (30 mg / kg and 100 mg / kg) and time points (45 min, 90 min) compared to rats treated with GTN and vehicle (see Figure 1B). Thus, as shown in Figures 1A-1B, NK3 antagonists, including the CNS penetrating fezolinethant and the peripherally restricted SB 235375, both demonstrate efficacy in treating migraine headaches.

[0069] Example 2: Luteinizing Hormone (LH) Inhibition Test A study was conducted to measure LH in castrated male Sprague-Dawley rats. Animals were castrated via midline scrotal incision using Zoletil® 50 as an anesthetic. Surgery was performed at least 15 days prior to compound testing.

[0070] Serum was collected at baseline and then every 15 min starting 30 min after PO (periorbital) administration of vehicle, fezorinetanant (30 mg / kg), or SB 235375 (30 mg / kg and 100 mg / kg). Blood was collected from the jugular vein, transferred to 1.5 mL centrifuge tubes, and serum was separated by centrifugation at 8000 g for 15 min. Serum LH levels were determined using a rat luteinizing hormone ELISA kit (Colorimetric, Novus). The assay was performed according to the manufacturer's protocol. Group sizes were from n=10 for vehicle and SB 235375 groups and n=4 for fezorinetanant.

[0071] Results of the LH inhibition study are shown in Figure 2. The data shown in Figure 2 confirm that brain exposure with SB 235375 at doses utilized to treat migraine is insufficient to induce substantial CNS-dependent effects. Both fezolinetant (30 mg / kg) and SB 235375 (30 mg / kg 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 fezolinetant (30 mg / kg) had significantly reduced LH serum concentrations at all measured time points (30 min, 90 min, and 150 min). On the other hand, animals treated with SB 235375 showed no significant difference in LH levels compared to the vehicle-treated group (see FIG. 2).

[0072] The mean LH values ​​underlying the data provided in Figure 2 are shown in Table 1 below.

[0073] [Table 1]

[0074] As shown in Table 1, 150 min after dosing, LH values ​​in vehicle, 30 mg / kg dose of SB 235375, and 100 mg / kg dose of SB 235375 were virtually equivalent (29.3 ng / mL, 30.4 ng / mL, and 31.1 ng / mL, respectively), while fezolinethant caused a significant decrease in LH values ​​(5.5 ng / mL). Thus, fezolinethant reduced LH levels by approximately 85% compared to vehicle treatment, whereas minimal changes were observed at 150 min after dosing with the test doses of SB 235375 (approximately 4% decrease at the 30 mg / kg dose and approximately 10% decrease at the 100 mg / kg dose, respectively). Similarly, at 30 and 90 minutes after treatment, fezolinethant caused a much more significant decrease in LH levels (approximately 60% and 85% decrease compared to vehicle, respectively) compared to the same 30 mg / kg dose of SB 235375 (approximately +4% and +13% increase, respectively) and the 100 mg / kg dose of SB 235375 (approximately 26% and 14% decrease, respectively).

[0075] The foregoing data presented in Figures 1A-1B and 2 show that NK3 modulators are effective in treating headaches (e.g., migraines) and that this effectiveness is maintained even when the NK3 modulator is peripherally restricted (e.g., does not accumulate to clinically significant concentrations in the brain). Furthermore, the data show that the use of peripherally restricted NK3 modulators provides the added benefit of avoiding undesirable side effects associated with NK3 modulation in the CNS (e.g., changes in gonadotropin levels such as LH). The foregoing examples are merely illustrative and are not intended to limit the scope of the present disclosure.

Claims

1. 1. A method for treating or preventing 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 neurokinin receptor 3 ("NK3") protein or modulates the expression of the 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. 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. 10. The method of claim 1, wherein the disease or condition is migraine.

4. The method of 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 an NK3 antagonist.

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

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

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

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

10. 10. The method of claim 9, wherein said administration of said therapeutic agent results in a ratio of plasma concentration to brain tissue concentration in said subject of at least 100:

1.

11. The method of any one of claims 1 to 10, wherein said administration of said therapeutic agent modulates the activity of said NK3 protein or the expression of said TACR3 gene in peripheral tissues.

12. The method of claim 11, wherein said administration of said therapeutic agent selectively modulates the activity of said NK3 protein or the expression of said TACR3 gene in peripheral tissues 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 therapeutic agent is selected from the group consisting of those described in EP 0673928, WO 1995032948, WO 1997010211, WO 1997019928, WO 1997019927, WO 1997021680, WO 1998018785, WO 1998057972, WO 1999026924, WO 1999001451, WO 2000021931, WO 2000064877, WO 2000039114, WO 2002013825, WO 200201421, and WO 200201517. WO 2002094821, WO 2002083645, WO 2002038547, WO 2002038548, WO 2002044154, WO 2002043734, WO 2002044165, WO 2004066951, WO 2004066950, WO 2005014575, WO 2005061462, WO 2005016884, WO 2005110987, U.S. Patent Application Publication No. 2005148601, WO 20060509 89, International Publication No. WO 2006050991, International Publication No. WO 2006050992, International Publication No. WO 2006130080, International Publication No. WO 2006137789, International Publication No. WO 2007086799, International Publication No. WO 2007018465, International Publication No. WO 2007018469, International Publication No. WO 200700396, International Publication No. WO 2007035157, International Publication No. WO 2007018466, International Publication No. WO 2007035156, International Publication No. WO 2007035158, International Publication No. WO 2007069977, International Publication No. WO 2007012900, International Publication No. WO 200 7028654, U.S. Patent Application Publication No. 20070219214, European Patent No. 1829556, International Publication No. WO 2008115140, International Publication No. WO 2008131779, International Publication No. WO 2008148688, International Publication No. WO 2008148689, International Publication No. WO 2008151969, International Publication No. WO 2008081012, International Publication No. WO 2009130240, International Publication No. WO 2009156339, International Publication No. WO 2009033995, International Publication No. WO 2009019163, International Publication No. WO 2009024502, International Publication No. WO 2009072643,WO 2010106081, WO 2010045948, WO 2010028655, WO 2010086259, WO 2010015626, WO 2020101017, JP201081888, WO 2011110183, WO 2011121137, WO 2012039718, WO 2012009227, WO 15. The method of claim 14, as disclosed in WO 2012004207, WO 2013050424, WO 2014154895, WO 2014154896, WO 2014089019, WO 2015200594, WO 2015033163, WO 2019210327, WO 2019074081, or WO 2021030335.

16. 15. The method of claim 14, wherein the small molecule is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, 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.

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

18. 17. The method of claim 16, wherein the small molecule is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, 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 functional fragment thereof that selectively binds to NK3 or neurokinin B.

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

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

23. 20. 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. 25. The method of claim 24, wherein the therapeutic agent is an RNAi molecule.

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

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

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

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

30. 1. An NK3 modulator for use in the treatment or prevention of a disease or condition in a subject in need thereof, wherein the disease or condition is selected from the group consisting of migraine, cluster headache, general headache, trigeminal neuralgia, and orofacial pain, and wherein the NK3 modulator is a therapeutic agent which modulates the activity of an NK3 protein or modulates the expression of the TACR3 gene.

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

32. 32. The NK3 modulator of claim 30 or claim 31, wherein the disease or condition is migraine.

33. 33. The NK3 modulator of any one of claims 30 to 32, which modulates the activity of an NK3 protein.

34. 34. The NK3 modulator of any one of claims 30 to 33 which is an NK3 antagonist.

35. The NK3 modulator of any one of claims 30 to 34, which regulates the expression of the TACR3 gene.

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

37. 37. The NK3 modulator of any one of claims 30 to 36, wherein administration of said NK3 modulator to said subject in a therapeutically effective amount does not decrease luteinizing hormone in said subject.

38. 38. The NK3 modulator of any one of claims 30 to 37, wherein administration of said NK3 modulator to said subject results in a ratio of plasma concentration to brain tissue concentration in said subject of at least 10 to 1.

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

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

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

42. 42. The NK3 modulator of any one of claims 30 to 41 which is a small molecule, protein, or nucleic acid.

43. The NK3 modulator of any one of claims 30 to 42 which is a small molecule.

44. The small molecule is selected from the group consisting of those described in EP 0 673 928, WO 1995032948, WO 1997010211, WO 1997019928, WO 1997019927, WO 1997021680, WO 1998018785, WO 1998057972, WO 1999026924, WO 1999001451, WO 2000021931, WO 2000064877, WO 2000039114, WO 2002013825, WO 2002013826, WO 2002013827, WO 200201680, WO 2002018785 ... WO 2002094821, WO 2002083645, WO 2002038547, WO 2002038548, WO 2002044154, WO 2002043734, WO 2002044165, WO 2004066951, WO 2004066950, WO 2005014575, WO 2005061462, WO 2005016884, WO 2005110987, U.S. Patent Application Publication No. 2005148601, WO 20060509 89, International Publication No. WO 2006050991, International Publication No. WO 2006050992, International Publication No. WO 2006130080, International Publication No. WO 2006137789, International Publication No. WO 2007086799, International Publication No. WO 2007018465, International Publication No. WO 2007018469, International Publication No. WO 200700396, International Publication No. WO 2007035157, International Publication No. WO 2007018466, International Publication No. WO 2007035156, International Publication No. WO 2007035158, International Publication No. WO 2007069977, International Publication No. WO 2007012900, International Publication No. WO 200 7028654, U.S. Patent Application Publication No. 20070219214, European Patent No. 1829556, International Publication No. WO 2008115140, International Publication No. WO 2008131779, International Publication No. WO 2008148688, International Publication No. WO 2008148689, International Publication No. WO 2008151969, International Publication No. WO 2008081012, International Publication No. WO 2009130240, International Publication No. WO 2009156339, International Publication No. WO 2009033995, International Publication No. WO 2009019163, International Publication No. WO 2009024502, International Publication No. WO 2009072643,International Publication No. 2010106081, International Publication No. 2010045948, International Publication No. 2010028655, International Publication No. 2010086259, International Publication No. 2010015626, International Publication No. 2020101017, JP201081888, International Publication No. 2011110183, International Publication No. 2011121137, International Publication No. 2012039718, International Publication No. 2012009227, International Publication No. 2012 44. The NK3 modulator of claim 43, as disclosed in WO2014004207, WO2013050424, WO2014154895, WO2014154896, WO2014089019, WO2015200594, WO2015033163, WO2019210327, WO2019074081, or WO2021030335.

45. 45. The NK3 modulator of claim 43 or 44, wherein the small molecule is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, 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. 46. ​​The NK3 modulator of any one of claims 43 to 45, wherein the small molecule is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, senktide, GSK172981, GSK256471, SB222200, SB235375, SJX-653, MLE-301, SB218795, GR138676, GR138678, CAM-2425, SSR241586, SSR146977, PD154740, PD157672, PD163416, PD160946, and PD161182.

47. 47. The NK3 modulator of any one of claims 43 to 46, wherein the small molecule is selected from fezolinethant, pavinetant, talnetant, osanetant, erinzanetant, GSK172981, GSK256471, SB222200, SB235375, SJX-653, and MLE-301.

48. 43. The NK3 modulator of claim 42 which is a protein.

49. 49. The NK3 modulator of claim 48 which is an antibody or functional fragment thereof that selectively binds to NK3 or neurokinin B.

50. 50. The NK3 modulator of claim 49, which is an antibody or functional fragment thereof that selectively binds to NK3 as disclosed in WO2012020162A1.

51. 51. The NK3 modulator of claim 50, wherein said therapeutic agent is an antibody or functional fragment thereof that selectively binds to Neurokinin B as disclosed in WO2003102136 or WO2020101017.

52. 49. The NK3 modulator of claim 48 which is a fusion protein.

53. 43. The NK3 modulator of claim 42 which is a nucleic acid.

54. 54. The NK3 modulator of claim 53 which is an RNAi molecule.

55. 55. The NK3 modulator of claim 54, wherein said RNAi molecule is an shRNA, siRNA, microRNA, or asymmetric interfering RNA.

56. 56. The NK3 modulator of claim 55 which is an antisense molecule, an lhRNA, an miRNA-embedded shRNA, or an internal segmented small RNA.

57. The NK3 modulator of any one of claims 30 to 56, which is administered by a viral vector.

58. The NK3 modulator of any one of claims 30 to 57, wherein the subject is a human.

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