CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 63/305,207, filed January 31, 2022, and United States Provisional Application Serial Number 63/306,216, filed February 3, 2022, and United States Provisional Application Serial Number 63/336,943, filed April 29, 2022, the contents of which are hereby incorporated by reference in their entirety.

FIELD

[0002] Provided herein are methods for treating schizophrenia, post-traumatic stress disorder, and other conditions with a NK3 antagonist.

BACKGROUND

[0003] Symptoms of Post-Traumatic Stress Disorder (PTSD) include re-experiencing memories of a traumatic event such as through intrusive thoughts, flashbacks, and nightmares. Estrogen dysfunction is implicated in a number of conditions such as PTSD, schizophrenia, and depression. Current FDA- approved pharmaceutical treatments for PTSD are antidepressants which have met with limited results in clinical trials. Current treatments for conditions such as schizophrenia include antipsychotics in combination with antidepressants, or anti-anxiety drugs. More effective and targeted approaches to prevention and treatment of PTSD, schizophrenia, and other conditions are needed.

[0004] Osteoporosis occurs as a result of an imbalance in the bone remodeling process in which bone resorption exceeds bone formation. Osteoclasts are cells that break down bone, then osteoblasts create new bone. Osteoclasts and osteoblasts generally coordinate a balance which maintains bone density under healthy conditions. However, with age, and/or during conditions of hormone deprivation, osteoclasts begin to remove more bone than the osteoblasts can create, i.e., bone resorption exceeds bone formation, resulting in loss of bone mass. Bone loss increases the risk and/or occurrence of fractures and generally diminishes quality of life. There is a need for therapies that can reduce or arrest or reverse bone loss. SUMMARY

[0005] Provided herein is a method for treating a disorder selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, bipolar disorder, schizoaffective disorder, premenstrual dysphoric disorder (PMDD), anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS), and vasomotor symptoms comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist in combination with estrogen deprivation therapy, wherein the patient has levels of estrogen above 1 ng/dL. Provided herein is a method for treating a disorder selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, premenstrual dysphoric disorder (PMDD), anxiety, depression, and vasomotor symptoms, comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist, wherein the patient has low or undetectable levels of estrogen. In some embodiments, the disorder is selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression prostate cancer, polycystic ovarian syndrome (PCOS), and premenstrual dysphoric disorder (PMDD). In some embodiments, the disorder is selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, anxiety, and depression. In some embodiments, the disorder is categorized as a DSM-5 disorder. In some embodiments, the patient is male and has total testosterone levels greater than 20 ng/dL and estrogen levels lower than 2 ng/dL. In some embodiments, the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL. In some embodiments the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments the patient is a postmenopausal female and has total testosterone levels greater than 40 ng/dL and estrogen levels lower than 2 ng/dL.

[0006] Provided herein is a method for treating a disorder selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD) and vasomotor symptoms comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist, wherein the patient has low or undetectable levels of an androgen or estrogen. In some embodiments, the patient is male and has total testosterone levels greater than 20 ng/dL and estrogen levels lower than 2 ng/dL. In some embodiments, the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL. In some embodiments the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments the patient is a postmenopausal female and has total testosterone levels greater than 40 ng/dL and estrogen levels lower than 2 ng/dL.

[0007] Provided herein is a method of modulating the response to an NK3 antagonist in a patient undergoing NK3 therapy, the method comprising administering to the patient an adjunct therapeutic that reduces estrogen levels in said patient. In some embodiments, the patient is male and has total testosterone levels greater than 20 ng/dL and estrogen levels lower than 2 ng/dL. In some embodiments, the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL. In some embodiments the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments the patient is a postmenopausal female and has total testosterone levels greater than 40 ng/dL and estrogen levels lower than 2 ng/dL.

[0008] Also provided herein is a method for reducing or inhibiting bone loss in a patient comprising administering a Neurokinin 3 receptor (NK3) antagonist to the patient in need thereof. In some embodiments, the patient is a cancer patient, a peri-menopausal or post-menopausal female patient, or a male patient with low levels of estrogen. In some embodiments, the patient is male and has total testosterone levels greater than 20 ng/dL and estrogen levels lower than 2 ng/dL. In some embodiments, the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL. In some embodiments the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments the patient is a postmenopausal female and has total testosterone levels greater than 40 ng/dL and estrogen levels lower than 2 ng/dL.

[0009] Provided herein is a method of treating a disorder in a patient, where the disorder is worsened by estrogen lowering or estrogen depletion, comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist. In some embodiments, the disorder is categorized as a DSM-5 disorder. In some embodiments, the patient is male and has total testosterone levels greater than 20 ng/dL and estrogen levels lower than 2 ng/dL. In some embodiments, the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL. In some embodiments the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments the patient is a postmenopausal female and has total testosterone levels greater than 40 ng/dL and estrogen levels lower than 2 ng/dL. [0010] In some embodiments, provided herein is a dosing schedule for an NK3 antagonist comprising dosing for a short period of time prior to onset of an aromatase inhibitor or an estrogen deprivation therapy or procedure for the patient. In some embodiments estrogen deprivation therapy is a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or surgery. In some embodiments, provided herein is a dosing schedule for the NK3 antagonist comprising dosing at about the nadir(s) of the estrogen diurnal cycle.

[0011] In some embodiments is a method for treating a disorder selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD) and vasomotor symptoms comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist, wherein the patient has high levels of androgen and optionally low or undetectable levels of estrogen. In some embodiments, the patient is male and has a total testosterone levels greater than 20 ng/dL and estrogen levels lower than 2 ng/dL. In some embodiments, the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL. In some embodiments the patient is a pre- or perimenopausal female and has total testosterone levels greater than 50 ng/dL and estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments the patient is a postmenopausal female and has total testosterone levels greater than 40 ng/dL and estrogen levels lower than 2 ng/dL.

DETAILED DESCRIPTION

[0012] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. As used herein, the below terms have the following meanings unless specified otherwise. Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of the compositions and methods described herein. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

[0014] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, references to “the agent” includes a plurality of such agents.

[0015] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X.”

[0016] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for human or veterinary pharmaceutical use.

[0017] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. [0018] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0019] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0020] A “prodrug” is any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g. , N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0021] As used herein, the term “solvate” refers to a complex formed by combining a compound and a solvent.

[0022] As used herein, the term “hydrate” refers to a complex formed by combining a compound and water (i.e., a solvate when the solvent is water). [0023] As used herein, the term “acid salt hydrate” refers to a complex formed by combining an acid salt compound with water.

[0024] As used herein, the term “N-oxide” refers to an oxidized tertiary or pyridinyl amine moiety.

[0025] As used herein, the term “isomorphic crystalline form” refers to two or more crystalline forms that have the same space group, unit-cell dimensions, and types and positions of atoms, with the exception of a replacement of one or more atoms in one isomorphic crystalline form with a different atom in its counterpart isomorphic crystalline form.

[0026] As used herein, the term “administration” refers to introducing an agent into a patient. For example, a therapeutic amount can be administered to the patient, which can be determined by the treating physician, medical professional, or the like. In some embodiments, a therapeutic amount is administered orally. In some embodiments, a therapeutic amount is administered subcutaneously. In some embodiments, a therapeutic amount is administered transdermally. In some embodiments, a therapeutic amount is administered intravenously. The related terms and phrases “administering” and “administration of,” when used in connection with a compound or tablet (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by selfadministration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. Administration entails delivery to the patient of the drug.

[0027] The term “dose” or “dosage” refers to the total amount of an active agent (e.g., osanetant or a pharmaceutically acceptable salt thereof) administered to a patient in a single day (24-hour period). The desired dose can be administered once daily. In some embodiments, the desired dose may be administered in one, two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day. The terms “dose” and “dosage” are used interchangeably herein.

[0028] As used herein, “effective amount,” “therapeutically effective amount,” or “therapeutic amount” refers to an amount of a drug or an agent (e.g., osanetant or a pharmaceutically acceptable salt thereof) that when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The full therapeutic effect does not necessarily occur by administration of one dose, and can occur only after administration of a series of doses and can be administered in one dose form or multiples thereof. For example, 500 mg of the drug can be administered in a single 500 mg strength tablet or two 250 mg strength tablets. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0029] As used herein, the term “patient” or “subject” refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. A patient as described herein can be a human. The patient can be a male or a female.

[0030] As used herein, “treatment,” “treating,” and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition.

[0031] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0032] “Adjunct therapy” or “adjunct procedure” refers to an additional agent or procedure that modifies the action of the principal agent. In some embodiments, an adjunct therapeutic or procedure enhances the efficacy of an NK3 antagonist.

[0033] “Nadir(s) of estrogen diurnal cycle” refers to the trough(s) or lower or lowest levels that occur in the levels of estrogen during the course of a day. Typically there are two troughs with one being lower than the other. Typically one trough or nadir is in the day and one at night, with one or the other being the lowest. “About the nadirs” includes within one hour or two hours or three hours.

[0034] “Exposure therapy” refers to a technique in behavior therapy to treat disorders such as anxiety, PTSD, acute stress disorder and the like. Exposure therapy involves exposing a patient to the anxiety and/or fear and/or stress source, or its context, without the intention to cause any danger.

[0035] “Androgen” as used herein means is any natural steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. It includes testosterone, dehydroepiandrosterone (DHEA), androstenedione (A4), androstenediol (A5), androsterone, and dihydrotestosterone. Levels of androgens are age and sex dependent and, in some embodiments, can be described by the total testosterone levels. Table 1 lists “normal” testosterone levels for human subjects:

TABLE 1 [0036] In some embodiments, total testosterone levels in subjects are greater than the average range for that subject’s age group. In some embodiments, total testosterone levels in male subject are considered “high” when greater than 25, 27, 30, 32, 34, 36, 38, or 40 nmol/L. In some embodiments, total testosterone levels in male subject are considered “high” when than 700, 720, 750, 800, 850, 890, 950, 1000, or 1080 ng/dL. In some embodiments, wherein the subject is male and being treated for prostate cancer, total testosterone levels in male subject are “high” when greater than 20, 30, 40, or 50 ng/dL. In some embodiments, total testosterone levels in female subject are “high” when greater than 40, 41, 50, 53, or 54 ng/dL. In some embodiments, total testosterone levels in female subject postmenopausal are “high” when greater than 40, 41, 50, 53, or 54 ng/dL. In some embodiments, total testosterone levels in female subject premenopausal are “high” when greater than 50, 53, or 54 ng/dL.

[0037] “Estrogen,” as used herein, means a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (El), estradiol (E2), and estriol (E3). Levels of estrogen are age and sex dependent, as well as ovulation phase in female subjects. In some embodiments, normal estrogen levels by ovulation phase may comprise 2. -35.0 ng/dL (follicular phase), 15-75 ng/dL (midcycle phase), 3-45 ng/dL (luteal phase) and <2 ng/dL (postmenopause). Levels of estrogen by age and sex are summarized in Table 2:

TABLE 2

[0038] “Low levels” of an androgen or estrogen refers to levels that are detectable but below the normal levels for a population as described in Table 1 and Table 2. In some embodiments, low levels of estrogen may be levels below about 3 ng/dL, below about 5 ng/dL, or below about 10 ng/dL. “High levels” of an androgen or estrogen refers to levels that are above normal levels for a population as described in Table 1 and Table 2. In some embodiments, “Levels of estrogen above 1 ng/dL” refers to levels that may be normal or in the range from about 1 ng/dL to about normal. By way of example only, in pre-menopausal women, the levels of estrogen range from about 3 ng/dL to about 45 ng/dL. Hyperandrogenism is a medical condition characterized by high serum levels of androgens in females. Numerous findings support a causative role for an excess of androgens in driving the pathogenesis of PCOS. Similarly, high androgens may adversely impact male subjects that are being treated for prostate cancer via chemically induced castration. In some embodiments, the NK3 receptor antagonists described herein may provide advantages in subjects having high serum androgen levels and low serum estrogen levels, wherein “high” and “low” are defined as described herein.. Some embodiments comprise treating a subject having high androgen levels and low estrogen levels with an NK3 receptor antagonist. Such embodiments may comprise treating a patient having total testosterone levels in subjects are greater than the average range for that subject’s sex age group and estrogen levels that are below average range for that subject’s sex and age group. In some embodiments, the subject is male and has been chemically castrated and has total testosterone levels greater than 20, 30, 40, or 50 ng/dL and estrogen levels lower than 2, 1.5, 1.4, or 1 ng/dL. In some embodiments, the subject is female and is premenopausal and has total testosterone levels greater than 50, 53, or 54 ng/dL and estrogen levels lower than 15, 10, 5, or 3 ng/dL or alternatively, estrogen levels lower than 3 ng/dL during the luteal phase. In some embodiments, the subject is female and is postmenopausal and has total testosterone levels greater than 40, 41, 50, 53, or 54 ng/dL and estrogen levels lower than 2 ng/dL.

[0039] “DSM5 disorder” refers to any disorder described in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (hereby incorporated by reference), including and not limited to neurodevelopmental disorders, schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, trauma- and stressor-related disorders, dissociative disorders, somatic symptom and related disorders, feeding and eating disorders, elimination disorders, sleep-wake disorders, sexual dysfunctions, gender dysphoria, disruptive, impulse-control, and conduct disorders, substance-related and addictive disorders, neurocognitive disorders, personality disorders, personality disorders, paraphilic disorders, other mental disorders, medication-induced movement disorders and/or other adverse effects of medication.

[0040] In some embodiments, a DSM5 disorder is schizoaffective disorder, bipolar type or depressive type with or without catatonia. In some embodiments, a DSM5 disorder is major depressive or bipolar disorder with psychotic or catatonic features. In some embodiments, a DSM5 disorder is schizophreniform disorder and brief psychotic disorder. In some embodiments, a DSM5 disorder is delusional disorder, schizotypal personality disorder, obsessive-compulsive disorder and body dysmorphic disorder, posttraumatic stress disorder, autism spectrum disorder or communication disorders, or other mental disorders associated with a psychotic episode. In some embodiments, a DSM5 disorder is substance/medication-induced psychotic disorder with delusions and/or hallucinations. In some embodiments, a DSM5 disorder is a manic episode, a hypomanic episode, or a major depressive episode. In some embodiments, a DSM5 disorder is generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or other anxiety disorder. In some embodiments, a DSM5 disorder is substance/medication-induced bipolar disorder, or attention-deficit/hyperactivity disorder. In some embodiments, a DSM5 disorder is acute anxiety, or medication induced manic or depressive or manic disorder.

[0041] In some embodiments, a DSM5 disorder is trauma- and stressor-related disorders including and not limited to disorders in which exposure to a traumatic or stressful event is implicated, reactive attachment disorder, disinhibited social engagement disorder, posttraumatic stress disorder (PTSD), PTSD with dissociative symptoms, acute stress disorder, and adjustment disorders.

[0042] In some embodiments a DSM5 disorder is a mood disorder. In some embodiments a DSM5 disorder is a mood disorder with peripartum onset. In some embodiments, a DSM5 disorder is a depressive disorder including and not limited to disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder (PMDD), substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. In some embodiments, a DSM5 disorder is recurrent brief depression, short-duration depressive episode, or peripartum / postpartum depression. In some embodiments a DSM5 disorder is seasonal affective disorder (SAD), atypical depression, psychotic depression, situational depression or treatment resistant depression. In some embodiments, a DSM5 disorder is generalized anxiety disorder, social anxiety disorder, or panic disorder. In some embodiments, a DSM5 disorder is anxiety disorder due to another medical condition, substance/medication-induced anxiety disorder, anxiety or depression due to other medical condition (e.g., eating disorders). In some embodiments, a DSM5 disorder is obsessive compulsive disorder, or body dysmorphic disorder.

Methods

[0043] It is contemplated that when estrogen levels fall, expression of NK3 receptors is enhanced. Accordingly, in some embodiments of the methods described herein, the timing of the dosing of an NK3 receptor antagonist may affect the therapeutic outcome when treating patients suffering from conditions such as post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS) and/or vasomotor symptoms. Administration of NK3 receptor antagonists at the nadirs of the estrogen diurnal cycle (when NK3 levels are elevated) can enhance the therapeutic effect of NK3 antagonists. Similarly, reducing estrogen levels in a patient (e.g., by administration of aromatase inhibitors and/or estrogen deprivation therapy) can also enhance the therapeutic effect of NK3 antagonists.

PTSD, acute stress disorder, schizophrenia, anxiety, depression and other conditions

[0044] Provided herein is a method for treating a disorder selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD), and vasomotor symptoms comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist in combination with estrogen deprivation therapy, wherein the patient has levels of estrogen above 1 ng/dL. In some embodiments, the disorder is selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS) and premenstrual dysphoric disorder (PMDD). In some embodiments, the treatment reduces the patient’s estrogen levels to below about 1 ng/dL.

[0045] Provided herein is a method for treating a disorder comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen (e.g., serum testosterone) or estrogen (e.g., serum estrogen levels), and wherein the disorder is selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, and vasomotor symptoms. In some embodiments, the disorder is selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS) and premenstrual dysphoric disorder (PMDD). [0046] In one embodiment, the patient is undergoing exposure therapy for the indications described. In this instance, the NK3 antagonist is provided before, during or after the exposure therapy to block the fear consolidation. In one embodiment, the patient has their estrogen level lowered to less than 5 ng/dL or to an undetectable level prior to administration of the NK3 antagonist.

[0047] In some embodiments, the patient’s estrogen is lower than or equal to 5 ng/dL. In some embodiments, the patient’s estrogen is lower than or equal to 3 ng/dL. In some embodiments, the patient’s estrogen is lower than or equal to 2 ng/dL. In some embodiments, the patient’s estrogen lower than or equal to 1 ng/dL. In some embodiments, the patient’s estrogen is at undetectable levels.

[0048] In some embodiments, provided is a method for treating PTSD comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen or estrogen (e.g., serum estrogen levels). In some embodiments, provided is a method for treating acute stress disorder comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen or estrogen (e.g., serum estrogen levels). In some embodiments, provided is a method for treating schizophrenia comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen or estrogen (e.g., serum estrogen levels). In some embodiments, provided is a method for treating anxiety comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen or estrogen (e.g., serum estrogen levels). In some embodiments, provided is a method for treating depression comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen or estrogen (e.g., serum estrogen levels). In some embodiments, provided is a method for treating vasomotor symptoms comprising administering a Neurokinin 3 receptor (NK3) antagonist to a patient in need thereof, wherein the patient has low or undetectable levels of an androgen or estrogen (e.g., serum estrogen levels).

[0049] In some embodiments is a method for treating a disorder selected from post-traumatic stress disorder (PTSD), acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, depression, prostate cancer, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD) and vasomotor symptoms comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist, wherein the patient has high levels of androgen and optionally low or undetectable levels of estrogen. In some embodiments, total testosterone levels in male subject are considered “high” when than 700, 720, 750, 800, 850, 890, 950, 1000, or 1080 ng/dL. In some embodiments, wherein the subject is male and being treated for prostate cancer, total testosterone levels in male subject are “high” when greater than 20, 30, 40, or 50 ng/dL. In some embodiments, total testosterone levels in female subject are “high” when greater than 40, 41, 50, 53, or 54 ng/dL. In some embodiments, total testosterone levels in female subject postmenopausal are “high” when greater than 40, 41, 50, 53, or 54 ng/dL. In some embodiments, total testosterone levels in female subject premenopausal are “high” when greater than 50, 53, or 54 ng/dL.

[0050] In some embodiments, the patient is a male patient and the NK3 antagonist is administered in combination with an aromatase inhibitor. In some of such embodiments the aromatase inhibitor reduces the conversion of testosterone to estrogen, thereby reducing levels of estrogen. In some embodiments, the patient has prostate cancer and is administered tamoxifen (or other estrogen deprivation therapy) and osanetant or other NK3 antagonist.

[0051] In some embodiments, the treatment further comprises administration of an estrogen deprivation therapy. In some of such embodiments, the NK3 antagonist is administered in combination with an aromatase inhibitor, and further in combination with an estrogen deprivation therapy.

[0052] In some embodiments, the patient is a post-menopausal female patient. In some embodiments, the patient is a peri-menopausal patient. In some embodiments, the peri-menopausal patient has irregular levels of estrogen. In some embodiments, the patient’s estrogen levels are tested prior to administration of the NK3 antagonists and the time for administration is selected based on the patient have the low or undetectable levels of estrogen. In some embodiments, the peri-menopausal patient is also administered hormone deprivation therapy.

[0053] In some embodiments, the NK3 antagonist is a dual NK1/NK3 antagonist. In some embodiments, the NK3 antagonist is a selective NK3 antagonist.

[0054] In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), pavinetant (AZD-4901/AZD- 2624), and SJX-653, or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), and pavinetant (AZD-4901/AZD- 2624), or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the NK3 antagonist is administered to the patient once a day. In some embodiments, the NK3 antagonist is administered to the patient twice a day. [0057] In some embodiments, the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 100 mg to about 500 mg.

[0058] In some embodiment the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is less than about 400 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is from about 10 to about 350 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is less than about 200 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is from about 10 to about 150 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is about 300 mg per day. In some embodiments, the osanetant is administered once a day. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose being about 150 mg.

[0059] In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 50 mg to about 200 mg. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose comprising from about 25 mg to about 100 mg of osanetant, or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments of the methods described herein, the osanetant is administered at about the nadirs in the diurnal cycle of estrogen. In some embodiments of the methods described herein, the osanetant is administered once a day at the about the daytime nadir in the diurnal cycle of estrogen. In some embodiments, the osanetant is administered such that the maximum concentration (C _max ) of the osanetant in the serum occurs at about the nadirs in the diurnal cycle of estrogen, or alternatively, the osanetant is administered once a day such that the C _max of the osanetant in the serum occurs at about the daytime nadirs in the diurnal cycle of estrogen.

[0061] It some embodiments of the methods described herein, the osanetant or other NK3 antagonists is administered in conjunction with the patient’s menstrual cycle. For example, estrogen levels rise and fall twice during the menstrual cycle. Estrogen levels rise during the mid-follicular phase and then drop precipitously after ovulation. This is followed by a secondary rise in estrogen levels during the mid-luteal phase with a decrease at the end of the menstrual cycle. Thus, in one embodiment, the osanetant, or other NK3 antagonist, is administered to the patient during or just after ovulation and/or at about the end of the menstrual cycle. In some embodiments, the patient is a female patient suffering from PMDD and is administered the NK3 antagonist for 7 - 14 days of the menstrual cycle. In one embodiment, the NK3 antagonist is delivered about 5 days, 4 days, 3 days before menstruation and in some embodiments, 3 days after, 4 days, or 5 days after menstruation. In another embodiment, when the patient’s estrogen levels are on the rise, the patient is also administered hormone deprivation therapy.

[0062] In some embodiments of the methods described herein, the treatment reduces a patient’s estrogen levels to below about 3 ng/dL, below about 2 ng/dL, below about 1 ng/dL, or to undetectable levels. In some embodiments of the methods described herein, administration of an aromatase inhibitor and/or estrogen deprivation therapy and/or an NK3 antagonist reduces a patient’s estrogen levels to below about 3 ng/dL, below about 2 ng/dL, below about 1 ng/dL, or to undetectable levels.

[0063] In some embodiments, the patient is a female patient suffering from PTSD, schizophrenia, schizoaffective disorder, bipolar disorder, acute stress disorder, anxiety, depression, PCOS, or PMDD, and with high levels of estrogen compared to baseline levels of estrogen prior to onset of said condition. In some embodiments, the patient is a female patient suffering from PTSD, schizophrenia, schizoaffective disorder, bipolar disorder, acute stress disorder, anxiety, depression, PCOS, or PMDD, and with baseline levels of estrogen prior to onset of said condition. In some of such embodiments, administration of an NK3 antagonist reduces estrogen levels. In some embodiments of the methods, the patient is treated with an NK3 antagonist which is administered according to dosing schedules described herein. In some other embodiments, the NK3 antagonist is administered in combination with hormone deprivation therapy (e.g., estrogen deprivation therapy).

[0064] In some embodiments, the patient is a male patient suffering from PTSD, schizophrenia, schizoaffective disorder, bipolar disorder, acute stress disorder, anxiety, depression, or prostate cancer and with high levels of an androgen (e.g., testosterone) or estrogen compared to baseline levels of estrogen prior to onset of said condition. In some embodiments, the patient is a male patient suffering from PTSD, schizophrenia, schizoaffective disorder, bipolar disorder, acute stress disorder, anxiety, depression, or prostate cancer, and with baseline levels of an androgen or estrogen prior to onset of said condition. In some of such embodiments, administration of an NK3 antagonist reduces estrogen levels. In some embodiments of the methods, the patient is treated with an NK3 antagonist which is administered according to dosing schedules described herein. In some other embodiments, the NK3 antagonist is administered in combination with hormone deprivation therapy. In some embodiments, hormone deprivation therapy comprises an aromatase inhibitor (which reduces conversion of testosterone to estrogen), estrogen deprivation therapy, or both. [0065] In some embodiments, the NK3 antagonist is administered for a period of at least 8 days. In some embodiments, the NK3 antagonist is administered for a period of 8 to 28 days. In some embodiments, the NK3 antagonist is administered for a period of at least 28 days. In some embodiments, the NK3 antagonist is administered for a period of at least 8 days at a first dose and thereafter administration is continued for a further period of at least 8 days at a second dose which is the same as, or different from, the first dose.

[0066] In some embodiments, the NK3 antagonist is administered for a period of at least 3 days before starting co-administration of an estrogen deprivation therapy and/or an aromatase inhibitor.

[0067] In some embodiments, the estrogen deprivation therapy and/or an aromatase inhibitor is administered for a period of at least 3 days before starting co-administration of an NK3 antagonist.

[0068] In some embodiments, the NK3 antagonist is administered for a period of at least 8 days after cessation of administration of an estrogen deprivation therapy and/or the aromatase inhibitor.

[0069] Aromatase inhibitors and/or inactivators interfere with the body's ability to produce estrogen from androgens by suppressing aromatase enzyme activity. In some embodiments, the aromatase inhibitor is selected from aminoglutethimide, fadrozole, vorozole, letrozole, anastrozole, exemestane and testolactone.

[0070] In some embodiments, the estrogen deprivation therapy is selected from a selective estrogen modulator (SERM) or a selective estrogen receptor degrader (SERD).

[0071] In some embodiments, the estrogen deprivation therapy is tamoxifen. In some embodiments, the SERM is raloxifene, toremifene, arzoxifene, lasofoxifene, broparestrol, clomifene (E, or Z), cyclofenil, ormeloxifene. ospemifene, acolbifene, afimoxifene (4-hydroxy tamoxifen), elacestrant, endoxifen (4-hydroxy-N-desmethyltamoxifen), clomiphene N-oxide, droloxifene (3-hydroxytamoxifen), etacstil, fispemifene, afimoxiphene, bazedoxifene, hydroxyetacstil, idoxifene (pyrrolidino-4- iodotamoxifen), levormeloxifene ((L)-ormeloxifene), miproxifene, nafoxidine, nitromifene (CI-628), NNC 45-0095, panomifene, pipendoxifene (ERA-923), trioxifene, or zindoxifene (D-16726). In some embodiments, the estrogen deprivation therapy is treatment with a selective estrogen receptor degrader (SERD). Examples of SERDs include and are not limited to

[0072] In some embodiments, the neurokinin receptor antagonist is administered to a patient for a time period prior to the estrogen deprivation therapy. In some embodiments, the NK3 antagonist is administered concurrently with estrogen deprivation therapy. In some embodiments, the patient continues to receive a NK3 antagonist after the estrogen deprivation therapy has been stopped. In some embodiments, the patient receives a NK3 antagonist after short-term (e.g., 1 to 6 months, 1 to 3 months, 1 month, 1-3 weeks, 1 week) estrogen deprivation therapy. In some embodiments, the patient receives the estrogen deprivation therapy for a short-term (e.g., 1 to 6 months, 1 to 3 months, 1 month, 1-3 weeks, 1 week) after an initial administration of an NK3 antagonist. Any combination of these therapeutic regimens is contemplated within the scope of embodiments presented herein.

[0073] In some embodiments, a patient selected for treatment using the methods described herein is a patient suffering from higher than normal estrogen levels, and/or suffering from conditions such as conditioned fear (e.g., PTSD), paranoia-related conditions (e.g., schizophrenia), acute stress disorder, anxiety or depression. In some embodiments, a patient selected for treatment using the methods described herein is a patient suffering from lower than normal estrogen levels, and/or suffering from conditions such as PCOS or PMDD. In some of such embodiments, the methods described herein provide for treatment with lower doses of the estrogen deprivation therapeutic compared to the recommended dosing, and/or for a longer duration of time compared to the recommended duration, along with administration of an NK receptor antagonist, thereby reversibly lowering estrogen levels in the patient. In some of such embodiments, the lower doses of the estrogen deprivation therapeutic reduce or avoid side effects such as vasomotor symptoms (hot flashes). As used herein “recommended dosing” or “recommended duration” for an estrogen deprivation therapeutic refers to dosing and/or durations approved by health agencies and/or provided on product labels.

[0074] In some embodiments, provided herein is a method to treat PTSD and/or schizophrenia and/or acute stress disorder and/or anxiety and/or depression by reducing estrogen to non-detectable levels comprising administration of a lower than recommended dose of an estrogen deprivation agent and driving estrogen to lower levels, e.g., less than 5 ng/dL, or less than 3 ng/dL. In some of such embodiments, an NK3 antagonist, e.g., osanetant is administered in combination with the estrogen deprivation therapy. In some of such embodiments, the reduction in estrogen occurs faster than the reduction if a recommended dose of the estrogen deprivation therapy would have been administered alone. In some of such embodiments, the lowest estrogen level achieved is lower than the level that would be achieved if a recommended dose of the estrogen deprivation therapy would have been administered alone.

[0075] Provided herein is a method of modulating the response to an NK3 antagonist in a patient undergoing NK3 therapy, the method comprising administering to the patient an adjunct therapy that reduces estrogen levels in said patient. In some embodiments, the reduction in estrogen levels in the patient upregulates NK3 receptors in the patient, thereby increasing the efficacy of the NK3 antagonist. In some embodiments, the patient suffers from PTSD, acute stress disorder, schizophrenia, schizoaffective disorder, bipolar disorder, anxiety, or depression. In some embodiments, the patient is a female patient.

[0076] In some embodiments the patient is a male patient. In some embodiments, the patient is a postmenopausal female patient. Estrogen is produced in the ovaries but may also be stored in adipose tissue. Accordingly, reducing body mass index (BMI) may also reduce estrogen levels and is contemplated within the scope of embodiments presented herein. In some embodiments, the patient has low body mass index. In some embodiments, the patient has undergone or is undergoing exposure therapy.

[0077] Provided herein is a method of treating a disorder in a patient, where the disorder is worsened by estrogen lowering or estrogen depletion, comprising administering to a patient in need thereof a Neurokinin 3 receptor (NK3) antagonist. [0078] In some embodiments, the patient is being treated with an estrogen deprivation therapy. In some embodiments, the patient is a female patient. In some embodiments, the patient has lowered or depleted estrogen because of recent childbirth, peri-menopause, or menopause, or the patient is postmenopause. In some embodiments, the patient is a male patient.

[0079] In some embodiments, the patient suffers from a DSM5 disorder.

[0080] In some embodiments, the NK3 antagonist is a dual NK1/NK3 antagonist. In some embodiments, the NK3 antagonist is a selective NK3 antagonist. In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), pavinetant (AZD-4901/AZD-2624), and SJX-653, or a pharmaceutically acceptable salt thereof. In some embodiments, the NK3 antagonist is selected from osanetant (SR- 142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), and pavinetant (AZD- 4901/AZD-2624), or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the NK3 antagonist is administered to the patient once a day. In some embodiments, the NK3 antagonist is administered to the patient twice a day. In some embodiments, the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 100 mg to about 500 mg. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 50 mg to about 200 mg. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose comprising from about 25 mg to about 100 mg of osanetant, or a pharmaceutically acceptable salt thereof.

Bone Loss

[0082] Tachykinin receptors play a role in bone metabolism. Ichiki et al. (Neuropeptides Volume 45, Issue 3, June 2011, Pages 239-244) report that in cultured rat osteoclasts, the addition of Neurokinin B (NKB) significantly increased the number of osteoclasts and the resorption area compared with the control. It is known that NKB acts predominantly via the neurokinin 3 receptor (NK3). Osteoclasts and osteoblasts generally coordinate a balance which maintains bone density under healthy conditions. When osteoclasts begin to remove more bone than the osteoblasts can create, loss of bone mass is observed. It is contemplated herein that antagonism of NKB (via antagonism of NK3) will reduce the number of osteoclasts, thereby reducing bone resorption, thus reducing bone loss. Also contemplated are methods to increase effectiveness of an NK3 antagonist by reducing the levels of estrogen in a patient. [0083] Provided herein is a method for preventing, including blocking, attenuating, or limiting, bone loss in a patient comprising administering a Neurokinin 3 receptor (NK3) antagonist to the patient in need thereof. Provided herein is the use of an NK3 antagonist for the manufacture of a medicament for preventing, including blocking, attenuating, or limiting, bone loss.

[0084] Provided herein is a method for reducing or inhibiting bone loss in a patient comprising administering a Neurokinin 3 receptor (NK3) antagonist to the patient in need thereof. In some embodiments, the method treats bone loss that has already occurred, e.g., in an osteoporosis patient, by limiting any further bone loss. In some embodiments, the method prophylactically delays or prevents bone loss (e.g., in a patient who will undergo hormone deprivation therapy).

[0085] In some embodiments, the NK3 antagonist is a dual NK1/NK3 antagonist. In some embodiments, the NK3 antagonist is a selective NK3 antagonist.

[0086] In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), pavinetant (AZD-4901/AZD- 2624), and SJX-653, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the NK3 antagonist is selected from osanetant (SR-142,801), elinzanetant (NT-814), fezolinetant (ESN-364), talnetant (SB-223,412), and pavinetant (AZD-4901/AZD- 2624), or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the NK3 antagonist is administered to the patient once a day.

[0089] In some embodiments, the NK3 antagonist is administered to the patient twice a day.

[0090] In some embodiments, the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 100 mg to about 500 mg.

[0092] In some embodiment the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is less than about 400 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is from about 10 to about 350 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is less than about 200 mg per day In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is from about 10 to about 150 mg per day. In some embodiments, the effective amount of osanetant, or a pharmaceutically acceptable salt thereof, is about 300 mg per day. In some embodiments, the osanetant is administered once a day. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose being about 150 mg.

[0093] In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered to the patient twice a day for a total daily dose ranging from about 50 mg to about 200 mg. In some embodiments, the osanetant, or a pharmaceutically acceptable salt thereof, is administered twice a day, each dose comprising from about 25 mg to about 100 mg of osanetant, or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the patient is a cancer patient. In some embodiments, the administration of a neurokinin receptor antagonist reduces or eliminates bone loss in a cancer patient, thereby improving prognosis (e.g., lifespan, regression of the cancer, and/or quality of life) for cancer patients. Accordingly, in some embodiments of any method described above and herein, the method further provides for alleviation of loss of bone mass and/or bone density in a cancer patient undergoing hormone deprivation therapy.

[0095] In some embodiments, the patient has cancer, has had cancer, or has an increased risk for cancer and suffers from bone loss. In some embodiments, the cancer is breast cancer, ovarian cancer, uterine cancer, testicular, or prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is hormone receptor-positive cancer, e.g., breast cancer or prostate cancer.

[0096] In some embodiments, the patient has suffered from cancer but is in remission and suffers from bone loss. In some embodiments, the patient has an increased risk for cancer. In some embodiments, such a risk may be from a genetic mutation implicated in cancer. In some embodiments, the patient has tested positive for a BRCA1, BRCA2, or PALB2 mutation. In some embodiments, the patient has tested positive for a BRCA1 mutation. In some embodiments, the patient has tested positive for a BRCA2 mutation. In some embodiments, the patient has tested positive for a PALB2 mutation. In some embodiments, the patient is menopausal. In some embodiments, the patient is perimenopausal.

[0097] Inherited mutations to certain genes can lead to the development of specific types of cancers.

BRCA1 and BRCA2 are genes that code for tumor suppressor proteins, which assist in repairing damage to DNA. When an individual has a mutated version of either gene, the individual will not produce a functional form of the related tumor suppressor protein, so DNA damage will accumulate, which can lead to the development of cancer. Mutations in BRCA1 and BRCA2 have been shown to increase the risk for the development of ovarian and fallopian tube cancer in women, prostate cancer in men, and, most notably, breast cancer in both women and men. In addition to BRCA1 and 2 mutations, patients having a mutation in PALB2 are also at risk for increase of cancer. In some embodiments provided herein, the genetic predisposition to developing certain mutation-linked or hormone-dependent cancers is having tested positive for a BRCA1 mutation. In some embodiments provided herein, the genetic predisposition to developing certain mutation-linked or hormone-dependent cancers is having tested positive for a BRCA2 mutation. In some embodiments provided herein, the genetic predisposition to developing certain mutation-linked or hormone-dependent cancers is having tested positive for a PALB2 mutation. In some embodiments provided herein, the genetic predisposition is in ATM, BARD1, BRIP1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 and/or MLH1, MSH2, MSH6, PMS2, EPCAM genes.

[0098] Given the significant increase in risk in developing these specific cancers associated with possessing a mutant BRCA1, BRCA2 or PALB2 gene, many women who are carriers opt for the prophylactic removal of breast tissue (mastectomy), fallopian tubes (salpingectomy), uterus (hysterectomy) and/or ovaries (oophorectomy), to stem the possibility of developing an associated cancer in these organs, as well as to limit the presence of the endogenous sex hormones that cause the proliferation of hormone-dependent cancers. In certain embodiments, the patient to be treated possess the BRCA1, BRCA2 or PALB2 gene and are having their breast tissue (mastectomy), fallopian tubes (salpingectomy), uterus (hysterectomy) and/or ovaries (oophorectomy) removed. In such embodiments, bone loss may occur subsequent to surgery.

[0099] For men suffering from prostate cancer, surgical resection of the prostate (prostatectomy), seminal vesicles, and neighboring lymph nodes, as well as estrogen suppression or deprivation therapy are common treatments for the disease. In situations of advanced prostate cancer, removal of the testes (orchiectomy), the primary source of endogenous estrogen in the male body, can be undertaken to further limit the growth and spread of the hormone-dependent prostate cancer. In such embodiments, bone loss may occur in the patient.

[0100] For hormone-dependent cancers, such as breast, ovarian, uterine, prostate, and testicular cancers, the proliferation of cells is driven by hormone-receptor interactions on cell surfaces. In the presence of these sex hormones, namely estrogen, progesterone, and estrogen, the hormone-dependent cells replicate more frequently, increasing the opportunity for genetic errors to occur and accumulate, potentially leading to cancer. Pharmaceutical interventions, e.g. hormone deprivation therapy, for the treatment or prevention of hormone-dependent cancers include compounds that inhibit the synthesis of these sex hormones, such as gonadotropin-releasing hormone (GnRH) agonists and antagonists, compounds which block receptor sites on hormone-dependent cancer cell surfaces, such as selective estrogen-receptor modulators (SERMs) or nonsteroidal antiestrogens (NSAAs), and selective estrogen receptor degraders (SERDS) . In certain embodiments, the patient will be undergoing hormone deprivation therapy. For instance, in the case of prostate cancer, the patient may be undergoing estrogen deprivation therapy. Bone loss can occur in such patients.

[0101] Many patients opt for medical or surgical interventions to remove a cancer and surrounding tissues. Many patients also elect for the removal of sex hormone producing organs, namely the ovaries or testes. In such instances osteoporosis may occur. In certain embodiments, the patient to be treated will be undergoing removal of ovaries or testes. In certain embodiments, the patient will already be receiving a SERM, e.g. tamoxifen for treatment of a cancer and suffers from bone loss.

[0102] In some embodiments, the patient is undergoing hormone deprivation therapy and the NK3 antagonist is administered in combination with the hormone deprivation therapy. In some embodiments, the hormone deprivation therapy is estrogen deprivation therapy. In some embodiment, the estrogen deprivation therapy is tamoxifen. In some embodiments, the hormone deprivation therapy is surgery selected from orchiectomy, hysterectomy, and oophorectomy.

[0103] In some embodiments, the osanetant is administered for a short period prior to onset of the hormone deprivation therapy, e.g., prior to surgery or prior to start of treatment with tamoxifen. In some embodiments, the osanetant is administered for a period of 1 day to 1 month prior to onset of hormone deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 3 weeks prior to onset of hormone deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 2 weeks prior to onset of hormone deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 1 week prior to onset of hormone deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 5 days prior to onset of hormone deprivation therapy. In some embodiments, the osanetant is administered for a period of 1 day to 3 days prior to onset of hormone deprivation therapy.

[0104] In some embodiments, the osanetant is administered prior to onset of hormone deprivation therapy, and during the hormone deprivation therapy. In some embodiments, the osanetant is administered after the hormone deprivation therapy (e.g., as maintenance therapy after cessation of treatment with, e.g., tamoxifen, or after surgery (e.g., after prostatectomy, orchiectomy, hysterectomy, or oophorectomy).

[0105] In some embodiments, the patient is a peri-menopausal or post-menopausal female patient. In some embodiments the patient is a male patient who may have undergone prostatectomy or orchiectomy.

[0106] In some embodiments, the hormone deprivation therapy is treatment with a SERM. In some of such embodiments, the patient is a female patient. In some embodiments, the SERM is tamoxifen. In some embodiments, the SERM is raloxifene or toremifene.

[0107] In some embodiments, the hormone deprivation therapy is treatment with a selective estrogen receptor degrader (SERD). Examples of SERDs include and are not limited to

[0108] In some embodiments, the cancer is breast cancer, ovarian cancer, uterine cancer, or prostate cancer. In some embodiments, the cancer is a hormone receptor-positive cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the patient has tested positive for a BRCA1, BRCA2 or PALB2 mutation. [0109] In some embodiments, the neurokinin receptor antagonist is administered to a patient for a time period prior to the hormone deprivation therapy, and/or medical or surgical procedure as described herein. In some embodiments, the NK antagonist is administered concurrently with hormone deprivation therapy, a medical and/or surgical procedure. In some embodiments, the patient continues to receive a NK antagonist after the hormone deprivation therapy, a medical and/or surgical procedure. In some embodiments, the patient receives a NK antagonist after short-term (e.g., 1 to 6 months, 1 to 3 months) hormone deprivation therapy. Any combination of these therapeutic regimens is contemplated within the scope of embodiments presented herein.

[0110] Also contemplated within the scope of embodiments presented herein is a method for preventing, e.g., blocking, attenuating, or limiting bone loss in astronauts who are, or have been, in reduced gravity environments for extended periods of time (e.g., residing in the international space station), the method comprising administering a NK3 antagonist to the astronaut. In some of such embodiments, the NK3 antagonist is administered prophylactically prior to start of space travel. In some of such embodiments, the NK3 antagonist is administered during space travel and/or after cessation of space travel. In some of such embodiments, the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.

[0111] Bone density is monitored using standard tests such as dual-energy X-ray absorptiometry (DEX A or DXA). Other biomarkers of bone density may be monitored such as alkaline phosphatase (ALP), osteocalcin, N-terminal propeptide of type I procollagen (PINP), urine N-terminal telopeptide (NTX). Provided herein is a method for improving such bone density biomarkers in a patient in need thereof, the method comprising administration of an NK3 antagonist to the patient in need thereof.

NK Antagonists

[0112] As discussed above, NK antagonists are useful in the methods described herein. As used herein, “NK receptor,” “neurokinin receptor,” or “tachykinin receptor” is a transmembrane G-protein coupled receptor. The three known tachykinin receptors are NK1, NK2, and NK3. These receptors act on a variety of human functions, which regulate numerous biological systems, including the reproductive system.

[0113] As used herein, “NK receptor antagonists,” “neurokinin receptor antagonists,” or “tachykinin receptor antagonists” are a class of drugs which interact with tachykinin receptors NK1, NK2, and NK3, and dampen the normal agonist-mediated biological responses. The tachykinin receptors have been associated with the transmission of stress signals and pain, the contraction of smooth muscles, inflammation, and modulating the hypothalamus-pituitary-gonadal axis. NK receptor antagonists are indicated for the treatment of migraine, emesis, gastrointestinal disorders, disorders of the reproductive system, and psychiatric disorders, including anxiety, addiction, depression, and schizophrenia. In certain embodiments, the NK antagonist is a NK1, NK2, or NK3 antagonist or a combination thereof.

[0114] In certain embodiments, the NK antagonist is a NK1 receptor antagonist selected from aprepitant, casopitant, ezlopitant, fosaprepitant, lanepitant, maropitant, rolapitant, vestipitant, L-733,060, L-741,671, L-742,694, RP-67580, RPR-100,893, CP-96345, CP-99994, GR-205,171, TAK-637, T-2328, and combinations thereof. In certain embodiments, the NK antagonist is a NK2 receptor antagonist selected from ibodutant, saredutant, GR-159,897, MEN-10376, and combinations thereof. In certain embodiments, the NK antagonist is a NK3 receptor antagonist selected from fezolinetant, osanetant, pavinetant, talnetant, SB-222,200 (structure below), SB-218,795 (structure below), NT-814 (structure below), and combinations thereof.

[0115] In certain embodiments, the NK antagonist is a NK3 antagonist. The NK3 receptor, and its associated tachykinin neuropeptide, neurokinin B, act on a variety of human functions, affecting the hypothalamus-pituitary-gonadal axis, which regulates numerous biological systems, including the reproductive system. In certain embodiments, the NK3 antagonist is osanetant.

[0116] In certain embodiments, the neurokinin-3 receptor antagonist is selected from osanetant, fezolinetant, pavinetant, talnetant, SB-222,200, SB-218,795, and NT-814. In certain embodiments, the neurokinin-3 receptor antagonist is osanetant. In certain embodiments, the neurokinin-3 receptor antagonist is fezolinetant. In certain embodiments, the neurokinin-3 receptor antagonist is pavinetant. In certain embodiments, the neurokinin-3 receptor antagonist is talnetant. In certain embodiments, the neurokinin-3 receptor antagonist is SB-222,200. In certain embodiments, the neurokinin-3 receptor antagonist is SB-218,795. In certain embodiments, the neurokinin-3 receptor antagonist is NT-814. In certain embodiments, the NK3 antagonist is osanetant.

[0117] Osanetant was originally developed for the treatment of schizophrenia and other central nervous system disorders. In certain embodiments the NK antagonist is osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof. The chemical name of osanetant is (R)-N-(l-(3-(l-benzoyl-3-(3,4- dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl )-N-methylacetamide, and has the following structure:

[0118] Osanetant can also form pharmaceutically acceptable salts, such as osanetant hydrochloride, osanetant hydrobromide, osanetant sulfate, osanetant hydrogen sulfate, osanetant dihydrogen phosphate, osanetant methanesulfonate, osanetant methyl sulfate, osanetant maleate, osanetant fumarate, osanetant 2- naphthalenesulfonate, osanetant benzenesulfonate, osanetant glycolate, osanetant gluconate, and osanetant citrate, osanetant isethionate, osanetant p-toluenesulfonate, and the like. In some embodiments provided herein, osanetant is administered as a hydrochloride salt thereof.

[0119] Osanetant, as well as pharmaceutically acceptable salts thereof, can be purchased from commercial sources or can synthesized using published procedures.

Administration

[0120] In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient prior to the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 12 weeks or 8 weeks or 4 weeks to the day of the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient prior to the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 3 weeks to the day of the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient prior to the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 2 weeks to the day of the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure. In some embodiments, the time period over which the neurokinin receptor antagonist is administered prior to the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 2 weeks. In some embodiments, the time period over which the neurokinin receptor antagonist is administered prior to the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 1 week.

[0121] In some embodiments, the neurokinin receptor antagonist is administered to a patient concurrently with the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure.

[0122] In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient after the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 12 weeks. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient after the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 8 weeks. In some embodiments, the time period over which the neurokinin receptor antagonist is administered to a patient after the hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure is about 4 weeks.

[0123] In some embodiments, the patient is administered osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, for about 1 week prior to, concurrently with, and for about 12 weeks after, a hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure. In some embodiments, the patient is administered osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, for about 2 weeks prior to, concurrently with, and for about 12 weeks or more after, hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure. [0124] In some embodiments, the patient is administered osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, for about 1 week prior to, concurrently with, and for about 8 weeks after a hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure. In some embodiments, the patient is administered osanetant for about 2 weeks prior to, concurrently with, and for about 8 weeks after, a hormone deprivation therapy (estrogen deprivation therapy), and/or surgical procedure.

[0125] In some embodiments, the neurokinin receptor antagonist is orally administered.

[0126] In some embodiments, the neurokinin receptor antagonist is subcutaneously administered.

[0127] In some embodiments, the neurokinin receptor antagonist is transdermally administered.

[0128] In some embodiments, the neurokinin receptor antagonist is intravenously administered.

[0129] In some embodiments, the neurokinin receptor antagonist is administered once daily. In some embodiments, the neurokinin receptor antagonist is administered as two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day.

[0130] In some embodiments, when the NK antagonist is osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, the therapeutically effective amount of the osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 0.25 mg/day to about 1000 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, osanetant is about 0.5 mg/day to about 500 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 0.75 mg/day to about 450 mg/day, is about 1 mg/day to about 400 mg/day or 10 mg/day to about 350 mg/day. In some embodiments, the osanetant is administered is less than about 400 mg/day. In some embodiments, the osanetant is administered is less than about 200 mg/day or about 10 mg/day to about 150 mg/day. [0131] In some embodiments, the therapeutically effective amount of the osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N- oxide or isomorphic crystalline form thereof, is about 1 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 50 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 100 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 200 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 300 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 400 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 500 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 600 mg/day. In some embodiments, the therapeutically effective amount of osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is about 800 mg/day. In some embodiments, the therapeutically effective amount of osanetant is about 1000 mg/day.

[0132] In certain embodiments, osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, is dosed at about 0.25 mg/day to about 1 mg/day, in order to treat bone loss while avoiding transient increases in liver transaminase (alanine aminotransferase) concentrations, and maintaining healthy liver function.

[0133] In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 5 mg per day to about 600 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 25 mg per day to about 500 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 50 mg per day to about 500 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 100 mg per day to about 400 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 150 mg per day to about 300 mg per day. In any of these embodiments, the total daily dose may be administered as a single dose, or split between multiple doses (e.g., daily dose of 300 mg QD or daily dose of 300 mg split into 150 mg BID, or daily dose of 300 mg split into 100 mg TID). In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 300 mg, split into two doses of 150 mg each, i.e., 150 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 200 mg, split into two doses of 100 mg each, i.e., 100 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 100 mg, split into two doses of 50 mg each, i.e., 50 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 50 mg, split into two doses of 25 mg each, i.e., 25 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 25 mg, split into two doses of 12.5 mg each, i.e., 12.5 mg BID. In any of such embodiments, the dose of an aromatase inhibitor or an estrogen deprivation therapy or procedure may be lower than the recommended dosing and may be for a longer duration of time compared to the recommended duration of estrogen deprivation therapy.

[0134] In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 5 mg per day to about 600 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 25 mg per day to about 500 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 50 mg per day to about 500 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 100 mg per day to about 400 mg per day. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose ranging from about 150 mg per day to about 300 mg per day. In any of these embodiments, the total daily dose may be administered as a single dose, or split between multiple doses (e.g., daily dose of 300 mg QD or daily dose of 300 mg split into 150 mg BID, or daily dose of 300 mg split into 100 mg TID). In any of these embodiments, the total daily dose of osanetant may be administered as a single dose at a nadir of the diurnal estrogen cycle.

[0135] In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 300 mg, split into two doses of 150 mg each, i.e., 150 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 200 mg, split into two doses of 100 mg each, i.e., 100 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 100 mg, split into two doses of 50 mg each, i.e., 50 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 50 mg, split into two doses of 25 mg each, i.e., 25 mg BID. In some embodiments, osanetant is administered prior to, and/or concurrently with, and/or after administration of an aromatase inhibitor or an estrogen deprivation therapy or procedure in a daily dose of 25 mg, split into two doses of 12.5 mg each, i.e., 12.5 mg BID. In any of these embodiments, the total daily dose of osanetant may be administered as a split dose at nadirs of the diurnal estrogen cycle.

[0136] In some embodiments, the dose of an aromatase inhibitor or an estrogen deprivation therapy may be lower than the recommended dosing and may be for a longer duration of time compared to the recommended duration of the aromatase inhibitor or estrogen deprivation therapy. Pharmaceutical Compositions

[0137] Also provided herein, in some embodiments, are pharmaceutical compositions that comprise osanetant, or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, and one or more pharmaceutically acceptable vehicles selected from carrier, adjuvants, and excipients.

[0138] Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0139] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, intravenous, subcutaneous, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0140] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0141] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example as a solution in 1,3-butanediol. Among the acceptable vehicles that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be useful in the preparation of injectables. Such solutions may be formulated as 0.01% -10% isotonic solutions, pH 5-7, with appropriate salts. [0142] The compound described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques. The compound described herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

[0143] A pharmaceutical composition, for example, for injection, may comprise a cyclodextrin. The cyclodextrin may be, for example, a hydroxypropyl cyclodextrin or a sulfobutylether cyclodextrin. The cyclodextrin may be, for example, an a-cyclodextrin, a P-cyclodextrin, or a y-cyclodextrin.

[0144] A compound described herein may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues including blood. Suitable examples of sustained release carriers include semi-permeable polymer matrices in the form of shared articles, e.g., suppositories or microcapsules. Examples can be found, e.g., in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, A. R., Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, N. C. et al. 7th Edition ISBN 0-683305-72-7, the entire disclosures of which are herein incorporated by reference.

[0145] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0146] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0147] The compositions that include at least one compound described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0148] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0149] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0150] The compound described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Furthermore, pharmaceutical compositions containing the compound described herein can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, which can include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).

[0151] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, orally, from devices that deliver the formulation in an appropriate manner.

[0152] Some examples of suitable mucoadhesive agents include agarose, chitosan, trimethylated chitosan, chitosan-EDTA, gelatin, hyaluronic acid, guar gum, hakea gum, xanthan gum, gellan gum, carrageenan, pectin, sodium alginate, cellulose derivatives, CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC, poly(acrylic acid)-based polymers, CP, PC, PAA, copolymers of acrylic acid and PEG, PVA, PVP, CP, aminodextran, dimethylaminoethyl-dextran, hydroxyethyl starch, poly(ethylene oxide), scleroglucan, cyanoacrylate, hydroxylated methacrylate, and poly(methacrylic acid). Some examples of suitable penetration enhancers include sodium lauryl sulfate, cetyl pyridinium chloride, Poloxamer, Brij, Span, Myrj, Tween, sodium glycocholate, sodium tauro deoxycholate, sodium tauro cholate, oleic acid, caprylic acid, lauric acid, lyso phosphatidyl choline, phosphatidyl choline, a-, P-, and y-cyclodextrin, methylated P-cyclodextrin, EDTA, citric acid, sodium salicylate, methoxy salicylate, chitosan, trimethyl chitosan, poly-L-arginine, and L-lysine. Some examples of suitable enzyme inhibitors include aprotinin, bestatin, and puromycin.

Combination Therapy

[0153] The neurokinin receptor antagonist may be administered in combination with one or more additional active agents. In some embodiments, the neurokinin receptor antagonist may be administered in combination with an adjunct therapy (e.g., estrogen deprivation therapy) or adjunct procedure (e.g., oophorectomy). In some embodiments, neurokinin receptor antagonist may be administered in combination with a second active agent that the patient is being treated with.

[0154] In some embodiments, the second active agent is an aromatase inhibitor as described herein. In some embodiments, the second active agent is a SERM or a SERD as described herein. In some embodiments, the adjunct procedure is a surgical procedure described herein.

[0155] Also provided is a pharmaceutical composition comprising osanetant and a second active agent.

Examples

[0156] It is understood that modifications which do not substantially affect the activity of the various embodiments of this disclosure are also included within the definition of the disclosure provided herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure.

Example 1 - Treatment of PTSD

[0157] This is a multicenter, randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study that will investigate the efficacy and safety of two doses of osanetant in combination with estrogen deprivation therapy. Following successful screening and randomization, eligible subjects will return regularly to the study clinic for weekly or biweekly visits for assessments of efficacy and safety.

[0158] Male or female subjects between 18 and 65 years of age, diagnosed with current PTSD as defined by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), will be enrolled. Subjects with significant traumatic brain injury, severe depression, bipolar and psychotic disorders, increased suicide risk, or history of alcohol or drug abuse will be excluded. Subjects undergo exposure therapy and are administered osanetant, or a pharmaceutically acceptable salt thereof, orally and twice daily, or are estrogen deprivation therapy to achieve low or undetectable levels of estrogen in the patient or both. Osanetant is administered to the treated group in a total daily dosage of between 100 and 400 mg. Subjects will return to the clinic for periodic evaluations using the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (CAPS-5) total symptom severity score over a 12-week period. Example 2 - Treatment of bone loss

[0159] Women between the ages of 40 to 65 years old are confirmed as menopausal per one of the following criteria at the outset of the study: spontaneous amenorrhea for at least 12 consecutive months; spontaneous amenorrhea for at least 6 months with biochemical criteria of menopause (follicle- stimulating hormone [FSH] > 40 IU/L); or having had bilateral oophorectomy at least 6 weeks prior to outset of study. Subjects are administered osanetant, or a pharmaceutically acceptable salt thereof, orally and twice daily, or are administered a placebo control. Osanetant is administered to the treated group in a total daily dosage of between 100 and 400 mg. Bone density is monitored using standard tests such as dual-energy X-ray absorptiometry (DEXA or DXA). Other biomarkers of bone density may be monitored such as alkaline phosphatase (ALP), osteocalcin, N-terminal propeptide of type I procollagen (PINP), urine N-terminal telopeptide (NTX).

[0160] Additional subjects are studied, including women with HR positive breast cancer who are receiving tamoxifen, and women who are BRCA positive and have had bilateral oophorectomy.

Example 3 - Effect of low estrogen in major depressive disorder

[0161] A double-blind, placebo- and fluoxetine-controlled, multicenter study evaluating the efficacy and safety of osanetant was conducted in outpatients with major depressive disorder (MDD).

[0162] Population: Male or female outpatient, 18 to 65 years of age with diagnosis of major depressive disorder

[0163] Endpoint: Hamilton Depression Rating Scale (HAM-D; 17 item)

[0164] Treatment: Osanetant (SR142801) 200 mg once daily, Placebo, or Fluoxetine 20 mg once daily for 6 weeks

[0165] Results: There were no statistically significant differences between the osanetant or fluoxetine groups and the placebo group in the change from baseline to Day 42 (final visit) or in total scores at Day 42 across efficacy variables and across analysis populations for the original analysis.

[0166] Female patients were reanalyzed for efficacy based on likely having “low” levels or “normal” levels of estrogen based on age, medical history, and use of oral contraceptives. [0167] Patients were considered likely to have “low” levels of estrogen if: >45 years of age; medical history of hysterectomy or oophorectomy; or taking oral contraceptives. Otherwise, patients were considered to have “normal” levels of estrogen.

[0168] Endpoint: A patient was defined as a HAM-D “treatment responder” if the HAMD total score at week 42 was at least 50% lower than the baseline HAM-D total score.

[0169] Table 3 below shows the results from the reanalysis.

Table 3

[0170] The data in Table 3 shows that no differences in the response rate were observed for female patients receiving placebo based on predicted estrogen levels. There was a greater response rate for female patients receiving osanetant with predicted “low” estrogen levels (47%) relative to predicted “normal” estrogen levels (30%). Although the response rate with osanetant was similar to the placebo group regardless of estrogen subgroup, the study showed that selection of patients with low estrogen does improve the response rate of osanetant. The study also showed that contrary to literature reports (Li et. al, Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling, Psychoneuroendocrinology. 2013 Jul; 38(7): 1145-1157), fluoxetine also showed higher response rates in patients with low estrogen. In male patients, osanetant had a greater response rate (43%) compared to placebo or fluoxetine.

* * *

[0171] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.