Methods for treating vasomotor symptoms in breast cancer patients with fezolinetant

Abstract

Provided herein is method of treating vasomotor symptoms (VMS) in a breast cancer patient being treated with an endocrine therapy drug comprising administering fezolinetant.

Description

METHODS FOR TREATING VASOMOTOR SYMPTOMS IN BREAST CANCER PATIENTS WITH FEZOLINETANT

[0001] CROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of U.S. Provisional Patent Application No. 63 / 716,958, filed November 06, 2024, the entire contents of which are incorporated by reference herein.

[0002] Fezolinetant was developed as a selective antagonist of NK-3 receptor and is useful as a therapeutic compound, particularly in the treatment and / or prevention of sex-hormone dependent diseases, such as moderate to severe vasomotor symptom (VMS). Fezolinetant corresponds to (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone or a pharmaceutically acceptable salt thereof, and is described in WO2014 / 154895.

[0003] Fezolinetant is an FDA approved drug for treating moderate to severe vasomotor symptoms due to menopause. Fezolinetant is a once a day 45 mg tablet formulated for oral consumption.

[0004] Breast cancer is one of the most commonly diagnosed cancers, with nearly 2.3 million new diagnoses in 2020 worldwide, with about 685,000 deaths. Approximately 80% of breast cancers are hormone receptor positive (HR+), with more than 80% of patients receiving adjuvant endocrine therapy, e.g., tamoxifen or aromatase inhibitors. Adjuvant treatment of breast cancer, including chemotherapy, immunotherapy, oophorectomy and / or endocrine therapy, can lead to treatment-related side effects including premature menopause and menopause-related symptoms such as VMS. These can be due to adjuvant chemotherapy inducing ovarian failure, surgical removal of ovaries, or adjuvant endocrine therapy [Atema V, van Leeuwen M, Kieffer JM, Oldenburg HSA, van Beurden M, Gerritsma MA, et al. Efficacy of internet-based cognitive behavioral therapy for treatment-induced menopausal symptoms in breast cancer survivors: results of a randomized controlled trial. J Clin Oncol. 2019;37:809-22; Mom CH, Buijs C, Willemse PHB, Mourits MJE, de Vries EGE. Hot flushes in breast cancer patients. Crit Rev Oncol Hematol. 2006;57:63-77; Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14:1718-29]. Compared to the relative short duration of chemotherapy, typically 6 months, adjuvant endocrine therapy is chronic and typically lasts up to 5 to 10 years.

[0005] Adjuvant endocrine therapies, including tamoxifen and aromatase inhibitors (such as anastrozole, letrozole and exemestane), are the most frequently prescribed antitumor therapies in the world; approximately 77% of breast cancers can be treated with adjuvant endocrine therapies. Tamoxifen has been available since the 1970s and aromatase inhibitors have been on the market for 3 decades with an established safety profile [Howell A and Howell SJ. Tamoxifen evolution. Br J Cancer. 2023;128:421-5]. However, these treatments may lead to acute and long-term consequences of estrogen deprivation including menopausal symptoms, with up to 97% of patients experiencing hot flashes (or night sweats) similar to or worse than those observed in menopausal women [Fenlon D, Morgan A, Khambaita P, Mistry P, Dunn J, Ah-See M-L, et al; NCRI CSG Breast Cancer Symptom Working Party. Management of hot flushes in UK breast cancer patients: clinician and patient perspectives. J Psychosom Obstet Gynaecol. 2017 Dec;38:276-83; Harris PF, Remington PL, Trentham-Dietz A, Allen CI, Newcomb PA. Prevalence and treatment of menopausal symptoms among breast cancer survivors. J Pain Symptom Manage. 2002;23:501-9]. Hot flashes, as the most prominent side effect of tamoxifen and aromatase inhibitors, can adversely affect patients’ quality of life and compliance with adjuvant treatment. There is currently no approved pharmaceutical treatment for VMS that can be used by these women, which leaves a clear unmet medical need for the effective and adequate treatment of hot flashes in breast cancer patients, especially for these patients, for whom hormone replacement therapy for VMS is contraindicated.

[0006] In one aspect, the present disclosure provides a method of treating vasomotor symptoms (VMS) in a breast cancer patient in need thereof comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof, wherein the patient is being treated with an endocrine therapy drug.

[0007] FIG. 1A shows the mean skin temperature (℃) for a 0-12 hour light phase, a 12-24 hour dark phase, and a 0-24 hour full phase in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0008] FIG. 1B shows the heat loss index for a 0-12 hour light phase, a 12-24 hour dark phase, and a 0-24 hour full phase in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0009] FIG. 1C shows the mean core temperature (℃) for a 0-12 hour light phase, a 12-24 hour dark phase, and a 0-24 hour full phase in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0010] FIG. 2A shows breast cancer tumor volume (mm3) over the course of 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0011] FIG. 2B shows breast cancer tumor volume (mm3) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0012] FIG. 2C shows rat body weight gain (g) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0013] FIG. 2D shows rat food intake (g / day) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0014] FIG. 2E shows uterine weight (g) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0015] FIG. 3A shows plasma estradiol levels (pg / mL) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0016] FIG. 3B shows plasma LH levels (ng / mL) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0017] FIG. 3C shows plasma FSH levels (ng / mL) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0018] FIG. 3D shows plasma progesterone levels (ng / mL) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0019] FIG. 3E shows plasma testosterone levels (ng / mL) at 4 weeks in breast cancer MRMT-1 transplanted rats administered with vehicle, 0.1 mg / kg tamoxifen, 0.3 mg / kg tamoxifen, 1 mg / kg tamoxifen, and 1 mg / kg tamoxifen with 10 mg / kg fezolinetant, compared with rats without any treatment.

[0020] DETAILED DESCRIPTIONProvided herein is a method of treating vasomotor symptoms (VMS) in a breast cancer patient in need thereof comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof, wherein the patient is being treated with an endocrine therapy drug.

[0021] DefinitionsFezolinetant, (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, is disclosed in WO2014 / 154895, the contents of which are incorporated herein by reference, and refers to the compound having the following chemical structure:

[0022] As used herein, “endocrine therapy” refers to treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. Hormones can also cause certain cancers (such as prostate and breast cancer) to grow. To slow or stop the growth of cancer, synthetic hormones or other drugs may be given to block the body’s natural hormones. As used herein, endocrine therapy is also called “hormonal therapy,” “hormone therapy,” and “hormone treatment.” For breast cancer, endocrine therapy slows or stops the growth of hormone-sensitive tumors by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells. There are several classes of endocrine therapy drugs are currently used for treating hormone-sensitive breast cancers (e.g., hormone receptor positive (HR+) breast cancers).

[0023] One type of the commonly used endocrine therapy drugs are those that block estrogen production. These include aromatase inhibitors that are used to block the activity of an enzyme called aromatase, which the body uses to make estrogen in the ovaries and in other tissues. Aromatase inhibitors are used primarily in postmenopausal women. Examples of aromatase inhibitors approved by the FDA are anastrozole (Arimidex) and letrozole (Femara), both of which temporarily inactivate aromatase, and exemestane (Aromasin), which permanently inactivates aromatase.

[0024] Another class of endocrine therapy drugs are those that interfere with estrogen’s ability to stimulate the growth of breast cancer cells. These include, for example, selective estrogen receptor modulators (SERMs) that bind to estrogen receptors, preventing estrogen from binding. Examples of SERMs approved by the FDA for treatment of breast cancer are tamoxifen (Nolvadex) and toremifene (Fareston). Antiestrogen drugs, such as fulvestrant (Faslodex), have also been used to block estrogen’s effects.

[0025] Unless otherwise indicated, the administrations described herein include administering fezolinetant prior to, concurrently with, or after administration of the endocrine therapy drug described herein. Thus, simultaneous administration is not necessary for therapeutic purposes. In one aspect, fezolinetant and a disclosed endocrine therapy drug are administered together. In another aspect, fezolinetant and a disclosed endocrine therapy drug are administered at different times on the same day. In another aspect, fezolinetant and a disclosed endocrine therapy drug are administered at different times as separate tablets or capsules.

[0026] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, or inhibiting the progression of vasomotor symptoms (VMS). As described herein, fezolinetant is used as a drug for treating VMS due to or induced by adjuvant endocrine therapy. In an embodiment, as described herein, fezolinetant is used in reducing adjuvant endocrine therapy induced VMS in a subject in need thereof. Administration of fezolinetant does not interfere with any adjuvant endocrine therapy.

[0027] As used herein, “vasomotor symptoms” or “VMS” refers to hot flashes and night sweats, and are often considered the cardinal symptoms of menopause. VMS are episodes of profuse heat accompanied by sweating and flushing, experienced predominantly around the head, neck, chest, and upper back. The majority of women often experiences VMS during the menopausal transition. Additionally, vasomotor symptoms are a common consequence of systemic therapies for breast cancer. These treatments, including endocrine therapies, ovarian function suppression, and chemotherapy, suppress endogenous estrogen levels through various mechanisms, ultimately leading to imbalances in thermoregulation.

[0028] The term “subject” means an animal, such as a mammal, and such as a human. The terms “subject” and “patient” may be used interchangeably.

[0029] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.001 - 100 mg / kg body weight / day.

[0030] The term “pharmaceutical composition” refers to a composition comprising fezolinetant, or a pharmaceutically acceptable salt thereof, alone or with a pharmaceutically acceptable carrier.

[0031] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is safe for human use. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0032] The term “pharmaceutically acceptable salts” refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts for the compounds described herein include, but are not limited to include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methane sulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.

[0033] As used herein, the term “about” and “approximately” when used in combination with a numeric value or range of values used to characterize a particular chemical form, combination therapy, etc. should be understood to mean that the numeric value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while describing a particular chemical form, combination therapy, etc. In some embodiment, the term “about” and “approximately” when used in combination with a numeric value or range of values mean ±10%, ±5%, ±2% or ±1% of the numeric value or range of values.

[0034] Method of TreatmentIn a first embodiment, provided herein is a method of treating vasomotor symptoms (VMS) in a breast cancer patient in need thereof comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof, wherein the patient is being treated with an endocrine therapy drug.

[0035] In a second embodiment, for the method of the first embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0036] In a third embodiment, for the method of the first or second embodiments, the pharmaceutical composition comprises from about 10 mg to about 180 mg, from about 10 mg to about 100 mg, from about 10 mg to about 50 mg, from about 25 mg to about 50 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 45 mg of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof.

[0037] In a fourth embodiment, for the method of any one of the first through third embodiments, the pharmaceutical composition is formulated for oral administration.

[0038] In a fifth embodiment, for the method of any one of the first through fourth embodiments, the pharmaceutical composition is administered once daily.

[0039] In a sixth embodiment, for the method of any one of the first through fifth embodiments, the VMS is endocrine therapy drug induced VMS.

[0040] In a seventh embodiment, for the method of any one of the first through sixth embodiments, the endocrine therapy drug is used for the treatment of breast cancer.

[0041] In an eighth embodiment, for the method of any one of the first through seventh embodiments, the pharmaceutical composition and the endocrine therapy drug are administered concurrently. In an alternative of the eighth embodiment, the pharmaceutical composition is sequentially administered with the endocrine therapy drug.

[0042] In a ninth embodiment, for the method of any one of the first through eighth embodiments, the endocrine therapy drug is tamoxifen, anastrozole, exemestane, letrozole, or any combination thereof.

[0043] In a tenth embodiment, for the method of any one the first through ninth embodiments, the endocrine therapy drug is tamoxifen. In an alternative of the tenth embodiment, about 20 mg of tamoxifen is administered once daily. In another alternative of the tenth embodiment, about 10 mg to about 30 mg of tamoxifen is administered once daily. In yet another alternative, about 10 mg, about 15 mg, about 25 mg, or about 30 mg of tamoxifen is administered once daily.

[0044] In an eleventh embodiment, for the method of the first through ninth embodiment, the endocrine therapy drug is anastrozole. In an alternative of the eleventh embodiment, about 1 mg of anastrozole is administered once daily. In another alternative of the eleventh embodiment, about 0.1 mg to about 5 mg of anastrozole is administered once daily. In yet another alternative, about 0.1 mg, about 0.5 mg, about 2.5 mg, or about 5 mg of anastrozole is administered once daily.

[0045] In a twelfth embodiment, for the method of any one of the first through ninth embodiments, the endocrine therapy drug is exemestane. In an alternative of the twelfth embodiment, about 25 mg of exemstane is administered once daily. In another alternative of the twelfth embodiment, about 15 mg to about 35 mg of exemstane is administered once daily. In yet another alternative, about 15 mg, about 20 mg, about 30 mg, or about 35 mg of exemstane is administered once daily.

[0046] In a thirteenth embodiment, for the method of any one of the first through ninth embodiments, the endocrine therapy drug is letrozole. In an alternative of the thirteenth embodiment, about 2.5 mg of letrozole is administered once daily. In another alternative of the thirteenth embodiment, about 1.5 mg to about 3.5 mg of letrozole is administered once daily. In yet another alternative, about 1.5 mg, about 2.0 mg, about 3.0 mg, or about 3.5 mg of letrozole is administered once daily.

[0047] In a fourteenth embodiment, for the method of any one of the first to thirteenth embodiments, the patient has hormone receptor positive (HR+) breast cancer. In an alternative of the fourteenth embodiment, the patient has stage 0 to 3 hormone receptor positive (HR+) breast cancer.

[0048] In a fifteenth embodiment, for the method of any one of the first to fourteenth embodiments, the patient is experiencing moderate to severe vasomotor symptom (VMS) prior to the treatment.

[0049] In a sixteenth embodiment, for the method of any one of the first to fifteenth embodiments, the patient is 18 years or older.

[0050] In a seventeenth embodiment, for the method of any one of the first to sixteenth embodiments, the patient is female.

[0051] In an eighteenth embodiment, provided herein is a pharmaceutical composition comprising (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating vasomotor symptoms (VMS) in a breast cancer patient, as described in any one of the first through seventeenth embodiment, wherein the patient is being treated with an endocrine therapy drug.

[0052] In a nineteenth embodiment, provided herein is a pharmaceutical composition comprising (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof, for use for treating vasomotor symptoms (VMS) in a breast cancer patient, as described in any one of the first through seventeenth embodiment, wherein the patient is being treated with an endocrine therapy drug.

[0053] The specific dosage and treatment regimen of fezolinetant, or a pharmaceutically acceptable salt thereof, to be used in combination with a disclosed endocrine therapy drug will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0054] Compositions and AdministrationPharmaceutical compositions and single unit dosage forms comprising fezolinetant and an endocrine therapy drug (e.g., tamoxifen) alone or together in a fixed dose for administration as described above (e.g., as in any one of the first to nineteenth embodiments) is included. Single unit dosage forms of the disclosed methods and compositions are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suit able for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0055] The composition, shape, and type of dosage forms of the will typically vary depending on their use. For example, a dosage form used in the acute treatment of VMS, breast cancer, both, or a related disorder may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0056] In a twentieth embodiment, for the method of any one of the first through nineteenth embodiments, fezolinetant is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally. In some embodiments, fezolinetant in the disclosed methods and compositions is administered orally.

[0057] In a twenty-first embodiment, for the method of any one of the first through twentieth embodiments, fezolinetant is administered orally in the form of a tablet or a capsule.

[0058] In a twenty-second embodiment, for the method of any one of the twenty-first embodiments, the tablet or capsule comprises 45 mg of fezolinetant and the following inactive ingredients: ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

[0059] Example 1Effects of fezolinetant and tamoxifen in rats bearing MRMT-1 rat breast cancer cellsESN364 (Fezolinetant) was prepared by Astellas Pharma Inc. (Tokyo, Japan), and tamoxifen (Lot No. WXBC6404V) was purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). These compounds were suspended in 0.5% methylcellulose (MC) solution.

[0060] MRMT-1 rat breast cancer cell line was purchased from Tohoku University (Miyagi, Japan) and cultured in RPMI-1640 medium supplemented with 5% heat-inactivated fetal bovine serum and 100 U / mL Penicillin-Streptomycin at 37°C in 5% CO2.

[0061] Female Sprague-Dawley rats were purchased from Japan SLC Inc. (Shizuoka, Japan) and housed in a 12 h light / 12 h dark cycle with food and water ad libitum (light on: 7:30).

[0062] MRMT-1 cells were suspended at 1.0 × 107cells / mL in phosphate buffered saline. Cell suspension was subcutaneously inoculated around the right fourth mammary gland of eight week-old rats at a volume of 0.15 mL per animal.

[0063] Tumor diameters, length and width, were measured once a week using a caliper.Tumor volume was calculated as follows:Tumor volume [mm3] = (length of tumor [mm]) × (width of tumor [mm])2× 0.5

[0064] Six days after MRMT-1 cell inoculation, rats were divided into 5 groups based on the average of tumor volume. Each group consisted of 6 rats and received vehicle (0.5% MC, 5 mL / kg), tamoxifen (three doses: 0.1, 0.3, 1 mg / kg), or tamoxifen (1 mg / kg) and ESN364 (10 mg / kg), respectively. As a control group, normal group received vehicle (0.5% MC, 5 mL / kg) without MRMT-1 cell inoculation. Vehicle or drug was orally administered twice a day for 3 weeks.

[0065] Body weight and food intake were measured once a week. At day 19 of repeatedadministration, one small thermo data logger (Thermochron SL, KN Laboratories Inc., Osaka, Japan) was implanted into the abdominal cavity by a surgical procedure under isoflurane anesthesia to measure core temperature and another was attached on the tail skin using surgical tape and aluminum protector. At day 21 of repeated administration, tail skin and core temperatures were measured every 3 min for 24 h. Room temperature was also measured every 3 min for 24 h to calculate heat loss index. In this study, 9:00 - 21:00 and 21:00 - 9:00 were defined as the light phase and the dark phase, respectively, and used for calculating 12 h average of temperature. Heat loss index was calculated as follows: Heat loss index = (tail skin temperature - room temperature) / (core temperature - room temperature)

[0066] After the 1st dosing on day 22, blood samples were collected from the abdominal vena cava in heparinized syringes under isoflurane anesthesia. The rats were sacrificed and the uterine was isolated and weighed. The blood samples were centrifuged, and plasma were separated and stored at -80°C until assay. Concentrations of estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone and testosterone were measured using commercially available ELISA kits (FSH: Cloud-Clone Corp., Houston, TX, USA; others: Endocrine Technologies, Inc., Newark, CA, USA) with the plate reader (SPECTRAmax 190, Molecular Device, San Jose, CA, USA).

[0067] The experimental results are expressed as the mean ± SEM. One animal which detached thermo data logger in tamoxifen / ESN364 group was excluded from the analysis on core and skin temperature and heat loss index. Differences between normal and vehicle groups, between vehicle and tamoxifen / ESN364-treated groups and between tamoxifen-treated and tamoxifen / ESN364-treated groups were assessed using Student’s t-test, and those among vehicle and tamoxifen-treated groups were assessed using Dunnett’s multiple comparison test. Statistical analysis was performed using GraphPad Prism software (Version 8.0.2; GraphPad Software, Inc., San Diego, CA, USA). A value of P<0.05 was considered statistically significant.

[0068] Tamoxifen at 0.3 and 1 mg / kg significantly suppressed tumor growth in rats bearing MRMT-1 cells. ESN364 (10 mg / kg) administered concomitantly with tamoxifen (1 mg / kg) had no effect on the anticancer effect of tamoxifen (Fig. 2A and Fig. 2B). Tamoxifen also significantly decreased body weight gain at 1 mg / kg, food intake and uterine weight at 0.3 and 1 mg / kg. Co-administration of ESN364 at 10 mg / kg did not affect those effects of tamoxifen at 1 mg / kg (Fig. 2C, Fig. 2D, and Fig. 2E).

[0069] Tamoxifen significantly increased plasma estradiol level at 1 mg / kg, LH and FSH levels at 0.3 and 1 mg / kg and did not affect plasma progesterone and testosterone levels in rat bearing MRMT-1 cells. Co-administration of ESN364 at 10 mg / kg attenuated the increases in plasma estradiol and LH levels but had no effect on other hormones (Fig. 3A, Fig. 3B, Fig. 3C, Fig. 3D, and Fig. 3E).

[0070] Tamoxifen did not affect core temperature at 0.1-1 mg / kg (Fig. 1A), however significantly increased tail skin temperature at 0.3 and 1 mg / kg in rats bearing MRMT-1 cells (Fig. 1C), which resulting in increasing heat loss index suggesting hot flash-like symptoms (Fig. 1B). Co-administration of ESN364 at 10 mg / kg attenuated these increases in tail skin temperature and heat loss index (Fig. 1B and Fig. 1C).

[0071] These results demonstrate that ESN364 prevent tamoxifen-induced hot flash-like symptoms without interfering the anticancer effect of tamoxifen.

[0072] Example 2Placebo-controlled, double-blind study to assess the efficacy and safety of fezolinetant for treating vasomotor symptoms in patients undergoing treatment for breast cancerThe safety and efficacy of treating moderate to severe vasomotor symptoms in females with stage 0 to 3 HR+ breast cancer who are receiving adjuvant endocrine therapy can be determined by conducting a randomized, 52-week, placebo-controlled, double-blind study. Participants must have a minimum average of 7 moderate to severe Hot flashes (VMS) per day for the last 10 days prior to randomization (with a minimum of 7 days of data). Participants are to record hot flashes using an electronic diary for the entirety of the screening period.

[0073] Participants must be receiving stable maintenance adjuvant endocrine therapy (tamoxifen 20 mg or daily aromatase inhibitors) with or without GnRH agonists / antagonists for a minimum of 4 months, be planning to continue on the same adjuvant endocrine therapy (type, dose and brand) for the duration of the trial and not receiving chemotherapy.

[0074] The study will consist of a screening period (days -28 to -1, including the screening visit assessments), a 52-week treatment period (day 1 to week 52) and a follow-up visit (week 55) 3 weeks after the end of treatment visit. The anticipated duration of the study for each participant, including screening and follow-up, is approximately 59 weeks.

[0075] Administration can be provided according to Table 1 below: *AxMP is Auxiliary Medicinal Product.**IMP is Investigational Medicinal Product.***NIMP is New Investigational Medicinal Product

Claims

1.A method of treating vasomotor symptoms (VMS) in a breast cancer patient in need thereof comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof, wherein the patient is being treated with an endocrine therapy drug.2.The method of Claim 1, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.3.The method of any one of Claims 1 to 2, wherein the pharmaceutical composition comprises from about 10 mg to about 180 mg, from about 10 mg to about 100 mg, from about 10 mg to about 50 mg, from about 25 mg to about 50 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof.4.The method of any one of Claims 1 to 3, wherein the pharmaceutical composition comprises about 45 mg of (4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]methanone, or a pharmaceutically acceptable salt thereof.5.The method of any one of Claims 1 to 4, wherein the pharmaceutical composition is formulated for oral administration.6.The method of any one of Claims 1 to 5, wherein the pharmaceutical composition is administered once daily.7.The method of any one of Claims 1 to 6, wherein the VMS is endocrine therapy drug induced VMS.8.The method of Claim 7, wherein the endocrine therapy drug is used for the treatment of breast cancer.9.The method of any one of Claims 1 to 8, wherein the pharmaceutical composition and the endocrine therapy drug are administered concurrently.10.The method of any one of Claims 1 to 9, wherein the pharmaceutical composition is sequentially administered with the endocrine therapy drug.11.The method of any one of Claims 1 to 10, wherein the endocrine therapy drug is tamoxifen, anastrozole, exemestane, letrozole, or any combination thereof.12.The method of Claim 11, wherein the endocrine therapy drug is tamoxifen.13.The method of Claim 11, wherein about 20 mg of tamoxifen is administrated once daily.14.The method of claim 11, wherein the endocrine therapy drug is anastrozole.15.The method of claim 14, wherein about 1 mg of anastrozole is administered once daily.16.The method of claim 11, wherein the endocrine therapy drug is exemestane.17.The method of claim 16, wherein 25 mg of exemestane is administered once daily.18.The method of claim 11, wherein the endocrine therapy drug is letrozole.19.The method of claim 18, wherein 2.5 mg of letrozole is administered once daily.20.The method of any one of claims 1 to 19, wherein the patient has hormone receptor positive (HR+) breast cancer.21.The method of any one of claims 1 to 20, wherein the patient has stage 0 to 3 hormone receptor positive (HR+) breast cancer.22.The method of any one of claims 1 to 21, wherein the patient is experiencing moderate to severe vasomotor symptom (VMS) prior to the treatment.23.The method of any one of claims 1 to 22, wherein the patient is 18 years or older.24.The method of any one of claims 1 to 23, wherein the patient is female.

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