Fezolinetant for use in methods for treating vasomotor symptoms in prostate cancer patients

Abstract

Provided herein is method of treating vasomotor symptoms (VMS) in a prostate cancer patient being treated with an androgen deprivation therapy or androgen receptor inhibitor drug comprising administering fezolinetant.

Description

FEZOLINETANT FOR USE IN METHODS FOR TREATING VASOMOTOR SYMPTOMS IN PROSTATE CANCER PATIENTS

[0001] CROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of U.S. Provisional Patent Application No. 63 / 730,206, filed December 10, 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 WO 2014 / 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] Prostate cancer is one of the most common cancers affecting older men, and a significant cause of death for elderly men worldwide. This cancer is often characterized by uncontrolled growth of cells in the prostate, a gland in the male reproductive system. As of 2024, 1.2 million men are diagnosed with prostate cancer per year, with 350,000 dying. Treatments for prostate cancer include surgery, radiation treatment, and hormone therapy.

[0005] An example of hormone therapy is androgen deprivation therapy (ADT), which is used to reduce testosterone levels in men. Testosterone is an androgen, a male hormone that is important for a healthy prostate, but it can also facilitate the growth of prostate cancer calls. ADT deprives the cancer cells of this hormone (and thus, growth) by blocking the production or action of androgen hormones.

[0006] Another example of hormone therapy is androgen receptor inhibitors (ARI), which prevent androgens, or male sex hormones, from binding to androgen receptors in prostate cells. This prevents the hormones from having an effect in the body, and can prevent further proliferation of prostate cancer cell growth.

[0007] However, one of the most commonly experienced adverse events associated with ADT are vasomotor symptoms (i.e., hot flashes and / or night sweats). Prevalence has been reported as high as 58-80% in patients receiving ADT with 15-27% reporting the hot flashes as the most significant adverse quality of life effects of ADT. As such, vasomotor symptoms associated with ADT may impact adherence and persistence with ADT.

[0008] Currently, there are very limited treatment options available for treating VMS associated with ADT in prostate cancer patients, which leaves a clear unmet medical need for an effective and adequate treatment of VMS (e.g., hot flashes) in prostate cancer patients, especially for patients on ADT.

[0009] Previously, it had been found that administration 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 (i.e., fezolinetant) to women suffering from vasomotor symptoms due to menopause (see, for example, WO2014 / 154895) , improves VMS symptoms. However, it has not been previously shown that fezolinetant works in male subjects for improving VMS-like symptoms. As demonstrated herein, administration of fezolinetant to male rats and male cynomolgus monkeys provides similar reductions in circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as their female counterparts.

[0010] Without being bound by mechanism, as KNDy (kisspeptin, neurokinin B, and dynorphin) neurons are involved in both hormone changes and VMS, the reduction in circulating LH and FSH indicate that fezolinetant would be effective in treating VMS. Accordingly, provided herein is a method of treating vasomotor symptoms (VMS) in a prostate 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 androgen deprivation therapy and / or androgen receptor inhibitor drug.

[0011] FIG. 1 shows the percent reduction of luteinizing hormone (LH) in castrated Sprague-Dawley male rats treated with a single oral dose of 0.8, 3, 10, and 20 mg / kg fezolinetant. LH level was measured at 45 minutes post dosing for rats treated with 0.8 and 3 mg / kg of fezolinetant, at 90 minutes post dosing from rat treated with 10 mg / kg of fezolinetant, and 150 minutes post dosing for rat treated with 20 mg / kg of fezolinetant.

[0012] FIG. 2 shows the reduction of LH (ng / mL) in castrated male cynomolgus monkeys treated with a single oral dose of 5 mg / kg fezolinetant as compared to a vehicle control and elagolix (GnRH antagonist) as a positive control.

[0013] FIG. 3 shows the effect of fezolinetant on plasma LH levels (ng / mL) in castrated male cynomolgus monkeys treated with 5 mg / kg fezolinetant by once daily oral administration for 5 days.

[0014] FIG. 4 shows the effect of fezolinetant on LH level (ng / L) in gonad-intact cynomolgus monkeys treated with 0, 10, 25, or 50 mg / kg of fezolinetant once daily for 35 days.Description of Embodiment

[0015] Detailed DescriptionProvided herein is a method of treating vasomotor symptoms (VMS) in a prostate cancer patient in need thereof comprising the step of administering to the subject an effective amount 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 (fezolinetant), or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutical composition comprising fezolinetant or a pharmaceutically acceptable salt thereof), wherein the patient is being treated with an androgen deprivation therapy and / or androgen receptor inhibitor drug.

[0016] 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:

[0017] As used herein, “androgen deprivation therapy,” “hormonal therapy,” “hormone therapy,” or “hormone treatment” can be used interchangeably and refers to treatment that reduces the level of androgens or blocks the action of androgens in the body of a patient. Hormone therapies, which are treatments that decrease androgen levels or block androgen action, can inhibit the growth of prostate cancers, which are therefore called castration sensitive, androgen dependent, or androgen sensitive. Several types of hormone therapies or ADT can be used in the treatment of prostate cancers. One class of ADT drugs called anti-androgens are used to block the activity of androgen receptors on prostate cancer cells, preventing androgen from acting on them. Examples of anti-androgens approved by the FDA include flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, darolutamide, and ketoconazole. Other types of ADT include, but are not limited to, orchiectomy (surgical castration), LHRH agonists and LHRH antagonists. Luteinizing hormone-releasing hormone (LHRH) agonists lowers the amount of testosterone made by the testicles by stopping the pituitary gland from making luteinizing hormone, which helps produce testosterone. Examples of LHRH agonists include, but are not limited to, goserelin, triptorelin, leuprolide mesylate, and leuprolide. LHRH antagonists are substances that antagonize LHRH receptor and thus the action of LHRH. Examples of LHRH antagonists include, but are not limited to degarelix and relugolix.

[0018] In addition to ADT, androgen receptor inhibitor (ARI) therapy / drug can also be used for treating prostate cancer. ARI is considered a more targeted treatment by directly blocking the androgen receptor. In some instances, such as advanced prostate cancer, adding ARI to ADT often leads to significantly improved overall survival compared to ADT alone. In some embodiments, ARI includes, but is not limited to, enzalutamide, apalutamide, bicalutamide, darolutamide, and abiraterone.

[0019] Unless otherwise indicated, the administrations described herein include administering fezolinetant prior to, concurrently with, or after administration of the androgen deprivation therapy and / or androgen receptor inhibitor drug described herein. Thus, simultaneous administration is not necessary for therapeutic purposes. In one aspect, fezolinetant and a disclosed androgen deprivation therapy and / or androgen receptor inhibitor drug are administered together. In another aspect, fezolinetant and a disclosed androgen deprivation therapy and / or androgen receptor inhibitor drug are administered at different times on the same day. In another aspect, fezolinetant and a disclosed androgen deprivation therapy and / or androgen receptor inhibitor drug are administered at different times as separate tablets or capsules. In another aspect, fezolinetant and an androgen deprivation therapy and / or androgen receptor inhibitor drug are administered in a fixed dose combination in the same tablet or capsule.

[0020] 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 supportive drug to androgen deprivation and / or androgen receptor inhibition therapy for prostate cancer by treating VMS, an adverse effect associated wth the ADT and / or ARI therapy. Administration of fezolinentant does not substantially interfere with any androgen deprivation and / or androgen receptor inhibition therapy.

[0021] 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. VMS are often experienced by the majority of women during the menopausal transition.

[0022] The term “subject” means an animal, such as a mammal, and such as a human. The terms “subject” and “patient” may be used interchangeably.

[0023] 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.

[0024] The term “pharmaceutical composition” refers to a composition comprising fezolinetant, or a pharmaceutically acceptable salt thereof, alone or with a pharmaceutically acceptable carrier.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] Method of TreatmentIn a first embodiment, provided herein is a method of treating vasomotor symptoms (VMS) in a prostate cancer patient in need thereof comprising the step of administering to the subject an effective amount 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 (fezolinetant), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising fezolinetant or a pharmaceutically acceptable thereof, wherein the patient is being treated with an androgen deprivation therapy and / or androgen receptor inhibitor drug.

[0029] In a second embodiment, for the method of the first embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0030] 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. In some embodiments, the pharmaceutical composition comprises about 60 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 method described herein comprises administering to the subject of 45 mg or 60 mg of fezolinetant.

[0031] In a fourth embodiment, for the method of any one of the first through third embodiments, the pharmaceutical composition is formulated for oral administration.

[0032] In a fifth embodiment, for the method of any one of the first through fourth embodiments, the pharmaceutical composition is administered once daily.

[0033] In a sixth embodiment, for the method of any one of the first through fifth embodiments, the VMS is androgen deprivation therapy and / or androgen receptor inhibitor drug induced VMS.

[0034] In a seventh embodiment, for the method of any one of the first through sixth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is used for the treatment of prostate cancer.

[0035] In an eighth embodiment, for the method of any one of the first through seventh embodiments, the pharmaceutical composition of fezolinetant and the androgen deprivation therapy and / or androgen receptor inhibitor drug are administered concurrently. In an alternative of the eighth embodiment, the pharmaceutical composition is sequentially administered with the androgen deprivation therapy and / or androgen receptor inhibitor drug.

[0036] In a ninth embodiment, for the method of any one of the first through eighth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, darolutamide, or any combination thereof.

[0037] In a tenth embodiment, for the method of any one of the first through ninth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is bicalutamide. In an alternative of the tenth embodiment, about 50 mg of bicalutamide is administered once daily. In another alternative of the tenth embodiment, about 40 mg to about 60 mg of bicalutamide is administered once daily. In yet another alternative, about 40 mg, about 45 mg, about 55 mg, or about 60 mg of bicalutamide is administered once daily.

[0038] In an eleventh embodiment, for the method of any one of the first through ninth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is flutamide. In an alternative of the twenty-sixth embodiment, about 250 mg of flutamide is administered three times daily. In another alternative of the eleventh embodiment, about 200 mg to about 300 mg of flutamide is administered thrice daily. In yet another alternative, about 200 mg, about 225 mg, about 275 mg, or about 300 mg of flutamide is administered thrice daily.

[0039] In a twelfth embodiment, for the method of any one of the first through ninth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is nilutamide. In an alternative of the twenty-seventh embodiment, about 300 mg of nilutamide is administered once daily. In another alternative of the twelfth embodiment, about 250 mg to about 350 mg of nilutamide is administered once daily. In yet another alternative, about 250 mg, about 275 mg, about 325 mg, or about 350 mg of nilutamide is administered once daily.

[0040] In a thirteenth embodiment, for the method of any one of the first through ninth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is enzalutamide. In an alternative of the twenty-eighth embodiment, about 160 mg of enzalutamide is administered once daily. In another alternative of the thirteenth embodiment, about 140 mg to about 180 mg of enzalutamide is administered once daily. In yet another alternative, about 140 mg, about 150 mg, about 170 mg, or about 180 mg of enzalutamide is administered once daily.

[0041] In a fourteenth embodiment, for the method of any one of the first through ninth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is apalutamide. In an alternative of the fourteenth embodiment, about 240 mg of apalutamide is administered once daily. In another alternative of the fourteenth embodiment, about 200 mg to about 280 mg of apalutamide is administered once daily. In yet another alternative, about 200 mg, about 220 mg, about 260 mg, or about 280 mg of apalutamide is administered once daily.

[0042] In a fifteenth embodiment, for the method of any one of the first through ninth embodiments, the androgen deprivation therapy and / or androgen receptor inhibitor drug is darolutamide. In an alternative of the fifteenth embodiment, about 600 mg of darolutamide is administered twice daily. In another alternative of the fifteenth embodiment, about 500 mg to about 700 mg of darolutamide is administered twice daily. In yet another alternative, about 500 mg, about 550 mg, about 650 mg, or about 700 mg of darolutamide is administered twice daily.

[0043] In a sixteenth embodiment, for the method of any one of the first to fifteenth embodiments, the patient has prostate cancer. In an alternative of the sixteenth embodiment, the patient has metastatic prostate cancer.

[0044] In a seventeenth embodiment, for the method of any one of the first to sixteenth embodiments, the patient is experiencing moderate to severe vasomotor symptom (VMS) prior to the treatment.

[0045] In an eighteenth embodiment, for the method of any one of the first to seventeenth embodiments, the patient is 18 years or older.

[0046] 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 preparing a medicament for treating vasomotor symptoms (VMS) in a prostate cancer patient, as described in any one of the first through eighteenth embodiment, wherein the patient is being treated with an androgen deprivation therapy and / or androgen receptor inhibitor drug.

[0047] In a twentieth 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 prostate cancer patient, as described in any one of the first through nineteenth embodiment, wherein the patient is being treated with an androgen deprivation therapy and / or androgen receptor inhibitor drug.

[0048] The specific dosage and treatment regimen of fezolinetant, or a pharmaceutically acceptable salt thereof, to be used in combination with a disclosed androgen deprivation therapy and / or androgen receptor inhibitor 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.

[0049] Compositions and AdministrationPharmaceutical compositions and single unit dosage forms comprising fezolinetant alone or in combination with an androgen deprivation therapy and / or an androgen receptor inhibitor drug together in a fixed dose for administration as described above (e.g., as in any one of the first to twentieth 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.

[0050] 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, prostate 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 ordisorder. 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).

[0051] In a twenty-first embodiment, for the combination therapy or the method of any one of the first through twentieth 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.

[0052] In a twenty-second embodiment, for the combination therapy or the method of any one of the first through twenty-first embodiments, fezolinetant is administered orally in the form of a tablet or a capsule.

[0053] In a twenty-third embodiment, for the combination therapy or the method of any one of the first through twenty-second 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.

[0054] In a twenty-third embodiment, for the combination therapy or the method of any one of the first through twenty-second embodiments, the tablet or capsule comprises 60 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.Examples

[0055] Example 1. Pharmacokenetic study of fezolinetant in male adults as compared to female adults.In order to test if fezolinetant had different pharmacokinetic properties in males versus females, fezolinetant was administered in a single ascending dose (3, 6, 12, 23, 46, 90, and 180 mg) and multiple ascending doses (20, 60, and 180 mg). The results are shown in Table 1 below.

[0056] As can be seen, fezolinetant exposures after single dosing or at steady-state were in general lower in men compared to women. The gender effect seems to differ slightly in all dose groups (point estimates ranged between 42% to 84% for Cmaxand AUClast). The gender effect seems to differ slightly in all dose groups (point estimates ranged between 42% to 84% for Cmaxand AUClast).

[0057] The gender effect seems to differ slightly in all dose groups (point estimates ranged between 42% to 84% for Cmaxand AUClast). No significant gender effect on Cmaxof the pooled data however, after pairwise comparison, a significant gender effect was observed on Cmaxafter 900 mg fezolinetant treatment, with Cmaxapproximately 35% lower for men. No significant gender effect on Cmaxof the pooled data however, after pairwise comparison, a significant gender effect was observed on Cmaxafter 900 mg fezolinetant treatment, with Cmaxapproximately 35% lower for men. No gender effect was observed on Tmax.

[0058] Example 2. Effect of fezolinetant on circulating LH levels in castrate male ratsSix groups of non-fasted castrate rats (male, Sprague-Dawley; n = 6 rats / group) were dosed via a single oral administration at 0.8, 3, 10, 20 mg / kg (Dose volume 5 ml / kg). This experiment was conducted in two parts therefore two control groups were dosed with the vehicle at the same dose volume for each experimental day.

[0059] Fezolinetant was prepared in a dose formulation of pyrogen-free water containing 0.5% methylcellulose LH hormone levels were determined by radioimmunoassay (RIA) for all groups at plasma collection timepoints of 5 minutes before administration (basal time) and 45, 90, 150, 300 and 420 minutes after dosing.

[0060] Blood samples were collected from the lateral tail vein at pre-determined intervals using EDTA-3K (Ethylenediamine-N,N,N',N'-tetraacetic acid, tripotassium salt) as anti-coagulant. Samples were chilled and rapidly processed by centrifugation to obtain corresponding plasma samples. Plasma samples were frozen (at -20°C) until analysis.

[0061] Results: A significant decrease in LH circulating level was observed at all timepoints after fezolinetant oral administration at 10 and 20 mg / kg in comparison to vehicle controls. A significant decrease in plasma LH was observed only at the 45 minute timepoint post-dosing of 3 mg / kg fezolinetant. No significant effect of fezolinetant on plasma LH was observed at 0.8 mg / kg.

[0062] As shown in FIG. 1, fezolinetant significantly reduced plasma LH levels in castrate male rats over the dose range of 3 to 20 mg / kg.

[0063] Example 3. Effect of fezolinetant on LH and FSH levels in castrate and intact male monkeys

[0064] Effect of fezolinetant on LH circulating levels:

[0065] Monkeys (castrate male, Cynomolgus, 3- 4 y; n = 4 / compound) were dosed via a single oral administration at a dose of 5 mg / kg (dose volume = 5 ml / kg). fezolinetant was prepared in a dose formulation of 9% (w / v) 2-hydroxypropyl-β-cyclodextrin in sterile water. LH hormone levels were determined by RIA (radioimmunoassay). Elagolix (Gonadotropin-releasing hormone antagonist) was used as a positive control.

[0066] Blood samples were collected via venipuncture of peripheral vessels at pre-determined intervals using EDTA-2K as anti-coagulant. Samples were chilled and rapidly processed by centrifugation to obtain corresponding plasma samples. Plasma samples were frozen (at -80°C) until analysis.

[0067] Results: A significant decrease in LH circulating level was observed from 90 to 480 minutes following the oral administration of fezolinetant at 5 mg / kg in castrate monkeys. Elagolix (positive control, 20 mg / kg) induced a similar decrease of plasma LH in castrate monkeys. Significance determined by one-way ANOVA followed by Dunnett’s Multiple Comparison Test; the fezolinetant and Elagolix treatment groups were significantly different from vehicle (p<0.05).

[0068] As shown in FIG. 2, fezolinetant significantly reduced circulating LH levels in castrated male cynomolgus monkeys following single oral administration at 5 mg / kg.

[0069] Effect of fezolinetant on LH plasma levels:

[0070] Monkeys (castrate male, Cynomolgus, 3- 4 y; n = 4 / compound) were dosed once daily by oral administration at a dose of 5 mg / kg (dose volume = 5 ml / kg). fezolinetant was prepared in a dose formulation of 9% (w / v) 2-hydroxypropyl-β-cyclodextrin in sterile water. LH and FSH levels were determined by RIA from exactly the same plasma samples collected from individual monkeys.

[0071] Blood samples were collected via venipuncture of peripheral vessels at pre-determined intervals using EDTA-2K as anti-coagulant. Samples were chilled and rapidly processed by centrifugation to obtain corresponding plasma samples. Plasma samples were frozen (at -80°C) until analysis.

[0072] Results: As shown in FIG. 3, a decrease in LH plasma levels was observed from 60 to 300 minutes following the oral administration of fezolinetant with a similar profile recorded after both the initial dose and five days of consecutive dosing. These data indicate that there are no compensatory mechanisms with repeated treatment that diminish the response to fezolinetant on plasma LH.

[0073] A decrease in FSH plasma levels was observed from 60 to 300 minutes after the initial dosing (Day 1). After five days of consecutive dosing, the baseline level of FSH was ~25% lower compared to Day 1. Administration of fezolinetant on Day 5 did not have any significant effect on FSH levels.

[0074] Effect of different dosing of fezolinetant on LH levels:

[0075] Fezolinetant, as a suspension in 0.5% Methylcellulose, was administered orally by daily gavage to three groups of cynomolgus monkeys at doses of 10, 25, and 50 mg / kg (Groups 2 through 4). Another group of Cynomolgus monkeys received vehicle-only at an equivalent, oral dose volume of 5 mL / kg and served as controls (Group 1).

[0076] Hormone analysis (luteinizing hormone and follicle stimulating hormone) were performed.

[0077] Blood samples were collected three times during the predose phase, in Weeks 1, 2, 3, 4, and 5 of the dosing phase, on Day 3 and the end of the recovery phase. About 2 .5 mL blood for approximately 1 mL serum were collected from the vena cephalica antebrachii at the same time in the morning, and kept deep-frozen at -20°C ± 4°C for hormone analysis.

[0078] Results: In male monkeys, hormone analysis showed a remarkable individual variation in LH level across intervals and treatment groups including controls to the extent that no clear treatment-related changes could be determined (see, FIG. 4). However, a small trend towards decreased levels of mean LH in males of the 25 and 50 mg / kg / day dosing groups (Groups 3 and 4) in Weeks 1 and 2 of the dosing phase was observed, whereas no test item-related effects were seen on male FSH levels.

[0079] Example 4. A randomized, placebo-controlled, double-blind Phase 2b study to assess the efficacy and safety of fezolinetant for treating vasomotor symptoms in patients undergoing treatment for prostate cancerA randomized, 12-week, placebo-controlled, double-blind study will be conducted to assess the safety and efficacy of fezolinetant for treating moderate to severe vasomotor symptoms in males at least 18 years of age who are receiving androgen deprivation therapy for prostate cancer. 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).

[0080] Participants must be receiving stable maintenance androgen deprivation therapy for a minimum of 28-days, be planning to continue on the same androgen deprivation therapy (type, dose and brand) for the duration of the trial.

[0081] The study will consist of a screening period (days -28 to -1, including the screening visit assessments), a 12-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 18 weeks.

[0082] Participants will be randomized in a 1:1:1 ratio of fezolinetant 45 mg qd or 60 mg qd versus matching placebo according to Table 2 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 prostate 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 androgen deprivation therapy or androgen receptor inhibitor 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 comprises about 60 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.6.The method of any one of Claims 1 to 5, wherein the pharmaceutical composition is formulated for oral administration.7.The method of any one of Claims 1 to 6, wherein the pharmaceutical composition is administered once daily.8.The method of any one of Claims 1 to 7, wherein the VMS is androgen deprivation therapy and / or androgen receptor inhibitor drug induced VMS.9.The method of Claim 8, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is used for the treatment of prostate cancer.10.The method of any one of Claims 1 to 9, wherein the pharmaceutical composition and the androgen deprivation therapy drug are administered concurrently.11.The method of any one of Claims 1 to 9, wherein the pharmaceutical composition is sequentially administered with the androgen deprivation therapy and / or androgen receptor inhibitor drug.12.The method of any one of Claims 1 to 11, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is bicalutamide, flutamide, nilutamide, enzalutamide, apalutamide, darolutamide, or any combination thereof.13.The method of Claim 12, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is bicalutamide.14.The method of Claim 13, wherein about 50 mg of bicalutamide is administrated once daily.15.The method of claim 12, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is flutamide.16.The method of claim 15, wherein about 250 mg of flutamide is administered three times daily.17.The method of claim 12, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is nilutamide.18.The method of claim 17, wherein 300 mg of nilutamide is administered once daily.19.The method of claim 12, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is enzalutamide.20.The method of claim 19, wherein 160 mg of enzalutamide is administered once daily.21.The method of claim 12, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is apalutamide.22.The method of claim 21, wherein 240 mg of apalutamide is administered once daily.23.The method of claim 12, wherein the androgen deprivation therapy and / or androgen receptor inhibitor drug is darolutamide.24.The method of claim 23, wherein 600 mg of darolutamide is administered twice daily.25.The method of any one of claims 1 to 24, wherein the patient has prostate cancer.26.The method of any one of claims 1 to 24, wherein the patient has metastatic prostate cancer.27.The method of any one of claims 1 to 26, wherein the patient is experiencing moderate to severe vasomotor symptom (VMS) prior to the treatment.28.The method of any one of claims 1 to 27, wherein the patient is 18 years or older.

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