Treatment of sexual desire disorders in patients treated with GLP-1 agonists and related agents

Abstract

The present disclosure provides methods of treating and / or preventing sexual desire disorders associated with treatment of patients with GLP-1 agonists and / or related compounds. In particular, the methods involve administration of flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The disclosure also provides related pharmaceutical compositions and kits containing one or more compositions including flibanserin and one or more GLP-1 agonists and / or related compounds.

Description

[0001] AtyDktNo. S107088 1170WO (00257)

[0002] TREATMENT OF SEXUAL DESIRE DISORDERS IN PATIENTS TREATED WITH GLP-1 AGONISTS AND RELATED AGENTS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Patent Application No. 63,741,789, filed January 3, 2025, the disclosures of which is incorporated herein by reference in its entirety.

[0005] FIELD OF THE DISCLOSURE

[0006] The present disclosure relates to methods of treating and / or preventing sexual desire disorders, particularly those associated with GLP-1 agonist (or related compound) treatment.

[0007] BACKGROUND

[0008] In today’s culture, being overweight or obese is contrary to the idealized image of beauty. Weightbased discrimination has been documented across multiple settings, with women and men increasingly reporting discriminatory experiences due to weight / height. As a result, individuals often turn to unproven dietary supplements and medications, or FDA-approved weight loss medications to attain a desired body image. One class of FDA-approved medications, the glucagon-like peptide-1 (GLP-1) agonists, has garnered extraordinary attention recently for its role in treating type II diabetes and inducing weight loss. While prevailing assumptions suggest that improved body image and erectile function, even in diabetics associated with GLP-1 agonism would correlate with heightened sexual desire and function, there is limited literature on the effects of GLP-1 agonists (and related compounds) on hedonistic pleasures such as sex in either men or women.

[0009] Surprisingly, it has been found that GLP-1 agonists (rather than fostering an increase in sexual interest due to improvement in body image and multiple other mechanisms) may characteristically lead to a decrease in sexual desire, with other confounding influences camouflaging that decrease. It would be useful to better understand this effect of GLP-1 agonists and related compounds and provide methods for prevention and / or treatment of sexual desire disorders associated with GLP-1 agonist (and related compound) use in patients.

[0010] BRIEF SUMMARY

[0011] The disclosure provides methods for preventing and / or treating sexual desire disorders associated with use of glucagon-like peptide-1 (GLP-1) agonists and related compounds in atients, e.g., human patients. In particular, the methods involve prescribing or administering flibanserin to tire patients. The disclosure further provides related pharmaceutical compositions and kits comprising such pharmaceutical compositions for preventing and / or treating sexual desire disorders associated with GLP-1 agonist and related compound use.

[0012] The disclosure includes, without limitation, the following embodiments:

[0013] WBD (US)4920-2595-2133, v. 2 -1-AtyDktNo. S107088 1170WO (00257)

[0014] Embodiment 1 : A method of treating or preventing onset of a sexual desire disorder, comprising prescribing or administering an effective amount of flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

[0015] Embodiment 2: A method of enhancing weight loss effects associated with GLP-1 agonists and related compounds, comprising prescribing or administering an effective amount of flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

[0016] Embodiment 3 : Flibanserin for use in a method of treating or preventing onset of a sexual desire disorder in a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound, the method comprising prescribing or administering an effective amount of flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

[0017] Embodiment 4: Flibanserin for use in a method of enhancing weight loss effects associated with GLP-1 agonists and related compounds, the method comprising prescribing or administering an effective amount of flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

[0018] Embodiment 5 : The method or flibanserin of any of Embodiments 1 -4, wherein the administering is concurrent with the patient beginning treatment with a GLP-1 agonist or related compound.

[0019] Embodiment 6: The method or flibanserin of any of Embodiments 1-4, wherein the administering is prior to the patient beginning treatment with a GLP-1 agonist or related compound.

[0020] Embodiment 7: The method or flibanserin of any of Embodiments 1-6, wherein the GLP-1 agonist or related compound is selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

[0021] Embodiment 8: The method or flibanserin of any of Embodiments 1-7, wherein the flibanserin and the GLP-1 agonist or related compound are administered on substantially the same treatment schedule (e.g., once daily, twice daily, once weekly, etc.).

[0022] Embodiment 9: The method or flibanserin of any of Embodiments 1-7, wherein the flibanserin and the GLP-1 agonist or related compound are administered on different treatment schedules.

[0023] Embodiment 10: The method or flibanserin of any of Embodiments 1-8, wherein the flibanserin and the GLP-1 agonist or related compound are administered as a single pharmaceutical composition comprising the flibanserin and the GLP-1 agonist or related compound in combination with one or more pharmaceutically acceptable excipients.

[0024] Embodiment 11 : The method or flibanserin of any of Embodiments 1-9, wherein the flibanserin is administered as a pharmaceutical composition comprising the flibanserin (e.g., as the sole active ingredient) in combination with one or more pharmaceutically acceptable excipients.

[0025] WBD (US)4920-2595-2133, v. 2 -2-AtyDktNo. S107088 1170WO (00257)

[0026] Embodiment 12: The method or flibanserin of any of Embodiments 1-11, wherein the flibanserin is administered once daily (e.g., in the evening / at night, including at or around bedtime).

[0027] Embodiment 13: The method or flibanserin of any of Embodiments 1-12, wherein the flibanserin is administered at a dosage of about 0.1 mg io about 400 mg per day.

[0028] Embodiment 14: The method or flibanserin of any of Embodiments 1-13, wherein the administering is oral administering.

[0029] Embodiment 15: The method or flibanserin of any of Embodiments 1-13, wherein the administering is parenteral administering.

[0030] Embodiment 16: The method or flibanserin of any of Embodiment 1-13, wherein the administering is subcutaneous administering.

[0031] Embodiment 17: Flibanserin for use in treating or preventing onset of a sexual desire disorder in a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

[0032] Embodiment 18: Flibanserin for use in enhancing weight loss effects associated with GLP-1 agonists and related compounds.

[0033] Embodiment 19: Flibanserin according to Embodiment 17 or 18, wherein the GLP-1 agonist or related compound is selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

[0034] Embodiment 20: Flibanserin according to any of Embodiments 17-19, in the form of a pharmaceutical composition for oral, parenteral, or subcutaneous administration.

[0035] Embodiment 21 : Use of flibanserin in the manufacture of a medicament for treating or preventing onset of a sexual desire disorder in a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

[0036] Embodiment 22: Use of flibanserin in the manufacture of a medicament for enhancing weight loss effects associated with GLP-1 agonists and related compounds.

[0037] Embodiment 23 : The use of Embodiment 21 or 22, wherein the GLP- 1 agonist or related compound is selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

[0038] Embodiment 24: The use of any of Embodiments 21-23, wherein the medicament is in the form of a pharmaceutical composition for oral, parenteral, or subcutaneous administration.

[0039] Embodiment 25: A pharmaceutical composition comprising flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof and one or more GLP-1 agonists and / or related compounds in combination with one or more pharmaceutically acceptable excipients.

[0040] Embodiment 26: The pharmaceutical composition of Embodiment 25, wherein the one or more GLP-1 agonists and / or related compounds are selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

[0041] WBD (US)4920-2595-2133, v. 2 -3-AtyDktNo. S107088 1170WO (00257)

[0042] Embodiment 27 : The pharmaceutical composition of Embodiment 25 or 26, wherein the flibanserin or pharmaceutically acceptable salt, solvate, or hydrate thereof and the one or more GLP-1 agonists and / or related compounds are each independently in the form of a pharmaceutical composition for oral, parenteral, or subcutaneous administration.

[0043] Embodiment 28: A kit labeled for prevention and / or treatment of sexual desire disorders associated with use of GLP-1 agonists and / or related compounds, the kit comprising flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof and one or more GLP-1 agonists and / or related compounds.

[0044] Embodiment 29: A kit comprising flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof and one or more GLP-1 agonists and / or related compounds.

[0045] Embodiment 30: A kit comprising a first pharmaceutical composition comprising flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a second pharmaceutical composition comprising one or more GLP-1 agonists and / or related compounds.

[0046] Embodiment 31: The kit of any of Embodiments 28-30, wherein the GLP-1 agonist or related compound is selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

[0047] Embodiment 32: The kit of any of Embodiments 28-31, wherein the flibanserin or pharmaceutically acceptable salt, solvate, or hydrate thereof and the one or more GLP-1 agonists and / or related compounds are each independently provided in the form of a pharmaceutical composition for oral, parenteral, or subcutaneous administration.

[0048] These and other features, aspects, and advantages of the disclosure will be apparent from a reading of the following detailed description together with the accompanying drawings, which are briefly described below. The disclosure includes any combination of two, three, four, or more of the above-noted embodiments as well as combinations of any two, three, four, or more features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined in a specific embodiment description herein. This disclosure is intended to be read holistically such that any separable features or elements of the disclosure, in any of its various aspects and embodiments, should be viewed as intended to be combinable unless the context clearly dictates otherwise.

[0049] DETAILED DESCRIPTION

[0050] The present disclosure now will be described more fully hereinafter. This disclosure may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. As used in this specification and the claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Reference to "dry weight percent" or "dry weight basis" refers to weight on the basis of dry ingredients (i.e., all ingredients except water). Reference to "wet weight" refers to the weight of the mixture including water.

[0051] WBD (US)4920-2595-2133, v. 2 -4-AtyDktNo. S107088 1170WO (00257)

[0052] Unless otherwise indicated, reference to "weight percent" of a mixture reflects the total wet weight of the mixture (i.e., including water).

[0053] The present disclosure provides certain methods, compositions, and kits relating generally to prevention and / or treatment of sexual desire disorders. In particular, the disclosure provides methods, compositions, and kits relating to prevention and / or treatment of sexual desire disorders associated with use of glucagon-like peptide-1 (GLP-1) agonists and / or related compounds. GLP-1 agonists in particular have garnered extraordinary attention for their role in treating type II diabetes and inducing weight loss.

[0054] GLP-1 agonists and related compounds are increasingly significant in the treatment of disorders including diabetes, metabolic syndrome, and obesity, mimicking the action of endogenous GLP-1, an anorectic hormone produced in multiple human body tissues, including the intestine, pancreas, and central nervous system. While not intending to be limited by theory, it is believed that the relationship between GLP-1 agonism and serotonin activity sets the foundation for understanding the impact of GLP-1 agonists on sexual function. Based on this theoretical model, an increase in serotoninergic 5-HT2C receptor activity enhances the effects of GLP-1 agonism. Conversely, it is known that increased synaptic serotonin, as seen in SSRIs, is associated with decreased sexual desire and response, i.e., anorgasmia. Therefore, it is believed that the modulation of GLP-1 agonists via increased serotoninergic activity at the 5-HT2C receptor may indeed have an associated negative effect on sexual behavior. Supporting this position, an analysis of sexual behavior in male mice showed that Ex4, a potent and selective GLP-1 agonist, in the laterodorsal tegmental area (LDTg) led to a decrease in sexual interaction behaviors. Administration of Ex4 into the posterior ventral tegmental area (pVTA) was similarly associated with decreased sexual behavior. Because LDTg and pVTA are reward-driven pathways in the brain, the influence of Ex4 on these brain regions provides valuable insight into the action of GLP-1 agonists on reward-driven behaviors, including sexual pursuits. These findings underscore the intimate inverse relationship between GLP-1 agonism and sexual pursuits.

[0055] A wide range of GLP-1 agonists and related compounds are known and / or in development and these (and other compounds within these classes) can be relevant in the context of the present disclosure; the specific GLP-1 agonist(s) and / or related compound(s) with which the referenced sexual desire disorder(s) are associated are not particularly limited. In some embodiments, any compound showing agonist activity at the GLP-1 receptor is relevant in the context of the present disclosure. Known GLP-1 agonists include, but are not limited to, Dulaglutide (Trulicity®), Exenatide (Byetta®), extended release Exenatide (Bydureon® BCise), Liraglutide (Victoza® and Saxenda®), Lixisenatide (Adlyxin®), Degludec / Liraglutide (Xultophy®), Insulin Glargine / Lixisenatide (Soliqua®), Albiglutide (Tanzeum®), Semaglutide injection (Ozempic® and Wegovy®), and Semaglutide tablets (Rybelsus®). Compounds that may work via other mechanisms are also implicated in the present disclosure, including, but not limited to, compounds that modulate the GLP-1 receptor and / or the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon receptor, and / or the ghrelin receptor. In some embodiments, the methods, compositions, and kits of the present invention can relate to dual GLP-l / GIP receptor agonists, e.g., including, but not limited to, Tirzepatide (Mounjaro® and Zepbound®).

[0056] WBD (US)4920-2595-2133, v. 2 -5-AttyDktNo. S 107088 1170WO (00257)

[0057] Certain next-generation GLP-1 agonists and related compounds are also encompassed by the present disclosure including, but not limited to, Retatrutide (a multi-target agonist for GLP-1, GIP, glucagon); CagriSema (Cagrilintide / Semiglutide) (a combination of semaglutide with cagrilintide, an amilyn-relate agonist); oral small-molecule GLP-1 agonists (e.g., Orforglipron), GLP-l / amilyn agonists (e.g., Amycretin); and GLP-l / glucagon dual agonists (e.g. , Pemvidutide). In one embodiment, a multi-hormone / quadruple agent is used in the disclosed methods, compositions, and kits, which targets multiple metabolic hormones, e.g., GLP-1, GIP, glucagon plus peptide YY).

[0058] It is to be understood that the disclosure is not limited to patients undergoing treatment or about to undergo treatment with the specific foregoing GLP-1 agonists and related compounds; rather, the foregoing GLP-1 agonists and related compounds are non-limiting examples of representative compounds of a much broader number of compounds (namely, “GLP-1 agonists and related compounds”) that typically impact the GLP-1 receptor either directly or indirectly, and that may result in sexual desire disorders in some patients, which sexual desire disorders can be addressed via the disclosed methods, compositions, and kits.

[0059] Although the application focuses on GLP-1 agonist and related compounds, in some embodiments, the principles outlined herein may be relevant in the context of other compounds known or recognized as current or emerging weight loss compounds. Such compounds include, but are not limited to, orlistat (a lipase inhibitor, marketed e.g. , as Alli® and Xenical®) and naltrexone / bupropion (a combination that acts on the central nervous system to reduce appetite, e.g., Contrave®). In some embodiments, such compounds include amilyn-mimetic compounds (e.g., GUB014295 / GUBamy), bupropion / zonisamide; or natural or adjunctive agents (e.g., berberine).

[0060] The disclosed methods, compositions, and kits involve use of the compound l-[2-(4-(3-trifluoromethyl-phenyljpiperazin- 1 -yljethyl] -2,3 -dihydro-lH-benzimidazol-2-one (flibanserin) to prevent and / or treat sexual desire disorders associated with use of one or more such GLP-1 agonists and related compounds. Flibanserin is disclosed (in hydrochloride form) in European Patent Application EP-A-526434, which is incorporated herein by reference in its entirety, and has the following chemical structure:

[0061]

[0062] Flibanserin acts, at least in part, by modifying the activity of hydroxytryptamine (5HT), serotonin. Flibanserin shows affinity for the 5 -HTIA receptor and the 5-HT2-receptor family and, in particular, modifies serotonin activity via antagonistic effects at 5-H12C and 5-HT2B receptors.

[0063] Flibanserin (optionally in the form of a pharmacologically acceptable acid addition salt) has previously been reported as a medicament for the treatment of disorders of sexual desire in men and women; see U.S. Patent Nos. 7,151,103; 8,227,471; 9,468,639; 9,782,403; 10,098,876; 10,307,420, 10,675,280, and WBD (US)4920-2595-2133, v. 2 -6-AtyDktNo. S107088 1170WO (00257)

[0064] 11,058,683 and see also U.S. Patent Application Publication Nos. 2005 / 0245539; 2009 / 0318469; and 2013 / 0190326. All of the aforementioned patents and publications are incorporated herein by reference in their entireties. Flibanserin has also been reported as a medicament for treatment of obesity and related diseases; see U.S. Patent Nos. 8,785,458; 8,227,476; 10,335,407; and 10,874,668, which are all incorporated herein by reference in their entireties. Further, flibanserin has been reported as a medicament for treatment of vasomotor symptoms, e.g., associated with menopause; see U.S. Patent Nos. 9,949,969; 10,596,170; and 10, 166,230, which are all incorporated by reference in their entireties and also as a medicament for the treatment of urinary incontinence and related diseases; see U.S. Patent Nos. 9,763,936 and 10,004,731, which are all incorporated herein by reference in their entireties.

[0065] According to the present disclosure, flibanserin uniquely has been found to be useful in preventing and / or treating sexual desire disorders in patients undergoing treatment with GLP-1 agonists and / or related compounds as described above. Although prior publications (e.g., the patents referenced above with respect to flibanserin as a medicament for the treatment of disorders of sexual desire in men and women) have mentioned the use of flibanserin in sexual desire disorders, its use in sexual desire disorders associated with GLP-1 use was not contemplated, particularly given that the first GLP-1 agonist (Exenatide) was not approved by the Food and Drug Administration for use until 2005 (while the effective filing dates of the referenced patents relating to sexual desire disorders are well before 2005). One of skill in the art will readily appreciate that the mechanism of actions of various drugs varies widely and the inventor of the presently disclosed subject matter has uniquely found that flibanserin may be effective in prevention and / or treatment specifically of sexual desire disorders in individuals undergoing (or planning to undergo) treatment with a GLP-1 agonist or related compound.

[0066] The disclosure thus provides, in certain embodiments, a method of preventing or treating sexual desire disorders associated with use of a GLP-1 agonist or related compound. In some embodiments, the method involves prescribing or administering flibanserin with a GLP-1 agonist or related compound to a patient to prevent the onset of sexual desire disorders associated with use of the GLP-1 agonist or related compound (or anticipated use of the GLP-1 agonist or related compound). In some embodiments, the method involves prescribing or administering flibanserin to treat a patient currently experiencing sexual desire disorders or to prevent sexual desire disorders in a patient concerned about experiencing such sexual desire disorders associated with his / her use of a GLP-1 agonist or related compound. Further, in some embodiments, the disclosure provides uses of flibanserin for the preparation of a medicament for the treatment or prevention of sexual desire disorders associated with use of a GLP-1 agonist or related compound (or anticipated use of a GLP-1 agonist or related compound). Such prevention and / or treatment is important in advancing patient care and adequately addressing the well-being of patients for whom GLP-1 agonists or related compounds are prescribed.

[0067] Sexual desire disorders that can be effectively prevented / treated according to the present disclosure include, but are not limited to, hypoactive sexual desire disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance, and frigidity.

[0068] WBD (US)4920-2595-2133, v. 2 -7-AtyDktNo. S107088 1170WO (00257)

[0069] The timeline and treatment schedule for administration of flibanserin according to the present disclosure can be similar to or different than the treatment schedule for administration of the GLP-1 agonist or related compound. In some embodiments, the administration of the GLP-1 agonist or related compound and administration of the flibanserin is begun together. In some embodiments, flibanserin is prescribed and / or administered to a patient who is already being treated with a GLP-1 agonist or related compound, and such treatment period may vary widely (i.e., the use of flibanserin can be effective at any time point following the onset of treatment with the GLP-1 agonist or related compound). In some embodiments, flibanserin is prescribed and / or administered to a patient who is already being treated with a GLP-1 agonist or related compound who has not yet observed signs of sexual desire disorder and in other embodiments, it is prescribed and / or administered to a patient who has observed signs or sexual desire disorder believed to be associated with his / her use of a GLP-1 agonist or related compound. In some embodiments, flibanserin is prescribed and / or administered to a patient who is not yet being treated with a GLP-1 agonist or related compound, e.g., to prevent sexual desire disorders associated with use of the GLP-1 agonist or related compound once treatment begins (where such treatment with flibanserin alone can be conducted for various time periods prior to the start of treatment with the GLP-1 agonist or related compound, e.g., 1-3 months prior to GLP-1 agonist / related compound treatment, 1-2 months prior to GLP-1 agonist / related compound treatment, 1-4 weeks prior to GLP-1 agonist / related compound treatment, 1-3 weeks prior to GLP-1 agonist / related compound treatment, 1-2 weeks prior to GLP-1 agonist / related compound treatment, or about 1 week prior to GLP-1 agonist / related compound treatment).

[0070] In some embodiments, the treatment schedule is such that the GLP-1 agonist or related compound and flibanserin are administered substantially simultaneously. They can be administered within the same formulation or within different formulations, as will be described further herein below. In some embodiments, the GLP-1 agonist or related compound and flibanserin are administered on different treatment schedules. For example, certain GLP-1 agonists and related compound are dosed once weekly and in some embodiments, the flibanserin can be dosed once or twice daily (e.g., once daily). Where the GLP-1 agonist or related compound and flibanserin are administered on the same or similar treatment schedules (e.g., once weekly, once daily, or twice daily), the GLP-1 agonist or related compound and the flibanserin can be administered at similar times of the week or day or at different times of the week or day (e.g. , both on the same day of the week for once-weekly administration or on different days of the week for once-weekly administration and both in the morning or one in the morning and one in the evening for once-daily administration).

[0071] The flibanserin may be prescribed and / or administered in any form. For example, the flibanserin may, in some embodiments, be administered in the form of its free base, a salt thereof (e.g., a pharmacologically acceptable acid addition salt), a solvate thereof, or a hydrate thereof. Suitable acid addition salts include, but are not limited to, those of the acids selected from, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used. In some embodiments in particular, the hydrochloride or hydrobromide salt of flibanserin is used. In WBD (US)4920-2595-2133, v. 2 -8-AtyDktNo. S107088 1170WO (00257)

[0072] some embodiments, a salt form of flibanserin is employed as disclosed in U.S. Patent No. 9,546,141, which is incorporated herein by reference in its entirety. Reference to prescribing, administering, or treating with flibanserin as used herein are intended to encompass treatment with any such form of flibanserin (i.e., free base, salt, solvate, or hydrate form), as well as with various pharmaceutical compositions comprising flibanserin.

[0073] In some embodiments, the flibanserin can be prescribed and / or administered within a pharmaceutical composition comprising flibanserin and one or more pharmaceutically acceptable excipients. Suitable pharmaceutical compositions can vary and include, but are not limited to, solid, liquid (including spray) forms. Compositions may, for example, be provided in a form suitable for oral, rectal, parenteral, or subcutaneous administration or for nasal inhalation: non-limiting forms include, for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal sprays. The flibanserin may be incorporated within a pharmaceutical composition further including one or more excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arable gum, lactose, gelatin, magnesium stearate, com starch, aqueous or non-aqueous vehicles, polyvinyl pyrrolidone, semisynthetic glycerides of fatty acids, benzalkonium chloride, sodium phosphate, EDTA, polysorbate 80, and combinations thereof. Various general additional components, e.g., sweeteners, colorants, glidants, pH adjusters, binders, disintegrants, lubricants, gums, fillers, preservatives, and the like can be optionally incorporated within the disclosed pharmaceutical compositions.

[0074] The compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient (flibanserin). The dose range applicable per day in some embodiments is about 0.1 mg to about 400 mg per day, preferably between 1.0 to 300, more preferably between 2 to 200 mg. As such, each dosage unit may, in some embodiments, conveniently contain from 0.01 mg to 200 mg, 0.1 mg to 150 mg, or 1 mg to about 125 mg, e.g., 50 mg to 150 mg, with one non-limiting example being a dosage unit containing about 100 mg flibanserin and further non-limiting examples being dosage units of 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 105, 110, 115, 120, and 125 mg of flibanserin.

[0075] Suitable tablets may be obtained, for example, by mixing flibanserin with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as com starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and / or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also, in some embodiments, comprise several layers.

[0076] Coated tablets may be prepared accordingly by coating cores produced analogously to the disclosed tablets with substances normally used for tablet coatings, for example colidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core may, in some embodiments, also consist of a number of layers. Similarly, the tablet coating may, in some embodiments, consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. ’

[0077] WBD (US)4920-2595-2133, v. 2 -9-AtyDktNo. S107088 1170WO (00257)

[0078] Syrups or elixirs containing flibanserin according to the present disclosure may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavor enhancer, e.g. , a flavoring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

[0079] Solutions for injection (e.g., for subcutaneous or parenteral administration) comprising flibanserin can be prepared in conventional manners, e.g., with the optional addition of preservatives such as p-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.

[0080] Capsules containing flibanserin may be prepared, for example, by mixing the flibanserin with one or more inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

[0081] Suitable suppositories may be made for example by mixing flibanserin with carriers provided for this purpose, such as neutral fats or polyethylene glycol or the derivatives thereof.

[0082] It is to be understood that the flibanserin can be formulated in various manners and with various excipients in the context of the present disclosure and suitable pharmaceutical compositions are not intended to be limited by way of the foregoing examples.

[0083] In some embodiments, the flibanserin is provided in a pharmaceutical composition independent of the GLP-1 agonist or related compound. In some such embodiments, the pharmaceutical composition may optionally be provided in the form of a kit comprising a pharmaceutical composition comprising flibanserin and a pharmaceutical composition comprising a GLP-1 agonist or related compound. The kit can further comprise labeling and instmctions associated with the independent administration of each pharmaceutical composition, e.g. , with an indication of treatment schedules for each pharmaceutical composition and the like. In some embodiments, the kit is specifically labeled for use in: 1) treatment of diabetes or obesity or obesity -related diseases (including weight loss or weight management) and 2) treatment or prevention of sexual desire disorders associated with GLP-1 agonists. In some embodiments, the kit can further comprise one or more additional components, e.g., one or more containers for the pharmaceutical compositions and / or one or more devices for administration of a pharmaceutical composition, such as an injectable pharmaceutical composition. For example, in one non-limiting embodiment, the kit can comprise an injection device for administration of the pharmaceutical composition comprising the GLP-1 agonist and / or the pharmaceutical composition comprising the flibanserin (or for a single pharmaceutical composition comprising the GLP-1 agonist or related compound and flibanserin, as described below) where such pharmaceutical compositions are provided in injectable form (e.g., for parenteral or subcutaneous administration). Suitable injection devices can vary and include, but are not limited to, durable pens and prefilled pens. In a non-limiting embodiment, a kit can comprise a so-called “blister-pack,” as generally known in the industry for the packaging of pharmaceutical dosage forms.

[0084] In some embodiments, the flibanserin and GLP-1 agonist or related compound are conveniently provided in a single pharmaceutical composition. In some embodiments, a single oral dosage form comprising flibanserin and one or more GLP-1 agonists and / or related compounds is provided. In some WBD (US)4920-2595-2133, v. 2 -10-AtyDktNo. S107088 1170WO (00257)

[0085] embodiments, a single solution for injection comprising flibanserin and one or more GLP-1 agonists and / or related compounds is provided. Suitable pharmaceutical compositions can be conveniently prepared as described above with respect to flibanserin-containing pharmaceutical compositions, with the exception that the one or more GLP-1 agonists and / or related compounds are also incorporated within the same pharmaceutical composition. The dose of flibanserin is generally within the range described herein above. The dose of the one or more GLP-1 agonists and / or related compounds can vary depending upon the particular compound, but can, in some embodiments, be roughly one-tenth to one times the clinically effective amount required to induce a desired therapeutic effect for that particular compound when used singly.

[0086] Both male and female patients can benefit from prevention and / or treatment provided by flibanserin according to the present disclosure. The disclosed prevention and / or treatment may, in some embodiments, be effective in pre-menopausal women and / or post-menopausal women.

[0087] Although the present disclosure focuses on the use of flibanserin to prevent and / or treat sexual desire disorders associated with GLP-1 agonist and related compound treatment in patients, the administration of flibanserin can, in some embodiments, have further and / or other positive effects on the patient. For example, in some embodiments, the flibanserin can enhance the effect of the GLP-1 agonist or related compound treatment, e.g., on obesity or obesity -related diseases. As noted above, flibanserin has been reported to be effective in obesity and obesity -related disorders. See, for example, U.S. Patent No. 10,874,668, previously incorporated herein by reference in its entirety. In some embodiments, the flibanserin administered according to the present disclosure may exhibit synergy with the GLP-1 agonist or related compound with regard to obesity and obesity -related diseases and / or disorders, including, e.g. , exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity and central obesity, as well as disorders associated with obesity, such as metabolic syndrome (syndromeX), hypertension, osteoarthritis, diabetes, especially type II diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, heart diseases, cardiac insufficiency, arteriosclerosis, arthritis, gonitis, stroke and dyslipidaemia, preferably metabolic syndrome, diabetes and dyslipidaemia.

[0088] The present disclosure further provides methods comprising prescribing and / or administering flibanserin and a GLP-1 agonist or related compound to treat any of the indications for which GLP-1 agonists or related compounds are being prescribed. For example, in some embodiments, flibanserin and the GLP-1 agonist or related compound are prescribed and / or administered to treat obesity and / or obesity-related diseases as referenced herein above. Advantageously, in some embodiments, the combination of flibanserin and the GLP-1 agonist or related compound provides a synergistic effect, e.g., determined by measuring the effect when the compounds are administered in combination and comparing the effect when the compounds are administered individually (and noting a greater effect when administered in combination than the combined effect of the compounds administered individually), e.g., using established test models. In WBD (US)4920-2595-2133, v. 2 -11-AtyDktNo. S107088 1170WO (00257)

[0089] some embodiments, the flibanserin can be effective in reducing the amount of or frequency of administration of the GLP-1 agonist or related compound. Synergy, where exhibited, can allow for e.g., lower dosages of the active ingredients to achieve the same results (or greater results). For example, prescribed / administered dosages can, in some embodiments, be smaller, may be administered less frequently, or fewer side effects may be observed with use of the combination rather than each component independently / alone.

[0090] In some embodiments, the disclosed methods thus can provide for both a decrease in and / or elimination of certain side effects noted with GLP-1 agonist or related compound treatment (namely, those associated with sexual desire disorders) and / or can, in some embodiments enhance the desired effects of the GLP-1 agonist or related compound treatment. For example, such methods can provide better / faster results e.g., in weight loss or treatment of obesity -related diseases and / or allowing for the use of smaller or less frequent doses of the GLP-1 agonist or related compound, while also ameliorating or preventing sexual desire disorders in the patient being treated. As such, the disclosure provides, in some embodiments, a method for enhancing treatment with a GLP-1 in a patient, comprising administering flibanserin to the patient (wherein the enhancing treatment can be evidenced by any of the benefits referenced herein above). It is understood that timelines and forms of flibanserin administration in such methods can be any of those described herein.

[0091] Many modifications and other embodiments of the disclosure will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing description. Therefore, it is to be understood that the disclosure is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0092] WBD (US)4920-2595-2133, v. 2 -12-

Claims

AtyDktNo. S107088 1170WO (00257)CLAIMSWhat is claimed is:

1. A method of treating or preventing onset of a sexual desire disorder, comprising administering an effective amount of flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a patient intending to undergo or currently undergoing treatment with a GLP-1 agonist or related compound.

2. The method of claim 1, wherein the administering is concurrent with the patient beginning treatment with a GLP-1 agonist or related compound.

3. The method of claim 1, wherein the administering is prior to the patient beginning treatment with a GLP-1 agonist or related compound.

4. The method of claim 1, wherein the GLP-1 agonist or related compound is selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

5. The method of any of claims 1-4, wherein the flibanserin and the GLP-1 agonist or related compound are administered on substantially the same treatment schedule.

6. The method of any of claims 1-4, wherein the flibanserin and the GLP-1 agonist or related compound are administered on different treatment schedules.

7. The method of any of claims 1-2, wherein the flibanserin and the GLP-1 agonist or related compound are administered as a single pharmaceutical composition comprising the flibanserin and the GLP-1 agonist or related compound in combination with one or more pharmaceutically acceptable excipients.

8. The method of any of claims 1-4, wherein the flibanserin is administered as a pharmaceutical composition comprising the flibanserin as the sole active ingredient in combination with one or more pharmaceutically acceptable excipients.

9. The method of any of claims 1-4, wherein the flibanserin is administered once daily.

10. The method of any of claims 1-4, wherein the flibanserin is administered at a dosage of about 0.1 mg to about 400 mg per da .WBD (US)4920-2595-2133, v. 2 -13-AtyDktNo. S107088 1170WO (00257)11. The method of any of claims 1-4, wherein the administering is oral administering.

12. The method of claim 11, wherein the flibanserin is administered in the form of a tablet.

13. The method of any of claims 1-4, wherein the administering is parenteral administering.

14. The method of any of claims 1-4, wherein the administering is subcutaneous administering.

15. A pharmaceutical composition comprising flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof and one or more GLP-1 agonists and / or related compounds in combination with one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition of claim 15, wherein the GLP-1 agonist or related compound is selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

17. A kit labeled for prevention and / or treatment of sexual desire disorders associated with use of GLP- 1 agonists or related compounds, the kit comprising flibanserin or a pharmaceutically acceptable salt, solvate, or hydrate thereof and one or more GLP-1 agonists and / or related compounds.

18. The kit of claim 17, wherein the one or more GLP-1 agonists and / or related compounds are selected from the group consisting of Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Degludec / Liraglutide, Insulin Glargine / Lixisenatide, Albiglutide, Semaglutide, Tirzepatide, and combinations thereof.

19. The kit of claim 17 or 18, wherein the flibanserin or pharmaceutically acceptable salt, solvate, or hydrate thereof and the one or more GLP-1 agonists and / or related compounds are each independently provided in the form of a pharmaceutical composition suitable for oral, parenteral, or subcutaneous administering.

20. The kit of claim 19, wherein the flibanserin is in the form of an oral tablet.WBD (US)4920-2595-2133, v. 2 -14-

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