Use of vibegron to treat overactive bladder symptoms in men with benign prostatic hyperplasia

Abstract

To provide methods to treat overactive bladder symptoms in men with benign prostatic hyperplasia.SOLUTION: The present disclosure is directed to a method comprising orally administering, to a subject in need of treatment of overactive bladder symptoms, an amount of from about 60 mg to about 90 mg (e.g., about 75 mg) of vibegron per day.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a joint venture of U.S. Provisional Patent Application No. 62 / 842,418, filed May 2, 2019, and U.S. Provisional Patent Application No. 62 / 842,418, filed April 5, 2019. No. 62 / 830,298, filed on December 5, 2018, and U.S. Provisional Patent Application This application claims priority to application Ser. No. 62 / 775,818, the entire contents of which are incorporated herein by reference. Import. [Background technology]

[0002] Benign prostatic hyperplasia (BPH) is a condition characterized by proliferation of smooth muscle and epithelial cells within the prostatic transition zone. It is a condition characterized by benign growth and / or changes in the prostatic glands. Historically, men with BPH: Lower urinary tract symptoms (LUTS) are presumed to be caused by bladder outlet obstruction secondary to prostatic hyperplasia. However, men may experience urinary and / or storage symptoms without or without BPH-related symptoms. In association with this, patients may present with overactive bladder (OAB) symptoms. BPH can also be associated with storage symptoms (e.g., frequent urination). urgency, nocturia, etc.) and urinary dysfunction (e.g., reduced and intermittent flow and incomplete urination) These may be related to debilitating LUTS, which are classified by the severity of symptoms (sensation of complete bladder emptying).

[0003] Overactive bladder (OAB) is a chronic, often painful condition of the lower urinary tract that affects both men and women. It can be a debilitating condition if left untreated. The function of the lower urinary tract is to store and periodically release urine. This requires coordination of the storage and micturition reflexes. Involves afferent and efferent neural pathways, resulting in modulation of central and peripheral neuroeffector mechanisms As a result, the sympathetic and parasympathetic components of the autonomic nervous system and the somatic motor pathways These result in coordinated regulation of the bladder (detrusor) and urethral smooth muscles, as well as the urethral sphincter. Regulates the contractile state of striated muscles proximally.

[0004] From a pathophysiological point of view, overactive bladder may be associated with detrusor overactivity. B: Urgency with or without urge urinary incontinence and is usually characterized by frequent and nocturnal episodes in the absence of urinary tract infection or other obvious medical conditions. It is associated with frequent urination. The prevalence of OAB in the United States and Europe is 16% in both women and men aged 18 years and older. The prevalence of overactive bladder is estimated at ~17%. Although overactive bladder is most often classified as idiopathic, It may also be secondary to neurological conditions, bladder outlet obstruction, and other causes.

[0005] Initial pharmacologic treatment of OAB symptoms in men with BPH traditionally focuses on minimizing obstruction. The aim is to stimulate alpha-1 adrenergic receptors to relax the muscles of the prostate and bladder neck. These BPH treatments include 5α-reductase inhibitors to reduce prostate growth or antagonists. Although the technique may provide some improvement in LUTS (e.g., improved urinary flow), OAB symptoms are poorly controlled and often include urgency, incontinence, frequency, or nocturia. To address persistent OAB symptoms in men with BPH, a combination of BPH therapy and anticholinergic medications is recommended. Combinations of OAB drugs have shown promise. However, the clinical use of anticholinergic drugs remains unclear. Use is associated with adverse effects including increased risk of dry mouth, constipation, urinary retention, and possible central nervous system side effects. In addition, the possibility of urinary retention limits the There are preventative measures and precautions.

[0006] Activation of beta-3 adrenergic receptors (β3-AR) relaxes the detrusor muscle under normal and pathogenic conditions. Functional evidence supports a key role for β3-AR in urinary storage These results are based on in vivo studies. β3-AR agonists have the effect of relieving symptoms of OAB. To date, the only β3-AR agonist, mirabegron (Astellas fulvest), Pharma Global Development Co., Ltd. sells it in both the United States and Japan as a treatment for OAB. Mirabegron activates β3-AR in the bladder detrusor muscle, which promotes muscle relaxation. Mirabegron has been shown to reduce urination frequency, urinary incontinence, and urgency episodes. A decrease in the number of voids and an increase in the average volume of urine voided per void were observed. nt Urol Nephrol. 45(1):53-60 (2013).

[0007] Vibegron, (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine 6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate Ruboxamide is a potent and highly selective beta-3 adrenergic receptor (β3-AR) agonist. and activation of the β3-AR in cell-based in vivo assays against the β2-AR and β1- It shows >9,000-fold selectivity over AR. Edmondson et al., J. Med. Chem. 59:609-623 (201 Vibegron is also in Phase 3 clinical trials to treat patients with overactive bladder (OAB). Studied in Yoshida et al., European Urology 73:783-790 (2018). [ka]

[0008] Vibegron is disclosed as a β3-AR agonist in U.S. Patent Nos. 8,399,480 and 8,247,415. A synthetic method for preparing vibegron is disclosed in U.S. Publication No. US2017 / 0145014, The present invention is disclosed in US2015 / 0087832, US2016 / 0176884, and US2014 / 0242645. All editions are incorporated herein by reference in their entirety.

[0009] There is a need to develop novel methods for treating overactive bladder symptoms in men with BPH. [Brief description of the drawings]

[0010] [Figure 1] Figure 1 shows an overlay of density plots of exposure at 100 mg and 75 mg of vibegron, estimated in special populations. [Diagram 2] FIG. 2 shows the chemical structures of the metabolites of vibegron. Summary of the Invention [Means for solving the problem]

[0011] The present disclosure provides a method for treating overactive bladder symptoms in a subject with benign prostatic hyperplasia. The method comprises administering to a subject in need of said treatment an amount of 60 mg to 90 mg of Vibegro per day. This involves orally administering DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless expressly defined herein, each of the following terms has the following meaning: Additional definitions are set forth throughout the application.

[0013] In this specification and the appended claims, the singular forms "a," "an," and "the" are used interchangeably. Includes plural referents unless the context clearly dictates otherwise. The terms "one or more" and "at least one" are used herein to refer to In certain embodiments, the terms "a" or "an" can be used interchangeably. In other embodiments, the terms "a" or "an" refer to "two or more" or "multiple" Includes "number".

[0014] Furthermore, as used herein, "and / or" refers to two particular embodiments without regard to the presence or absence of the other. should be construed as a specific disclosure of each of the specified features or components. As used herein in phrases such as "A and / or B," the term "and / or" "A and B", "A or B", "A" (alone), and "B" (alone) are intended to include Similarly, the term "and / or" used in phrases such as "A, B, and / or C" It is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or is C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone) .

[0015] Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present disclosure. The designations have the same meaning as commonly understood by one of ordinary skill in the art to which they pertain.

[0016] As used throughout this specification and claims in connection with numerical values, the term "about" means It indicates an interval of accuracy that is familiar to the trade and acceptable to the trader. Such an interval of accuracy is ±10%. be.

[0017] As used herein, the term "nocturia" refers to the frequency of passing urine during the primary sleep period. According to the International Urinary Continence Society, the first time you wake up to pass urine is the number of times each urination must be followed by sleep or the intention to sleep, which is quantified using a bladder diary. In some aspects, nocturia is the interruption of sleep one or more times due to the need to urinate. In some cases, each urination may occur before or after sleep. This is not always the case. (Hashim, H. et al., “International Continence Society (I CS) Report on the Terminology for Nocturia and Nocturnal Lower Urinary Tract Fun ction,” Neurology and Urodynamics 2019, 1-10.)

[0018] The term "overactive bladder" is generally used in the absence of a urinary tract infection or other obvious medical condition. Urgency to urinate, which may be accompanied by frequency and nocturia, with or without urge incontinence The term "overactive bladder" refers to a clinical syndrome characterized by As defined by: Overactive bladder (OAB) is a condition characterized by localized pathological or hominid causes. There is no clinical cause, and usually frequency and nocturia with or without urge incontinence. It is a symptom complex consisting of the urgency of the pain and the associated discomfort (Abrams P et al., Urology 2003, 61(1): 37-49; Abrams P et al., Urology 2003, 62(Supplement 5B): 28-37 and 40-42). overactive bladder Synonyms for (OAB) include "urgency syndrome" and "urgency-frequency syndrome."

[0019] As used herein, "urge urinary incontinence" (UUI) The term "urge urinary incontinence" refers to the complaint of involuntary urine loss associated with urgency. UUI can be used interchangeably with "unary incontinence." Involuntary urinary incontinence due to physical activity (e.g. sports activities), or sneezing or coughing It is distinct from stress incontinence. "Urge incontinence" refers to the complaint of involuntary loss of urine.

[0020] As used herein, the term "disorder" refers to acute or chronic impairment of function. For example, renal dysfunction is when the kidneys cannot maintain normal function and waste products and metabolic products accumulate in the blood. This refers to a medical condition in which the patient is

[0021] As used herein, the term "urgency" refers to a sudden urge to urinate that is difficult to postpone. This refers to the complaint of a constant urge to urinate.

[0022] As used herein, the term "frequent urination" refers to a condition in which one or more of the following occurs: Refers to a complaint by a patient who believes they are experiencing urinary

[0023] The term "benign prostatic hyperplasia" refers to the proliferation of smooth muscle and epithelial cells within the transitional zone of the prostate. This is a histological diagnosis.

[0024] The term "detrusor" refers to the muscle of the bladder.

[0025] As used herein, the term "detrusor overactivity" refers to involuntary voiding during filling cystometry. This refers to the occurrence of urinary muscle contractions. These contractions may be spontaneous or induced and cannot be inhibited by the patient. They are seen on the cystometrogram as waves of varying duration and amplitude ( Urinary incontinence may or may not occur. These contractions may be micturition contractions, partial micturition contractions, non-micturition contractions (NVC), or a combination of these. The term "detrusor overactivity" has been coined by the International Continence Society (ICS) It is defined as follows: Detrusor overactivity is a condition that occurs during the filling phase, which may be spontaneous or induced. This is a urodynamic observation characterized by involuntary detrusor contractions in the urinary tract (Abrams P et al., Urology 2 003, 62(Supplement 5B): 28-37 and 40-42).

[0026] As used herein, the term "free base" refers to the basic compound itself, not in salt form. For example, vibegron free base is (6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(furan) phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo It refers to [1,2-a]pyrimidine-6-carboxamide.

[0027] As used herein, the term "micturition" means urination. Taste.

[0028] As used herein, the term "OAB wet" refers to frequent and urgent urination accompanied by incontinence. Overactive bladder (OC) is defined as:

[0029] As used herein, the term "OAB dry" refers to frequent and incessant urination without incontinence. Overactive bladder (OCB) refers to overactive bladder defined as urinary tract infection.

[0030] The term "pharmaceutical acceptable salt" refers to a compound that is safe and effective for use in a subject. By this is meant a salt of a compound possessing the desired biological activity.

[0031] The pharma- ceutically acceptable salts of basic compounds may be salts of organic or inorganic acids. In some embodiments, the organic and inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, liquoric acid, and the like. These include carboxylic acid, citric acid, maleic acid, mandelic acid, succinic acid and methanesulfonic acid. In general, see, but are not limited to, Journal of Pharmaceutical Science, 66, 2 (1977) See, which is incorporated herein by reference in its entirety.

[0032] As used herein, "C max " refers to the maximum plasma concentration of a drug following drug administration. Point.

[0033] As used herein, "T max The term "maximum plasma concentration" refers to the time when the maximum plasma concentration is reached after drug administration. Refers to the time.

[0034] As used herein, the term "AUC" refers to the profile of plasma concentration versus time after drug administration. This refers to the area under the curve of the lot.

[0035] The term "steady state" refers to the state in which the amount of drug reaching the system is approximately equal to the amount of drug leaving the system. Therefore, at "steady state," the patient's body is The drug is cleared through the vasopressin receptors at approximately the same rate as it becomes available to the patient's system.

[0036] As used herein, the terms "treat," "treatment," or "therapy" refer to a benign prostatic hyperplasia. Partial or complete relief, improvement, amelioration, or relaxation of one or more overactive bladder symptoms associated with prostatic hyperplasia (c) reducing the severity of, delaying the onset of, inhibiting progression of, reducing the severity of, or reducing the incidence of, or any of these It refers to a combination of

[0037] The term "treatment period" refers to the period during which a drug is administered to a subject. The duration may be from about 2 weeks to about 2 years. In some embodiments, the treatment duration is: About 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 24, about 52, about 76 or about 10 The efficacy of the drug is evaluated by measuring specific parameters and the baseline over the treatment period. Efficacy parameters can be evaluated by calculating the change from baseline. These include urination, urge urinary incontinence episodes, and total urinary incontinence episodes. These include, but are not limited to, mood swings, and urgency episodes.

[0038] As used herein, the term "subject" refers to a subject who is at high risk for suffering from overactive bladder symptoms. Currently suffering from or have suffered from benign prostatic hyperplasia (BPH) H) A subject with BPH refers to, for example, a subject who has BPH symptoms unrelated to overactive bladder symptoms. If symptoms have previously been alleviated, reduced or relieved in a subject, or if symptoms of overactive bladder have previously been alleviated, reduced or relieved in a subject, are at higher risk of suffering from overactive bladder symptoms.

[0039] Additional definitions related to urological conditions can be found, for example, in Chapple et al. (2018) "Terminology report from the International Continence Society (ICS) Working Group on Underac The results can be found in "UAB" Neurology and Urodynamics 37:2928-2931. Additional definitions related to benign prostatic hyperplasia can be found, for example, at www.auanet.org / benign-prostatic-hy Guidelines for These documents can be found in the journal "The Management of Benign Prostatic Hyperplasia." all of which are incorporated herein by reference in their entireties.

[0040] <Treatment method> The present disclosure relates to a method for treating overactive bladder symptoms in men with BPH without undesirable side effects. Vibegro should be administered to subjects who need it to maintain the desired efficacy while minimizing By selecting the dose of vibegron, max Rise of The potential for a heterogeneous reduction in side effects associated with

[0041] The present disclosure provides a method of treating overactive bladder symptoms in men with BPH, comprising administering The study involves administering vibegron orally in amounts of 50 mg to 100 mg per day to subjects in need. As used herein, "per day" refers to a consecutive 24-hour period, sometimes refers to "per 24 hours."

[0042] The present disclosure provides a method for decreasing or reducing urination in a subject with BPH in need thereof. The method comprises providing to the subject an amount of about 60 mg to about 90 mg of Vibegro per day. This involves orally administering

[0043] The present disclosure provides a method of treating overactive bladder symptoms in a subject with BPH, comprising administering to said subject Urgency urinary incontinence, urge urinary incontinence e), urinary urgency, frequency, nocturia, and combinations thereof. Have symptoms.

[0044] In some embodiments, the subject with BPH has urge urinary incontinence. tinence, urge incontinence, urgency, frequency, nocturia, and the like In some embodiments, the patient has persistent OAB symptoms selected from the group consisting of: In this study, subjects with BPH are treated with vibegron and receive concomitant pharmacologic therapy for BPH. In some embodiments, the methods disclosed herein also treat urinary dysfunction (e.g., , decreased and intermittent flow and a feeling of urgency).

[0045] In some embodiments, the amount of vibegron administered per day is from about 55 mg to about 100 mg. About 100 mg, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 10 0 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, or about 95 mg to about 10 0mg.

[0046] In some embodiments, the amount of vibegron administered per day is from about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, or about 50 mg to about 55 mg .

[0047] In some embodiments, the amount of vibegron administered per day is from about 60 mg to In some embodiments, the amount is from about 65 mg to about 85 mg, or from about 70 mg to about 80 mg. The amount of vibegron administered per day is 60 mg to 90 mg, 65 mg to 85 mg, or 70 mg. from 80 mg.

[0048] In some embodiments, the amount of vibegron administered per day is about 55 mg, about 6 0 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or about 95 mg. In one embodiment, the amount of vibegron administered per day is about 75 mg. In some embodiments, the amount of vibegron administered per day is 75 mg.

[0049] In some embodiments, the amount of vibegron administered per day is about 50 mg. In some embodiments, the amount of vibegron administered per day is about 100 mg. In some embodiments, the amount of vibegron administered per day is 50 ml or less. g. In some embodiments, the amount of vibegron administered per day is 10 Not 0mg.

[0050] In some embodiments, the treatment period does not include dose titration of vibegron. In some embodiments, treatment is initiated with 75 mg of vibegron per day.

[0051] In some embodiments, the treatment period includes dose titration of vibegron. In an embodiment, treatment does not begin with administration of 75 mg of vibegron per day.

[0052] In some embodiments, the subject is diagnosed with urge urinary incontinence. ce), urgency, and frequency of urination.

[0053] In some embodiments, the subject is diagnosed with urge urinary incontinence. ce) (or urge urinary incontinence), a feeling of urgency, frequency and nocturnal Have one or more of the following symptoms: frequent urination.

[0054] In some embodiments, the subject has 12 or fewer urinary episodes per day prior to treatment. In some embodiments, the subject has more than 12 daily doses prior to treatment. The patient has urinary episodes.

[0055] In some embodiments, the subject has symptoms of urinary incontinence. In the present study, the subject is free of symptoms of urinary incontinence.

[0056] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human or an animal.

[0057] In some embodiments, the subject is over 18 years of age. The subject is over 45 years old. In some embodiments, the subject is over 50 years old. In some embodiments, the subject is over 55 years of age. In some embodiments, the subject is over 65 years of age. In some embodiments, the subject is over 70 years old. In some embodiments, the subject is over 75 years old. .

[0058] In some embodiments, the subject is suffering from or has renal dysfunction. In some embodiments, the subject is at risk of developing mild renal impairment, moderate renal impairment, If you have mild or severe renal dysfunction.

[0059] In some embodiments, the subject has previously undergone OAB therapy. In some embodiments, the subject has not previously received OAB therapy.

[0060] In some embodiments, the subject is receiving treatment for BPH or BPH prior to initiation of vibegron treatment. In some embodiments, the subject has undergone or has undergone relevant surgery. Have undergone or have undergone prostate surgery. In some embodiments, the subject Having had or undergone an invasive prostate procedure.

[0061] Examples of BPH procedures or BPH-related surgeries include transurethral resection of the prostate, transurethral incision of the prostate, pre-operative Laser enucleation of the prostate, prostatectomy, prostatic stent placement, UroLift, catheterization, Transurethral microwave thermotherapy, transurethral electrical vaporization of the prostate, transurethral needle ablation, and high intensity focused ultrasound. Including, but not limited to, sound waves.

[0062] In some embodiments, the subject receives vibegron prior to a BPH treatment or BPH-related surgery. In some embodiments, the subject is administered the drug simultaneously with a BPH treatment or BPH-related surgery. The patient was given vibegron.

[0063] In some embodiments, the subject is suffering from impaired renal function and is receiving about 75 mg / day The patient was given vibegron.

[0064] In some embodiments, the subject is taking a cytochrome P450 inhibitor, such as a CYP3A inhibitor; and drugs that are substrates of the following CYPs: CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 simultaneously. Receive, ingest, or otherwise be exposed to.

[0065] In some embodiments, the subject is also receiving, taking, or receiving a CYP 2D6 substrate. Being exposed in other ways.

[0066] In some embodiments, the subject is receiving, taking, or administering a P-glycoprotein inhibitor at the same time. or otherwise exposed.

[0067] CYP3A / P-glycoprotein inhibitors include amiodarone, carvedilol, and clarithromycin. dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propranolol Phenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevivir , tipranavir and ritonavir, verapamil, curcumin, cyclosporine A, Thrombopag, atazanavir and ritonavir, clarithromycin, cyclosporine, Rithromycin, Gemfibrozil, Lopinavir and Ritonavir, Rifampin (single dose) administration), simeprevir, p-aminohipuric acid (PAH)(b), probenecid, teriflunomide cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, and and vandetanib.

[0068] CYP 2D6 substrates include imipramine, amitriptyline, fluoxetine, and paroxetine. , fluvoxamine, venlafaxine, duloxetine, mianserin, mirtazapine, Opioids, codeine, morphine, tramadol, O-desmethyltramadol, N,O-di Desmethyltramadol, oxycodone, hydrocodone, hydromorphone, tapentadol haloperidol, risperidone, perphenazine, thioridazine, zuclopentidine Sol, Iloperidone, Aripiprazole, Chlorpromazine, Levomepromazine, Remo xyprid, minaprine, tamoxifen, hydroxytamoxifen, beta blockers -, metoprolol, timolol, alprenolol, carvedilol, bufuralol, Nebivolol, propranolol, debrisoquine, flecainide, propafenone, en Cainide, mexiletine, lidocaine, sparteine, ondansetron, donepezil, Phenformin, tropisetron, amphetamine, methoxyamphetamine, dextran Lomethamphetamine, atomoxetine, chlorpheniramine, dexfenfluramine, Dextromethorphan, dextrorphan, metoclopramide, perhexiline, Enacetin, promethazine, m-tyramine, warfarin, tolterodine, and p-tyramine Examples of such applications include, but are not limited to:

[0069] In some embodiments, the subject is administered about 75 mg of vibegron per day; Concurrently receiving, taking, or otherwise being exposed to a CYP3A inhibitor.

[0070] In some embodiments, the subject is administered about 75 mg of vibegron per day; Concurrently, one receives, takes, or is otherwise exposed to a CYP 2D6 substrate.

[0071] In some embodiments, the subject is administered about 75 mg of vibegron per day; Concurrently, the subject receives, takes, or is otherwise exposed to a P-glycoprotein inhibitor.

[0072] In some embodiments, the subject is concurrently receiving, taking, or administering a beta blocker. Not otherwise exposed.

[0073] In some embodiments, the subject is receiving, taking, or concurrently administering an alpha blocker. are not otherwise exposed.

[0074] In some embodiments, the subject is receiving, taking, or concurrently administering an alpha blocker. are exposed in other ways.

[0075] Alpha blockers include phenoxybenzamine, phentolamine, tolazoline, and trazoline. Zodone, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin, silodine Synth, atipamezole, idazoxan, mirtazapine, yohimbine, carvedilol, la These include, but are not limited to, betalol.

[0076] In some embodiments, the subject is administered 75 mg of vibegron per day. At times, people receive, take, or are otherwise exposed to alpha blockers.

[0077] In some embodiments, the subject is taking a 5-alpha reductase inhibitor (5-ARI). Received, taken, or otherwise exposed to at the same time.

[0078] 5-ARIs include alphatradiol, dutasteride, epristeride, and finasteride. Extracts of glycerin, ...yl-2 stearate, and saw palmetto extracts are included, but are not limited to these.

[0079] In some embodiments, the subject is administered 75 mg of vibegron per day. At times, people receive, take, or are otherwise exposed to a 5-ARI.

[0080] In some embodiments, the subject is receiving an alpha blocker and a 5-ARI simultaneously. , ingested, or otherwise exposed to

[0081] In some embodiments, vibegron is administered with a meal, within 60 minutes after a meal, or within 2 hours after a meal. It is administered within hours.

[0082] In some embodiments, vibegron is administered without food or before a meal. In some embodiments, vibegron is administered two or more hours before a meal.

[0083] In some embodiments, vibegron is administered once daily, twice daily, or three times daily. In some embodiments, vibegron is administered once daily.

[0084] The efficacy of treatment is evaluated over the treatment period (e.g., 8 weeks or 12 weeks) in subjects with BPH. It can be measured by the change from baseline in the average number of urinations per 24 hours.

[0085] In some embodiments, the subject is administered about 75 mg of vibegron per day; Baseline mean number of voids per 24 hours over the treatment period (e.g., 8 or 12 weeks) subjects experience a change from baseline, where the change is compared to that of subjects taking a placebo The difference with the Brasepo is about -0.2 to about -1.5, for example, about -0.2, -0.3, -0.4 , -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4 or -1.5, or The range is between any two of the values ​​listed above.

[0086] In some embodiments, the subject receives about 60 mg to about 90 mg, e.g., about 65 mg, per day. g to about 85 mg, about 70 mg to about 80 mg, or about 75 mg of vibegron per day, Baseline mean number of voids per 24 hours over a period (e.g., 8 or 12 weeks) subjects experience changes in their schizophrenia that are greater than those of subjects taking a placebo. The difference from the Brasepo is about -0.5 to about -1.0, for example, about -0.5, -0.6, -0.7, -0.8, -0.9 or -1.0, or a range between any two of the preceding values.

[0087] In some embodiments, the subject receives about 60 mg to about 90 mg, e.g., about 65 mg, per day. g to about 85 mg, about 70 mg to about 80 mg, or about 75 mg of vibegron per day, experience a reduction or decrease in the average number of urinations per day, wherein said reduction or decrease is greater than or equal to placebo were about 1.5 to about 3.0 times greater than those of subjects taking bo, e.g., about 1.5, 1.6, 1. 7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0, or prior The range is between any two of the values ​​listed above.

[0088] In some embodiments, the subject receives about 60 mg to about 90 mg, e.g., about 65 mg, per day. g to about 85 mg, about 70 mg to about 80 mg, or about 75 mg of vibegron per day, experience a reduction or decrease in the average number of urinations per day, wherein said reduction or decrease is greater than or equal to placebo The mean mean mean blood glucose levels were about 2.0 to about 2.5 times higher than those of subjects taking morphine, e.g., about 2.0, 2.1 , 2.2, 2.3, 2.4 or 2.5, or a range between any two of the preceding values.

[0089] In some embodiments, the subject receives about 60 to about 90 mg, e.g., about 65 mg, per day. to about 85 mg, about 70 to about 80 mg, or about 75 mg of vibegron per day, Patients experience a reduction in the average number of urinations per day, where the reduction is greater than or equal to the administration of extended-release tolterodine (ER) greater than those in subjects taking the 4 mg dose.

[0090] In some embodiments, the subject is administered about 75 mg of vibegron per day; Approximately -1.0% decrease in the mean number of urinations per 24 hours over the treatment period (e.g., 8 or 12 weeks) to about -2.5, e.g., about -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9 , -2.0, -2.1, -2.2, -2.3, -2.4 or -2.5, or a range between any two of the preceding values. experience changes in

[0091] The efficacy of treatment is evaluated over the treatment period (e.g., 8 weeks or 12 weeks) in subjects with BPH. Measured by change from baseline in the mean number of urgency episodes per 24 hours This can be done.

[0092] In some embodiments, the subject is administered about 75 mg of vibegron per day; Mean number of urgency episodes per 24 hours over the treatment period (e.g., 8 or 12 weeks) and experiencing a change from baseline in the number of patients receiving placebo. The difference between the two is about -0.2 to about -1.5, e.g., about -0.2 , -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4 or -1.5, or the range between any two of the preceding values.

[0093] In some embodiments, the subject receives about 60 mg to about 90 mg, e.g., about 65 mg, per day. g to about 85 mg, about 70 mg to about 80 mg, or about 75 mg of vibegron per day, The average number of urgency episodes per 24 hours over a period (e.g., 8 or 12 weeks) experience a change from baseline, where the change is greater than or equal to subjects taking a placebo The difference with the Brasepo is about -0.4 to about -1.0, for example, about -0.4, -0.5, -0 .6, -0.7, -0.8, -0.9 or -1.0, or a range between any two of the preceding values.

[0094] In some embodiments, the subject receives about 60 mg to about 90 mg, e.g., about 65 mg, per day. g to about 85 mg, about 70 mg to about 80 mg, or about 75 mg of vibegron per day, experience a reduction or decrease in the average number of urgency episodes per day, wherein said reduction or decrease The reduction is about 1.2 to about 3.0 times greater than that of subjects taking a placebo, e.g., about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0, or a range between any two of the preceding values.

[0095] In some embodiments, the subject receives about 60 to about 90 mg, e.g., about 65 mg, per day. to about 85 mg, about 70 to about 80 mg, or about 75 mg of vibegron per day, and experiencing a reduction in the average number of urgency episodes per day, wherein said reduction is achieved by administering sustained release tortello greater than those of subjects taking 4 mg of gin (ER).

[0096] In some embodiments, the subject is administered about 75 mg of vibegron per day; Average number of urgency episodes per 24 hours over the treatment period (e.g., 8 or 12 weeks) An even number between about -1.0 and about -2.5, e.g., about -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7 , -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4 or -2.5, or any two of the preceding values The range of variation between the two is experienced.

[0097] In some embodiments, the subject is administered about 75 mg of vibegron per day; Average number of urgency episodes per 24 hours over the treatment period (e.g., 8 or 12 weeks) The subjects will experience a change from baseline in mean number of urinations and mean number of urinations per 24 hours, where The change is greater than that of subjects taking a placebo. and the change from baseline in the average number of voids per 24 hours is from about -1.0 to about -2.5, For example, approximately -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1 , -2.2, -2.3, -2.4 or -2.5, or a range between any two of the preceding values, The change from baseline in the mean number of urgency episodes per session is from about -1.0 to about -2. .5, e.g., about -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.3, -2.4 or -2.5, or a range between any two of the preceding values.

[0098] The efficacy of treatment is evaluated over the treatment period (e.g., 8 or 12 weeks) in subjects with BPH. Change from baseline in mean number of urge urinary incontinence (UUI) episodes per day It can be measured.

[0099] In some embodiments, the subject consumes the medication on average 1 or more times, 2 or more times, or 3 or more episodes of urge urinary incontinence (UUI) and taking approximately 75 mg of vibegron per day Based on the average number of UUI episodes administered over the treatment period (e.g., 8 or 12 weeks) subjects experience a change from baseline, where the change is the same as that of subjects taking a placebo The difference with the Brasepo is about -0.2 to about -1.5, for example, about -0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4 or -1.5, or is a range between any two of the preceding values.

[0100] In some embodiments, the subject is administered about 75 mg of vibegron per day to treat The mean number of UUI episodes over the treatment period (e.g., 8 or 12 weeks) was measured from baseline. to about -1.3 to about -2.5, for example, about -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2 .1, -2.2, -2.3, -2.4 or -2.5, or a range change between any two of the above values experience.

[0101] The efficacy of treatment is evaluated based on the average loss of urine per void over the treatment period (e.g., 8 or 12 weeks). It can be measured by the change from baseline in urine volume (mL).

[0102] In some embodiments, the subject is administered about 75 mg of vibegron per day; experience a change in average voided volume (mL) per urination, where the change is greater than or equal to taking a placebo The difference between the two is about 20 mL to about 35 mL, e.g. , about 20mL, 21mL, 22mL, 23mL, 24mL, 25mL, 26mL, 27mL, 28mL, 29mL, 30mL, 31mL, 32mL , 33 mL, 34 mL, or 35 mL, or a range between any two of the above values.

[0103] In some embodiments, the subject consumes the medication on average 1 or more times, 2 or more times, or 3 or more episodes of urge urinary incontinence (UUI) and taking approximately 75 mg of vibegron per day The number of UUI episodes per day over the treatment period (e.g., 8 or 12 weeks) was At least 30%, at least 40%, at least 45%, at least 50%, at least 55% of the average %, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least The patient experiences at least an 85%, at least a 90%, or at least a 95% reduction.

[0104] In some embodiments, the subject consumes the medication on average 1 or more times, 2 or more times, or 3 or more urgency episodes and receiving approximately 75 mg of vibegron per day for treatment A low mean number of urgency episodes per day over a period (e.g., 8 or 12 weeks) at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least or experience a decrease of 60%, at least 65%, at least 70% or at least 75%.

[0105] In some embodiments, the subject is administered about 75 mg of vibegron per day; At least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least The mean voided volume (mL) per void was 85%, 90%, 95%, or 100%. ), where the change is greater than that of subjects taking a placebo. big.

[0106] The efficacy of treatment is also evaluated in subjects with BPH over the treatment period (e.g., 8 or 12 weeks). Mean International Prostate Symptom Score (IPSS) (i.e., IPSS total score) and / or IPSS It can be measured by the change from baseline in Quality of Life (QoL) scores.

[0107] The International Prostate Symptom Score (IPSS) is a questionnaire that consists of seven questions about urinary symptoms and one about quality of life. Based on responses to four questions. Each question about urinary symptoms increases the severity of a particular symptom. Participants were asked to select one of six answers that indicated their level of satisfaction. Answers were scored from 0 to 5. Thus, the total score ranges from 0 to 35 (asymptomatic or to very symptomatic). The response to a single question assessing quality of life questions was: The scale ranges from "delighted" to "terrible" or from 0 to 6, i.e., IPSS QoL score.

[0108] In some embodiments, the subject has an IPSS score of ≧5, ≧8, or ≧10, Approximately 75 mg of vibegron is administered daily for the duration of treatment (e.g., 8 or 12 weeks). and experiencing a change from baseline in mean IPSS score, wherein said change is greater than or equal to placebo. The difference between the two is about -0.5 to about -2.5, e.g. For example, approximately -0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.1, -2.2, -2.3, -2.4, -2.5 or It ranges between any two of the above values.

[0109] In some embodiments, the subject is administered about 75 mg of vibegron per day; From baseline to mean IPSS score over the treatment period (e.g., 8 or 12 weeks): About -2.5 to about -5.0, for example, about -2.5, -2.6, -2.7, -2.8, -2.9, -3.0, -3.1, -3.2, -3.3 ,-3.4,-3.5,-3.6,-3.7,-3.8,-3.9,-4.0,-4.1,-4.2,-4.3,-4.4,-4.5,-4.6, It may experience changes ranging from -4.7, -4.8, -4.9, -5.0 or between any two of the above values.

[0110] The efficacy of treatment is evaluated in subjects with BPH over the treatment period (e.g., 8 weeks or 12 weeks). As measured by change from baseline in mean International Index of Erectile Function (IIEF) domain scores It is possible.

[0111] The 15-question IIEF questionnaire was used to assess erectile dysfunction and treatment outcomes in clinical trials. It is a validated, multidimensional, self-administered survey that has been found to be useful. The five main areas of sexual function are erectile function, orgasmic function, sexual desire, and sexual satisfaction. Participants are given a score from 0 to 5 for each of 15 questions that measure their overall satisfaction with the IIEF. No total score is generated, only domain scores are calculated.

[0112] In some embodiments, the subject has <25, <20, <15, or <10 erections prior to treatment. Patients with a functional domain score were administered approximately 75 mg of vibegron per day and had a treatment period (e.g. Changes from baseline in erectile function domain scores over a period of 8 or 12 weeks were assessed. where the change is greater than that of subjects taking a placebo. The difference from Sepo is about 5.0 to about 20.0, for example, about 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 , 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0 or 20.0, or any of the above values. The range is between one or the other.

[0113] In some embodiments, the subject has <8, <6, <4, or <2 orgasms prior to treatment. Patients with a ≥ 75 mg / day vibegron were randomly assigned to receive a ≥ 75 mg / day treatment with a ≥ 75 mg / day vibegron dose. Changes in orgasmic function domain scores from baseline over a period of 8 or 12 weeks subjects experience a change in the serotonin level that is greater than that of subjects taking a placebo. The difference from the Brasepo is about 2.0 to about 8.0, for example, about 2.0, 2.5, 3.0, 3.5, 4.0, 4. .5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5 or 8.0, or a range between any two of the above values It is.

[0114] In some embodiments, the subject has a sexual desire of <8, <6, <4, or <2 prior to treatment. domain score, receive approximately 75 mg of vibegron per day, and have a treatment duration (e.g., 8 experience a change from baseline in sexual desire domain scores over a period of 12 weeks or 7 days. Here, the change is greater than that of subjects taking a placebo. is about 2.0 to about 8.0, for example, about 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5 or 8.0, or a range between any two of the above values.

[0115] In some embodiments, the subject has an overall RR of <8, <6, <4, or <2 prior to treatment. had a satisfaction domain score, were administered approximately 75 mg of vibegron per day, and had a long treatment period (e.g. Changes in overall satisfaction domain scores from baseline over a period of 8 or 12 weeks (e.g., 8 or 12 weeks) subjects experience a change in the serotonin level that is greater than that of subjects taking a placebo. The difference from the Brasepo is about 2.0 to about 8.0, for example, about 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5. 0, 5.5, 6.0, 6.5, 7.0, 7.5, or 8.0, or a range between any two of the above values .

[0116] In some embodiments, the subject has <12, <10, <8, or <6 sexual intercourse episodes prior to treatment. Patients with a foot domain score were administered approximately 75 mg of vibegron per day and were maintained on treatment for the duration of the treatment (e.g. Changes from baseline in sexual satisfaction domain scores over a period of 1, 8 or 12 weeks were assessed. where the change is greater than that of subjects taking a placebo. The difference from Sepo is about 2.0 to about 10.0, for example, about 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 , 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0, or any two of the above values The range is between .

[0117] The safety of treatment will be evaluated over the treatment period (e.g., 8 or 12 weeks) in subjects with BPH. It can be measured by the change from baseline in post-void residual volume (PVR).

[0118] In some embodiments, the subject is administered about 75 mg of vibegron per day; Approximately 5 mL, 4 mL, or 3 mL reduction in PVR from baseline over the treatment period (e.g., 8 or 12 weeks) In some embodiments, the subject experiences an increase of no more than 2 mL or 1 mL per day. Patients were administered approximately 75 mg of vibegron each day, and the PVR over the treatment period (e.g., 8 or 12 weeks) was evaluated. Experience a decrease from baseline of at least about 1 mL, 2 mL, 3 mL, 4 mL, or 5 mL.

[0119] In some embodiments, the subject is administered about 75 mg of vibegron per day; From baseline to about -10 mL to about -20 mL of PVR over the treatment period (e.g., 8 or 12 weeks) L, e.g. about 10mL, 8mL, 6mL, 5mL, 4mL, 3mL, 2mL, 1mL, 0mL, -1mL, -2mL, -3mL, -4m L, -5mL, -6mL, -7mL, -8mL, -9mL, -10mL, -12mL, -14mL, -16mL, -18mL or -20mL, young or experience a change in the range between any two of the above values.

[0120] The efficacy of treatment is evaluated over the treatment period (e.g., 8 or 12 weeks) in subjects with BPH. Measured by change from baseline in the mean number of nocturia episodes per night This can be done.

[0121] In some embodiments, the subject has an average of ≥ 1, ≥ 2, or Patients with ≥3 nocturia episodes, receiving approximately 75 mg of vibegron per day, and receiving Based on the average number of nocturia episodes per night over a period (e.g., 8 or 12 weeks) subjects experience a change from baseline, where the change is the same as that of subjects taking a placebo The difference with the Brasepo is about -0.2 to about -1.5, for example, about -0.2, -0.3, -0.4, -0.5, -0.6, -0.7, -0.8, -0.9, -1.0, -1.1, -1.2, -1.3, -1.4 or -1.5, or is a range between any two of the above values.

[0122] In some embodiments, the subject is administered about 75 mg of vibegron per day; Baseline nocturia episodes per night over the treatment period (e.g., 8 or 12 weeks) From about -1.3 to about -2.5, for example, about -1.3, -1.4, -1.5, -1.6, -1.7, -1.8, -1.9 , -2.0, -2.1, -2.2, -2.3, -2.4 or -2.5, or a range between any two of the above values experience changes in

[0123] In some embodiments, the subject is administered about 75 mg of vibegron per day; Substantial changes in post-void residual (PVR) volume over the treatment period (e.g., 8 or 12 weeks) were assessed. No. Baseline blood pressure (BP) and heart rate (HR) in subjects taking vibegron The change from baseline was not substantially different from that observed in subjects taking placebo. In this embodiment, subjects receive placebo over the treatment period (e.g., 8 weeks or 12 weeks). Less than 2.0mm / Hg, less than 1.9mm / Hg, and less than 1.8mm / Hg from the mean maximum change in subjects taking , less than 1.7mm / Hg, less than 1.6mm / Hg, less than 1.5mm / Hg, less than 1.4mm / Hg, less than 1.3mm / Hg, 1.2mm / Hg less than 1.1mm / Hg, less than 1.0mm / Hg, less than 0.9mm / Hg, less than 0.8mm / Hg, less than 0.7mm / Hg, 0.6m Mean maximum change from baseline in systolic blood pressure (SBP) of less than m / Hg or less than 0.5 mm / Hg Experience.

[0124] In some embodiments, the subject is administered about 75 mg of vibegron per day; and subjects taking placebo for the treatment period (e.g., 8 or 12 weeks). Experience a mean maximum change from baseline in SBP of less than 2 mm / Hg. In some embodiments, the subject is administered about 75 mg of vibegron per day during the treatment period. The mean maximum change in subjects taking placebo over a period of time (e.g., 8 or 12 weeks) experience a mean maximum change from baseline in SBP of less than 1 mm / Hg.

[0125] In some embodiments, the subject is over 65 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects will experience a mean maximum change from baseline in SBP of less than 2 mm / Hg from the mean maximum change In some embodiments, the subject is over 65 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects experienced a mean maximum change from baseline in SBP of less than 1 mm / Hg below the mean maximum change do.

[0126] In some embodiments, the subject is over 45 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects will experience a mean maximum change from baseline in SBP of less than 2 mm / Hg from the mean maximum change In some embodiments, the subject is over 45 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects experienced a mean maximum change from baseline in SBP of less than 1 mm / Hg below the mean maximum change do.

[0127] In some embodiments, subjects receive and experiencing a mean maximum change from baseline in diastolic blood pressure (DBP), were less than 2.0 mm / Hg, 1.9 mm / Hg, and 1. Less than 8mm / Hg, Less than 1.7mm / Hg, Less than 1.6mm / Hg, Less than 1.5mm / Hg, Less than 1.4mm / Hg, Less than 1.3mm / Hg , less than 1.2mm / Hg, less than 1.1mm / Hg, less than 1.0mm / Hg, less than 0.9mm / Hg, less than 0.8mm / Hg, 0. Less than 7mm / Hg, less than 0.6mm / Hg, or less than 0.5mm / Hg.

[0128] In some embodiments, the subject is administered about 75 mg of vibegron per day; The mean maximum placebo-received mortality rate for subjects over the treatment period (e.g., 8 or 12 weeks) experience a mean maximum change from baseline in DBP of less than 2 mm / Hg from a major change. In an embodiment, a subject is administered about 75 mg of vibegron per day for the duration of treatment (e.g., For example, 1 mm from the mean maximum change in subjects taking placebo over a period of 8 or 12 weeks. experience a mean maximum change from baseline in DBP of less than 1 / Hg.

[0129] In some embodiments, the subject is over 65 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects will experience a mean maximum change from baseline in DBP of less than 2 mm / Hg from the mean maximum change In some embodiments, the subject is over 65 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects experienced a mean maximum change from baseline in DBP of less than 1 mm / Hg from the mean maximum change do.

[0130] In some embodiments, the subject is over 45 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects will experience a mean maximum change from baseline in DBP of less than 2 mm / Hg from the mean maximum change In some embodiments, the subject is over 45 years of age and is receiving about 75 mg of vibegron per day. Subjects will receive a placebo for the duration of the treatment (e.g., 8 or 12 weeks). Subjects experienced a mean maximum change from baseline in DBP of less than 1 mm / Hg from the mean maximum change do.

[0131] In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron once daily. Subjects who are given the drug and take a placebo for the treatment period (e.g., 8 or 12 weeks) Mean maximum change from baseline in DBP of less than 1 mm / Hg from the mean maximum change during the treatment period The mean maximum change in subjects taking placebo over a period of time (e.g., 8 or 12 weeks) experience a mean maximum change from baseline in SBP of less than 1 mm / Hg.

[0132] In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron once daily. Subjects who are given the drug and take a placebo for the treatment period (e.g., 8 or 12 weeks) mean maximum change from baseline in DBP of less than 1 mm / Hg from the mean maximum change in DBP over the treatment period The mean maximum change in subjects taking placebo over a period (e.g., 8 or 12 weeks) experience a mean maximum change from baseline in SBP of less than 1 mm / Hg.

[0133] In some embodiments, subjects receive Less than 10mm / Hg, less than 9.5mm / Hg, less than 9mm / Hg, less than 8.5mm / Hg, less than 8mm / Hg, less than 7.5mm / Hg systolic blood pressure less than 7mm / Hg, less than 6.5mm / Hg, less than 6mm / Hg, less than 5.5mm / Hg, or less than 5mm / Hg experience mean maximum change from baseline in blood pressure (SBP).

[0134] In some embodiments, the subject is administered about 75 mg of vibegron per day; A mean SBP decrease of less than 10 mm / Hg from baseline over the treatment period (e.g., 8 or 12 weeks) experience the maximum average change.

[0135] In some embodiments, the subject is over 65 years of age and is receiving about 75 mg of vibegron per day. and a 10 mm reduction in SBP from baseline over the treatment period (e.g., 8 or 12 weeks) / Hg.

[0136] In some embodiments, the subject is over 45 years of age and is receiving about 75 mg of vibegron per day. and maintain a mean blood glucose level of >10 mm / Hg from baseline over the treatment period (e.g., 8 or 12 weeks). experience a mean maximum change in SBP of 100 mg / kg / day.

[0137] In some embodiments, subjects receive Less than 7mm / Hg, less than 6.5mm / Hg, less than 6mm / Hg, less than 5.5mm / Hg, less than 5mm / Hg, less than 4.5mm / Hg , less than 4mm / Hg, less than 3.5mm / Hg, less than 3mm / Hg, less than 2.5mm / Hg, or less than 2mm / Hg, baseline The mean maximum change in diastolic blood pressure (DBP) from the in-group was experienced.

[0138] In some embodiments, the subject is administered about 75 mg of vibegron per day; Mean DBP < 7 mm / Hg from baseline over the treatment period (e.g., 8 or 12 weeks) experience the greatest change.

[0139] In some embodiments, the subject is over 65 years of age and is receiving about 75 mg of vibegron per day. and maintain a mean blood glucose level of >7 mm / Hg from baseline over the treatment period (e.g., 8 or 12 weeks). experience a mean maximum change in DBP of 100.

[0140] In some embodiments, the subject is over 45 years of age and is receiving about 75 mg of vibegron per day. and maintain a mean blood glucose level of >7 mm / Hg from baseline over the treatment period (e.g., 8 or 12 weeks). experience a mean maximum change in DBP of 100.

[0141] In some embodiments, the subject is over 45 years of age and is administered about 75 mg of vibegron once daily. and maintain a D of <7 mm / Hg from baseline over the treatment period (e.g., 8 or 12 weeks). The mean maximum change in BP and baseline SBP over the treatment period (e.g., 8 or 12 weeks) were experience a mean maximum change of less than 10 mm / Hg from the in.

[0142] In some embodiments, the subject is over 65 years of age and is administered about 75 mg of vibegron once daily. and a reduction of 7 mm / Hg from baseline in DBP over the treatment period (e.g., 8 or 12 weeks) The mean maximum change in SBP over the treatment period (e.g., 8 or 12 weeks) was experience a mean maximum change of less than 10 mm / Hg from the in.

[0143] Pharmaceutical unit dose composition The present disclosure provides a pharmaceutical unit dose composition comprising a dosage amount of vibegron disclosed herein. wherein the unit dose composition is suitable for oral administration. Oral dosage forms include, for example, Forms that are understood by those skilled in the art to include liquid formulations, tablets, capsules, gelcaps, and the like. In some embodiments, the unit dose composition is in the form of a tablet or capsule. In some embodiments, the unit dose composition is a tablet. .

[0144] Pharmaceutically acceptable excipients include lactose, microcrystalline cellulose, starch, calcium carbonate, etc. Sodium, Magnesium Stearate, Stearic Acid, Talc, Colloidal Silicon Dioxide, Mannitol, croscarmellose sodium, hydroxypropyl cellulose, etc. In some embodiments, the excipients disclosed herein are generally recognized as safe. The pharmaceutical unit dose compositions described herein include diluents, disintegrants, binders, and lubricants. Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000) See, which is incorporated herein by reference in its entirety.

[0145] In one embodiment, the pharmaceutical unit dose composition disclosed herein comprises mannitol, Crystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and and magnesium stearate.

[0146] Oral dosage forms can be prepared by standard pharmaceutical manufacturing techniques. These include, for example, wet granulation, wet milling, fluid bed drying, dry milling, lubrication, tableting, and aqueous filling. Includes film coating.

[0147] In some embodiments, the pharmaceutical unit dose composition of the present disclosure comprises from about 50 mg to about 100 mg. Includes vibegron.

[0148] In some embodiments, the pharmaceutical unit dose composition of the present disclosure comprises from about 55 mg to about 100 mg, About 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, or about 95 mg to about 100 mg Including Gron.

[0149] In some embodiments, the pharmaceutical unit dose composition of the present disclosure comprises from about 50 mg to about 95 mg, about 50mg to about 90mg, about 50mg to about 85mg, about 50mg to about 80mg, about 50mg to about 75mg, about 50mg to About 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, or about 50 mg to about 55 mg of vibegron. nothing.

[0150] In some embodiments, the pharmaceutical unit dose composition of the present disclosure comprises from about 60 mg to about 90 mg, about In some embodiments, the composition comprises about 65 mg to about 85 mg, or about 70 mg to about 80 mg of vibegron. Thus, the pharmaceutical unit dose compositions of the present disclosure may contain between 60 mg and 90 mg, between 65 mg and 85 mg, or between 70 mg and 80 mg. Includes vibegron.

[0151] In some embodiments, the pharmaceutical unit dose composition of the present disclosure comprises about 55 mg, about 60 mg, about 65 mg, mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg or about 95 mg of vibegron. In some embodiments, the pharmaceutical unit dose composition of the present disclosure contains about 75 mg of vibegron. In some embodiments, the pharmaceutical unit dose composition of the present disclosure comprises 75 mg of vibegron.

[0152] In some embodiments, the AUC 0-inf is approximately 500ng·hr / mL to approximately 1800 ng·hr / mL.

[0153] In some embodiments, the C after a single dose of vibegron max ranges from about 30ng / mL to about 200 ng / mL.

[0154] In some embodiments, the T max Approximately 2 to 3 hours Between.

[0155] In some embodiments, the T after a single dose of vibegron 1 / 2 Approximately 50 to 70 hours Between.

[0156] In some embodiments, after a single administration of vibegron, the AUC 0-inf is about 500ng·hr / mL Approximately 1800 ng·hr / mL, C max is about 30 ng / mL to about 200 ng / mL, and T max From about 2 hours About 3 hours, T1 / 2 is about 50 to 70 hours.

[0157] In some embodiments, the AUC after multiple administration of vibegron 0-inf is about 500ng·hr / mL to approximately 3000 ng·hr / mL.

[0158] In some embodiments, the C after a single dose of vibegron max ranges from about 40 ng / mL to about 400 ng / mL.

[0159] In some embodiments, the T after multiple administrations of vibegron max From about 1 hour to about 3 hours Between.

[0160] In some embodiments, the T after multiple administrations of vibegron 1 / 2 Approximately 70 to 80 hours It's time.

[0161] In some embodiments, after multiple administrations of vibegron, the AUC 0-inf is about 500ng·hr / mL to approximately 3000 ng·hr / mL, and C max is about 40 ng / mL to about 400 ng / mL, and T max Approximately 1 hour It is about 3 hours from T 1 / 2 is about 70 to 80 hours.

[0162] In vitro assay Vibegron was tested in several in vitro assays to assess its agonism at the human β3-AR. The efficacy of β-AR in humans, its selectivity for other human β-AR subtypes, and its activity on β3-AR from other species The efficacy of was evaluated.

[0163] Vibegron activity was assessed in Chinese hamster ovary (CHO) mice stably expressing human β3-AR. ) measured in a functional assay that measures the increase in cellular adenylyl cyclase activity in cells. The degree of activation in response to a proven full agonist (isoproterenol) was determined by the compound EC 50 was measured together.

[0164] Vibegron is a potent and selective agonist of the β3-AR with an EC 50 and Isopro It has 84% ​​activation compared to loterenol. The EC 50 = 1.7 nM, 102% activity), the low plasma protein binding of this compound ( This coincides with 49% unbound in humans.

[0165] Furthermore, the selectivity of vibegron for β3-AR over β1-AR and β2-AR subtypes was This was determined by testing in CHO cells expressing either the β1-AR or the β2-AR. Glon is highly selective for the β3-AR versus the β1-AR and β2-AR, and is a cell-based inhibitor of 9000-fold more potent in activating the β3-AR than the β1-AR or β2-AR in in vitro functional assays It shows selectivity exceeding that of

[0166] Bibegron IC 50 were prepared from cells expressing recombinant β1-AR, β2-AR or β3-AR. The binding of vibegron to the membrane was assessed in a standard competitive binding assay. Assay with non-specific β-AR radiolabeled antagonist 125 β3-AR IC to compete with I-CYP 50 = 193 nM (86 ng / mL). The relative lack of binding affinity compared to antagonist activity was not observed in any of the antagonist binding assays. This relates to the relative ability of a compound to compete for unbound versus bound receptors as measured by In addition, the compounds have been shown to bind to either the β1-AR or the β2-AR as shown by binding competition assays. The compound does not bind to either of these receptors and is neither an agonist nor an antagonist at these receptors. I have confirmed that this is not the case.

[0167] <Animal Model> Tests for OAB and BPH have been conducted in species including rats, mice, rabbits, guinea pigs, dogs, and pigs. A partial bladder outlet obstruction (BOO) animal model was used in this study. The common method involves narrowing the diameter of the urethra by ligating it through a transperitoneal or transperineal incision. (See, for example, Int. J. Urology (2018) 25, 36-44.) It can be used to record the interval and pressure of non-voiding contractions (NVC). Changes in these parameters following administration of a therapeutic agent such as rituximab may indicate that a particular treatment is effective in treating BPH in humans. It can be shown whether a compound is useful for treating a disease.

[0168] <Absorption, distribution, metabolism, and excretion> Vibegron achieves maximum plasma concentrations approximately 1 to 3 hours after oral administration in healthy volunteers. (C max ) is reached. max and AUC increased dose-proportionally up to 400 mg. Concentrations were achieved within 7 days of once-daily administration of vibegron. Steady-state AUC Geometric mean accumulation rate was less than 2 in young male subjects and less than 2.8 in elderly subjects (male and female). Vibegron exposure in female subjects was significantly higher than that in foreign young male subjects. There was a moderate increase (less than 2-fold) after a single dose.

[0169] Multiple oral doses of 150 mg of vibegron with food in healthy middle-aged and elderly women The doses administered were 42% and 59% lower on day 1 and 20% lower on day 14 compared to the same dose administered in the fasted state. Below and 43%, the mean AUC 0-24 Value and average C max brought value.

[0170] A Two-Part, Open-Label, Single-Dose Study to Investigate the Pharmacokinetics of Vibegron in Patients With Hepatic Failure In studies, the apparent volume of distribution (Vd / F) of vibegron was approximately 9120 L. is bound to human plasma proteins (approximately 49%).

[0171] Vibegron is eliminated via various pathways, including urinary excretion, biliary excretion, and hepatic metabolism. CYP3A4 is the predominant CYP involved in in vitro metabolism, but metabolism is not involved in the elimination of vibegron. Mass balance in healthy subjects In the study, the majority of the recovered dose was eliminated as unchanged vibegron. The average total recovery of radioactivity was 79%, with approximately 59% and 20% of the dose recovered in feces and urine, respectively. .

[0172] The majority of the vibegron dose was found to be eliminated as unchanged parent drug. Seven minor metabolites were detected in the feces, six of which (M1, M3, M4, M6, M11, and M17) were oxidized. Metabolite M7 was an O-glucuronide conjugate of vibegron. The plasma 14C" The concentration of radioactivity derived from vibegron is average C max is 0.3 μM, T max 2 The radioactivity profiles of the 2- and 4-hour plasma samples were Less than 78% and 73%, respectively, were accounted for by unchanged vibegron, while the O-glucuronide ( M7) are the predominant circulating metabolites (<12-14% of all circulating drug-related substances). Two additional minor oxidative metabolites, M4 (4-6%) and M17 (6-7%), were also detected in human plasma. Radioactivity in plasma samples at other time points beyond 4 hours post-dose was too low to be profiled The potential for accumulation of circulating metabolites in plasma was examined post-mortem to allow estimation of half-lives. There was insufficient data from this time point to estimate.

[0173] Vibegron reduced terminal t 1 / 2 has. At steady state, mean renal clearance (CLR) in young men ranged from 150 to 187 m at all dose levels. L / min, whereas the CLR in older adults (males and females) was slightly lower at 127 mL / min. With increasing dose, reflecting the increasing bioavailability as the dose increases. Steady state (fe 0-24hr There was a trend towards an increased proportion of the dose excreted in the fe 0-24hr , The ss was similar in young men and older men, being less than 14% at 100 mg and 150 mg in young men and less than 14% at 150 mg in older men. The average fe in young Japanese subjects was less than 17% at 100 mg. 0-24hr and C.L. R is a foreigner This was similar to what was observed in human subjects.

[0174] Example 1 Vibegron Tablet Formulation

[0175] The composition of vibegron tablets (50 mg, 75 mg, and 100 mg) is shown in Table 1.

[0176] [Table 1]

[0177] Example 2 Pharmacokinetic Data 2.1 Single-dose pharmacokinetics

[0178] The single-dose pharmacokinetics of vibegron were evaluated in two double-blind, randomized, placebo-controlled, single-ascending oral All subjects were healthy adults. The results are summarized in Table 2. After single oral vibegron doses ranging from 2 to 600 mg, the mean t max Between 0.8 and 3 hours after administration In healthy young male subjects, terminal elimination t 1 / 2 averaged 43 to 75 hours. Systemic exposure was greater than dose-proportional up to 600 mg.

[0179] Exposure to vibegron in young Japanese men was moderately increased compared with exposure in young non-Japanese men. Vibegron AUC 0-inf and the corresponding 90% confidence intervals of the geometric mean ratio (GMR; Japanese / foreign The mean mean mean 1.75 (1.38, 2.23) at 10 mg and 1.17 (0.99, 1.4) at 300 mg were observed with increasing dose. 0). GMR (Japanese / foreign) and vibegron C max The 90% confidence intervals for The effect of 1.75 (1.35, 2.26) on the efficacy and safety of 1.75 in patients with 1.35-fold increased creatinine levels in the 1.35-fold increase in ... T for Japanese subjects max Median values ​​(1-3 hours) and harmonic mean apparent terminal t 1 / 2 Estimated value (58~ 71 hours) was similar to that of foreign subjects. AUC 0-inf and C max appeared to increase proportionally with dose up to 300 mg.

[0180] Pharmacokinetics of a single dose of 50 mg vibegron in foreign elderly male and female subjects The clinical features are also shown in Table 2. In elderly male and female subjects, Average AUC 0-inf and C max compared with the corresponding values ​​after a 50 mg dose in young men, respectively. The results were approximately 70% lower and 60% higher. max was similar to that observed in younger men (median T max = 1.0 hours) is the apparent final time t 1 / 2 was slightly longer in older people compared with younger people (survey Sum average t 1 / 2 Exposure to vibegron in elderly women was somewhat higher than in elderly men. I did.

[0181] [Table 2]

[0182] 2.2 Multiple-dose pharmacokinetics

[0183] The multiple-dose pharmacokinetics of vibegron were evaluated in healthy non-Japanese young male subjects, middle-aged male subjects, and Female subjects, elderly male and female subjects, and healthy young male Japanese subjects Two randomized, double-blind, placebo-controlled trials in adult and elderly male and female subjects. A multiple ascending dose Phase 1 study was conducted. Foreign subjects received multiple doses ranging from 25 to 400 mg. for 7 to 28 days, while Japanese subjects received multiple doses of 50 to 200 mg for 14 days. The pharmacokinetic results after 14 days of dosing are summarized in Table 3.

[0184] On average, women tend to have 50% higher exposure (AUC) compared to men, regardless of age. Steady-state AUC and C after QD administration of 100 mg vibegron in elderly subjects max Value is young Compared to men, the rates were approximately 1.7 and 1.3 times higher, respectively.

[0185] GMC max and the AUC accumulation ratios were 1.78 and 1.84 for Japanese subjects at the 200 mg dose level. On average, the steady-state exposure of young Japanese male subjects was 100% higher than that of young foreign male subjects. The difference in exposure was statistically significant. Pooled vibegron AUC and C across subjects and doses max The corresponding 90% confidence interval for The mean mean ages were 1.27 (1.09, 1.48) and 1.33 (1.06, 1.67), respectively.

[0186] On average, steady-state exposure on day 14 in elderly Japanese male and female subjects was: 35% higher than those in foreign elderly male and female subjects, and the difference in exposure was statistically significant. The AUC of vibegron in GMR (Japanese / foreigners) and elderly panel on day 14 was significant. 0-24 and C max The corresponding 90% confidence intervals for were 1.35 (1.09, 1.68) and 1.82 (1.32, 2.51), respectively. ) was.

[0187] [Table 3]

[0188] 2.3 Bioavailability and bioequivalence

[0189] Five Phase 1 trials have been conducted using the capsule formulation of Vibegron, while seven Phase 1 trials have been conducted using the capsule formulation of Vibegron. The first and one Phase 2b study used a tablet formulation. In an open-label, randomized, two-period crossover PK study, vibegron capsules (1 x 150 mg) The single-dose pharmacokinetics of the 50 mg capsule (100 mg capsule) and tablet (3 × 50 mg tablets) formulations were compared.

[0190] The tablet formulation provided comparable exposure to the capsule formulation, as shown in Table 4. max And see The End of the World 1 / 2 was also similar between the two formulations.

[0191] [Table 4]

[0192] In this open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover Phase 1 study, The relative bioavailability of two slightly different tablet types: aqueous (test) and non-aqueous (reference) tablets. Physical equivalence was evaluated.

[0193] [Table 5]

[0194] 2.4 Effect of food on oral absorption

[0195] The effect of food on the single-dose pharmacokinetics of vibegron 50 mg was evaluated in two randomized, double-blind, randomized, placebo-controlled trials. A placebo-controlled, single-dose, ascending-dose phase 1 study was evaluated in healthy young non-Japanese and Japanese men. On the other hand, the effect of food on the pharmacokinetics of multiple doses of vibegron 150 mg in middle-aged women was Efficacy was evaluated in a randomized, double-blind, placebo-controlled, multiple ascending dose Phase 1 study. A summary of the behavioral results is shown in Table 6.

[0196] When 50 mg of vibegron was administered to young foreign men with a high-fat meal, the results were comparable to those of the fasting Compared with AUC 0-inf and C max decreased by 46% and 67%, respectively, and T max Delays of less than an hour occurred. When young Japanese men were administered 50 mg of vibegron with a standard Japanese breakfast, AU C 0-inf and C max were reduced by 37% and 52%, respectively, compared with the same dose with a high-fat meal. The findings are nearly identical to those of the foreign male subjects who were administered the drug.

[0197] Multiple oral doses of 150 mg of vibegron administered with food in healthy middle-aged women On day 14, compared with the same dose in the fasted state, the mean AUC 0-24 Time and C max 20% of This resulted in a 47% decrease in T max is delayed in the fed state compared to the fasted state (6.0 hours vs. 2.0 hours).

[0198] [Table 6]

[0199] 2.5 Pharmacokinetics in target disease populations

[0200] A randomized, double-blind, placebo- and active-controlled, parallel-group, two-part phase 2b study in patients with OAB In the experiment, the sparse Bibegron trough concentration (C trough) was measured; vibegron 50 mg and and 100mgQD mean (±SD) C trough were 27.4 (±18.3) ng / mL and 73.6 (±65.5) n The mean (±SD) C of vibegron 50 mg in healthy young men was trough is 15.2 (±5.07) ng / mL. The mean (±SD) C trough Values, healthy young man The mean age-related morbidity ranged from 31.9 (± 11.5) in unaffected individuals to 54.2 (± 15.3) in healthy older adults.

[0201] Example 3 Pharmacokinetics in Special Populations 3.1 Effect of age

[0202] Vibegron exposure was assessed in young (18 to 45 years), middle-aged (46 to 64 years), and elderly (65 to 85 years) Exposure was assessed in middle-aged men compared with younger men. However, plasma concentrations were higher in elderly compared with middle-aged and younger subjects. Vibegron AUC after a single dose of 0-inf and C max was significantly higher in older subjects compared to younger subjects. In a randomized, double-blind, placebo-controlled, single-dose ascending study, removal t 1 / 2 The mean mean time to death was 92 hours in the elderly compared with 52 hours in the younger subjects. Vibegron AUC 0-24h and C max Values ​​are from a randomized, double-blind, placebo-controlled, multiple ascending dose study In comparison with younger men, the rates were 1.7 and 1.3 times higher in older men, respectively. Furthermore, the steady-state AUC geometric mean accumulation ratio was ≤2 in young men and ≤2.8 in elderly men. In elderly Japanese people, AUC 0-24 and C.max are approximately 35% or less compared to elderly foreigners. and increased by 82%.

[0203] 3.2 Gender influence

[0204] The effect of gender on steady-state vibegron exposure after dosing with 100 or 150 mg in a randomized, double-blind The plasma concentrations of vibegron were evaluated in a placebo-controlled, multiple ascending dose study in young men and When compared, middle-aged men were similar; however, exposure was higher in middle-aged women compared with middle-aged men. The steady-state AUC was slightly higher in middle-aged women than in older women (~1.5-fold higher in steady-state women), which is consistent with the exposure in older women. This was also observed when comparing exposure to older men with that of older women.

[0205] 3.3 Effects of renal dysfunction

[0206] In 24 patients with renal dysfunction (8 severe, 8 moderate, and 8 mild), The pharmacokinetics of a single dose of vibegron 100 mg was evaluated in eight healthy controls in an open-label, single-dose PK study. A summary of pharmacokinetic parameters and the results of the study were compared between subjects with various degrees of renal impairment. Statistical comparisons between the control and healthy matched subjects are shown in Table 7.

[0207] Mild (eGFR ≥ 60 to < 90 mL / min / 1.73 m2), moderate (eGFR ≥ 30 to < 60 mL / min / 1.73 m2 ), and in severely ill (eGFR < 30 mL / min / 1.73 m2, but not on dialysis) patients Gron AUC 0-inf In the 14-week study, renal dysfunction was 49% and 18% greater, respectively, than in the 14-week study compared with healthy matched control subjects. 06% and 83% higher in patients with mild, moderate, and severe renal impairment. max teeth, These were 96%, 68%, and 42% higher, respectively, compared with healthy matched control subjects. The worsening of renal dysfunction was associated with an increase in vibegron AUC 0-inf is associated with an increase in C max So it is clear No significant trends were observed. Decreased renal function was associated with decreased clearance. The relationship between AE and renal function was modeled using linear regression. Based on the slope from the regression, We found that CL / F increased by 0.8% for every mL / min / 1.73m2 increase in eGFR. CL / F ratios for mild, moderate, and severe populations compared to healthy subjects based on linear relationships were predicted to be 0.81, 0.64, and 0.50, respectively. The corresponding prediction ratios for AUC were 1.2 4, 1.57, and 2.00. The relationship between CL / F and creatinine clearance was modeled as Similar results were obtained. Renal clearance (CLR) and 48-hour collection interval (fe[urine]48hr ) decreased with increasing degree of renal impairment. In patients with mild, moderate, and severe renal impairment, compared with healthy matched control subjects The CLR decreased by 39%, 65%, and 82%, respectively. fe[urine]48hr was indicative of mild renal dysfunction. The incidence of moderate and severe renal disease was similar between patients (8.5%) and healthy matched control subjects (7.9%). In patients with functional impairment, the rates were 5.5% and 2.1%, respectively.

[0208] [Table 7]

[0209] 3.4 Effects of liver dysfunction

[0210] The pharmacokinetics of a single dose of vibegron 100 mg was evaluated in 8 patients (7 (Child-Pugh score of 9 or higher) and a two-part, open-label, single-dose Phase 1 study The study was evaluated in eight healthy subjects matched for age, sex and BMI. A statistical comparison of the pharmacokinetic parameters of the drug is shown in Table 8. AUC 0-inf and C max The GMR (90%CI) was 1.27 (0.96, 1.67) and 1.35 (0.88, 2.06), respectively. and moderate hepatic impairment did not have a clinically significant effect on vibegron exposure. This suggests that...

[0211] [Table 8]

[0212] 3.5 Drug interaction studies

[0213] Four drug interaction studies were conducted evaluating vibegron in combination with six compounds. Table 9 shows the effect of ketoconazole, diltiazem, or tolterodine on the pharmacokinetics of vibegron. Table 10 summarizes the effects of digoxin, ethinyl estradiol, and levothyroxine on the pulmonary circulation. The effects of vibegron on the pharmacokinetics of bonorgestrel or tolterodine are summarized below. That is why.

[0214] Ketoconazole 200mg, a strong CYP3A4 / P-gp inhibitor, and moderate CYP3A4 / P-gp inhibitor Multiple doses of diltiazem 240 mg, a serotonin-releasing agent, were evaluated in combination with a single dose of vibegron 100 mg. The AUC of GM Vibegron 0-inf and C maxThe current study has demonstrated that multiple doses of 200 mg ketoconazole The AUC of GM Vibegron increased by 2.08 and 2.22 times, respectively. 0-inf and C max is 240 mg or 180 mg of multiple doses of diltiazem increased by 63% and 68%, respectively. 1 / 2 Vibegron was administered alone, with diltiazem, or with ketoconazole. The mean time to death for ketoconazole or zilch was 75, 75.4, and 80.2 hours, respectively. Vibegron t in the presence of Azem 1 / 2 The lack of an increase in β indicates that the interaction occurred primarily in the absorption phase. However, these interactions are not expected to be clinically significant. No. Tolterodine ER 4 mg did not affect the pharmacokinetics of vibegron.

[0215] Multiple doses of vibegron were evaluated in combination with the p-gp substrate digoxin. AUC of digoxin when coadministered with Glon 0-inf The 90% CI of the GMR is 80 to 125% for biological equality. The pharmacokinetic profile of vibegron was within the range of 0.01 mg / kg / day, indicating that vibegron does not affect the pharmacokinetics of digoxin to a clinically significant extent. The study suggests that there is no effect of ethinyl ethoxylates, two common ingredients in oral contraceptives. The pharmacokinetics of streptomycin (EE) and levonorgestrel (LNG) differs with multiple doses of vibegron. The 90% CI of GMR for AUC (EE / LNG and vibegron to E E / LNG only) and EE C max were within the range of 0.8 and 1.25. max teeth , increased by 18–21% in the presence of multiple doses of vibegron, but these increases were not clinically significant. Vibegron 100 mg or 150 mg was coadministered with tolterodine ER 4 mg. No clinically significant pharmacokinetic interactions occur when

[0216] [Table 9]

[0217] [Table 10]

[0218] Drug interactions between vibegron and metoprolol succinate, a moderately sensitive CYP2D6 substrate A pharmacokinetic study to evaluate the efficacy and safety of morphine was also completed. All subjects were healthy adults. A summary of the results is shown in Table 11. Subjects received metoprolol succinate on day 1 along with 10 mg warfarin. 100 mg of lorlatinib administered as a single dose, 75 mg of vibegron administered QD on days 8 to 16, and 75 mg of vibegron administered QD on day 17. 75 mg was administered concomitantly with metoprolol succinate 100 mg and warfarin 10 mg on days 18 to 23. Vibegron 75 mg QD was administered. The study treatment was well tolerated and had no significant effect during coadministration with vibegron. There was no evidence of increased adverse events. max and the AUC value is The elimination half-life of metoprolol was slightly increased in the presence of vibegron. The same was true when administered with vibegron, suggesting that CYP2D6 is unlikely to be inhibited. The time course of plasma concentrations of metoprolol alone was similar to that seen with metoprolol and vibegron. The profile was similar to that observed in the control group (Figure 3).

[0219] [Table 11]

[0220] 3.6 Effect on QT interval prolongation

[0221] The effect of vibegron on the QT interval was evaluated in a single oral dose study. Subjects were randomly assigned to receive a single dose of vibegron 400 mg, a single dose of vibegron 200 mg, or moxifloxacin. They received a single dose of 400 mg of Cin and a single dose of matching placebo.

[0222] A 400 mg dose of vibegron resulted in a QTcF interval of 4.60 (2.71, 6.48) milliseconds at 1 hour after administration. The 200 mg single dose yielded the largest least squares mean difference (90% CI) from placebo. The greatest least squares mean (90% CI) difference from placebo was 1 hour after dosing. The upper bounds of the 90% CIs for all mean differences were within the target of 10 ms. The statistically significant effect of moxifloxacin on QTcF was less than 100 ms (Table 12). was observed.

[0223] GM(CV%) achieved after a single dose of 200 mg max and AUC 0-23.5hr are 366(5 0.4) ng / mL and 2270 (37.3) ng·h / mL. max The study was conducted in a double-blind randomized controlled trial. In a placebo-controlled, alternating (Panels A and B) multi-period, single-dose, oral Phase 1 study, multiple doses of 100 mg were administered. This was 1.63 times the value obtained in the elderly patients who received 400 mg of ketamine, and the AUC was similar. GM(CV%)C max and AUC 0-23.5hr were 1020 (39.9) ng / mL and 6450 (34.0 ) ng·h / mL. max and AUC 0-23.5hr The values ​​were obtained by administering 100 mg of vibegron multiple times. These are 4.55 and 2.89 times the values ​​obtained in the elderly subjects given the same dietary intake.

[0224] Target PK exposures were achieved at both the 200 mg and 400 mg dose levels. Highest clinical dose of 100 mg Steady-state C achieved in elderly female subjects at max and AUC 0-24hr The values ​​were 278 ng / mL, respectively. and 2620 ng·h / mL.

[0225] [Table 12]

[0226] Example 4 Clinical Efficacy Data

[0227] Vibegron in men and women with OAB (stratified as OAB wet and OAB dry) A randomized, double-blind, placebo- and active-controlled, parallel-group, two-part Phase 2b study was completed. Part 1 included: This is a dose-finding study to evaluate the safety, tolerability, and efficacy of vibegron. This was a proof-of-concept study of combination therapy with tolterodine ER 4 mg. Subjects were randomized equally in a double-blind fashion to one of seven treatment arms: vibegron 3 mg , vibegron 15 mg, vibegron 50 mg, or vibegron 100 mg administered once daily for 8 weeks; toltero placebo once daily for 8 weeks; or vibegron 50 mg tol Part 2 will be administered in combination with terodine ER 4 mg for 4 weeks, followed by vibegron 50 mg for 4 weeks. Part 2 was designed to continue to evaluate the safety and efficacy of the combination. Subjects were randomized in a double-blind fashion in a 2:2:2:1 ratio to one of four treatment arms: Vibegron 100 mg, tolterodine ER 4 mg, vibegron 100 mg with tolterodine ER 4 mg, or placebo Part 1 and Part 2 subjects will be enrolled in a one-year extension. Participants kept a voiding diary and recorded symptoms of strong urge, complete incontinence, and urge incontinence. The occurrence of each episode of urge incontinence had to be recorded. Efficacy data from Phase 2 are summarized here.

[0228] At baseline, subjects were required to have an average of 8 or more voids per diary day. In addition, subjects in the OAB wet group were required to have urinary frequency of ≥1 urinary stool per day on average. The subjects in the OAB dry group were required to have experienced urgency incontinence episodes of 1 or more per day. Urge incontinence episodes averaging 3 or more times per day and less than 1 episode per day For all subjects, the total number of urge incontinence episodes was The total number of sexual incontinence episodes had to be exceeded.

[0229] The primary objective of this study is to evaluate the efficacy and safety of selected doses of vibegron (alone or in combination with tolterodine) To evaluate the safety and tolerability of treatment at week 8 and to compare dose-related mean daily The objective of this study was to investigate the reduction in mean micturition frequency.

[0230] In part 1, vibegron 100 mg and 50 mg treatments were compared with placebo at week 8 A statistically significant reduction in mean daily urination frequency was observed in the serotonin-releasing hormone (SHR) group compared with placebo. Statistically significant reduction from incontinence in both urge and total incontinence (OAB wet subjects) and secondary endpoints including urgency episodes in all subjects , and was also observed in the vibegron 100 mg and 50 mg treatment groups. A statistically significant increase from the 15 mg, 50 mg, and 100 mg vibegron treatment groups was observed in seizures per void. This was also observed in the candidacy endpoint of urinary output (Tables 13 and 14).

[0231] [Table 13]

[0232] [Table 14]

[0233] Designed to evaluate the safety and efficacy of vibegron in men and women with OAB completed a double-blind, randomized, placebo-controlled, multicenter Phase 3 study with a placebo run-in period. Upon completion, 1,232 patients were randomized to receive 12 weeks of blinded study treatment, which included: : Vibegron 50 mg (N = 370), Vibegron 100 mg (N = 369), placebo (N = 369), or imidazolium stearate (IMS) Dafenacin 0.2 mg (comparator; N=117). Results showed that once-daily vibegron reduced urination, Efficacy parameters included UUI episodes, total urinary incontinence episodes, and urgency episodes. The results show that this resulted in a statistically significant reduction (Table 15).

[0234] [Table 15]

[0235] Example 5 Safety Data 5.1 Phase I Safety Data

[0236] 15 completed Phase 1 trials and 1 trial that was terminated early (which did not provide any evidence of efficacy or safety) Safety data from 16 phase 1 trials were collected, including one that was terminated for reasons unrelated to CR. A total of 466 subjects received at least one dose of vibegron in the Phase 1 program 238 subjects received a single dose ranging from 2 to 600 mg, and 238 subjects received multiple doses ranging from 25 to 400 mg. Patients received multiple doses over a maximum period of 28 days. Across the Phase 1 program, vibegron was generally well tolerated. No treatment-related serious adverse events (SAEs) or deaths were reported, and The majority of adverse events (AEs) were transient and mild or moderate in severity.

[0237] Phase 1 trials included patients with and without symptoms (e.g., lightheadedness, dizziness, vertigo). Regardless of the cause, orthostatic hypotension (a decrease in systolic blood pressure of more than 20 mmHg and / or a decrease in diastolic blood pressure of more than 10 mmHg) There were isolated incidences of decreased blood pressure during the first 24 hours of treatment with vibegron 100 mg or 150 mg and tolterodine ER. The incidence of orthostatic AEs after coadministration of vibegron and tolterodine at 4 mg was 100% higher than that after administration of vibegron or tolterodine alone. The incidence of these AEs was similar in both groups. AEs such as postural dizziness, dizziness, fainting dizziness, and syncope did not show a clear dose-response relationship. However, postural dizziness appears to increase at doses of 100 mg or more, and the AE "symptomatic onset of dizziness" was The incidence of postural hypotension tended to be higher with doses of vibegron above 200 mg. Toprolol (a typical beta blocker) or amlodipine (a typical vasodilator) Vibegron 100 mg was coadministered to subjects with essential hypertension on any stable regimen When administered, no orthostatic AEs occurred.

[0238] A review of the preliminary Phase 1 safety data included laboratory safety parameters (chemistry, hematology, and There were no clinically significant changes in urine analysis or ECG parameters, including PR, QRS, and QTc intervals. A thorough QT study has been completed and no clinically significant effects on QTc or blood pressure have been reported. It couldn't be seen.

[0239] 5.2 Phase II Safety Data

[0240] A single completed Phase 2B trial in which 933 subjects received at least one dose of vibegron Phase 2 safety data from the study was collected. Subjects were randomly assigned to receive 3-100 mg / kg / day for up to 8 weeks during the main study period. Patients received vibegron in doses ranging from 0.1 mg to 0.5 mg (alone or in combination with tolterodine). Of the subjects who completed the study, 605 subjects received vibegron 50 mg (alone) for up to 52 weeks during the extension study. or vibegron 100 mg (alone or in combination with tolterodine 4 mg). The loop was included in the main study, and the tolterodine monotherapy group was included in the main study and in the extension. No deaths were reported during the study. Vibegron was generally well tolerated. There was a significant difference in the overall incidence or severity of AEs or drug-related AEs between treatment groups compared with placebo. No differences were observed.

[0241] Adverse events were reported in 607 (43.6%) of the 1,393 subjects assigned to the study. The proportion of subjects with ≥1 AE in the vibegron 50 mg and vibegron 100 mg treatment groups was Rates were similar to placebo (see Table 14). A higher rate compared with placebo of subjects had at least one AE in the vibegron 15 mg and vibegron 50 mg and tolterodine 4 mg treatment groups The most frequently reported AEs were dry mouth, headache, urinary tract infection (UTI), and nasopharyngeal The incidence of dry mouth was significantly higher in the tolte group compared with the placebo or vibegron monotherapy groups. The rate was higher in the groups receiving Rosin (alone or in combination with vibegron).

[0242] There were 221 subjects with drug-related AEs, with no drug-related AEs reported in the vibegron 100 mg treatment group. The proportion of subjects with drug-related AEs was 1.4% compared with placebo. The results were similar in the vibegron monotherapy group compared with placebo or either monotherapy. The proportion of subjects who discontinued due to drug-related AEs was low; The results were similar across all treatment groups.

[0243] There were a total of 9 SAEs reported in 8 subjects, occurring across treatment arms (2 in placebo). ; 1 case with vibegron 3 mg; 1 case with vibegron 50 mg; 3 cases with tolterodine 4 mg; vibegron 50 mg and 1 with tolterodine 4 mg). Reported SAEs included atrial fibrillation, anaphylactic reactions, pulmonary One subject had stage IV adenocarcinoma, chronic obstructive pulmonary disease, hypertension, overdosing, and a broken leg. In this study, both gastroesophageal reflux and dizziness occurred after panendoscopic surgery with prolonged hospital stay. No specific AE terms were reported for any of the subjects. All SAEs were reported by the treating investigator. were considered to be unrelated to the study drug.

[0244] There was a significant difference in the overall incidence of adverse events or serious adverse events between the treatment groups during the 52-week extension. was not observed.

[0245] Adverse events were reported in 531 of 845 subjects (62.8%). The proportion of subjects was similar across all treatment groups. The most frequently reported adverse events were UT The incidence of dry mouth was 1.1% compared with the other treatment groups. The incidence of constipation was higher in the tolterodine ER 4 mg group compared with the monotherapy group. was higher in the law group.

[0246] The proportion of subjects with drug-related AEs was 10.1% in the tolterodine ER 4 mg and combination dose groups. The treatment groups were slightly higher than those in the Begron 50 mg and 100 mg groups due to AEs or drug-related AEs. The proportion of subjects who discontinued was higher in the tolterodine ER 4 mg group compared with the other treatment groups. A total of 46 SAEs were reported in 41 subjects treated with tolterodine ER 4 mg and vibegron 50 mg. An overall higher incidence was reported in the vibegron 100 mg group compared with the tortero group. One drug-related SAE of paralytic ileus was reported in the 4 mg azithromycin ER treatment arm; The subject was discontinued.

[0247] Table 16 below shows common findings in the Phase 2 program of vibegron in patients with overactive bladder. Adverse events reported will be summarised.

[0248] [Table 16]

[0249] Serious adverse events observed during the first 12 weeks of treatment with vibegron monotherapy included: Patients with stage IV lung adenocarcinoma (n=1) and chronic obstructive pulmonary disease (n=1); SAEs of overdose were The study was reported in the combination of vibegron and tolterodine. SAEs reported by two or more subjects included cerebrovascular accident (n=2) and osteoarthritis (n=3). The only SAE reported in the vibegron plus tolterodine arm was vomit relia infection. Possible association with changes in heart rate or blood pressure (at any time during treatment) SAEs with positive outcomes included: intention after 8 weeks of vibegron that did not recur on retrial Disorientation (n=1), and atrial fibrillation (n=1) and dizziness (n=1) in the tolterodine monotherapy group. The incidence of injuries was numerically higher in the tolterodine group than in the vibegron group (2.1%, n = 5; Given the low incidence and lack of pattern of SAEs, vibegron was associated with significant It is believed that no such events are anticipated.

[0250] Based on preclinical data and data available for similar compounds, Potential risks that may arise include orthostatic hypotension and concomitant use of strong P-gp inducers. This includes increased patient exposure (up to 2-fold).

[0251] 5.3 Cardiovascular safety

[0252] The cardiovascular safety of vibegron has been evaluated in patients with OAB and in healthy volunteers. Randomized placebo and active comparator (tolterodine) controlled trial with 52-week extension In the two-part efficacy and safety study, seven orthostatic-related AEs (postural dizziness, fainting, etc.) were reported. Adverse events (including postural hypotension and orthostatic hypotension) occurred in 6 (0.4%) subjects. Placebo group (0.5%), vibegron 15 mg group (0.3%), and vibegron 50 mg and tolterodine group One subject each in the ER / vibegron 50 mg treatment group (0.8%) and the vibegron 100 mg group (1.1%) Events occurred in 3 subjects. Events occurred at random times throughout the study and were reported by the treating physician. The severity was judged to be mild by the nurse. None led to discontinuation. The overall incidence was low.

[0253] Changes from baseline in BP and HR across treatment groups are shown in Table 17. Systolic Blood Pressure (SBP) and for diastolic blood pressure (DBP), the mean change in the first week at 50 mg and 100 mg and the mean maximum over 8 weeks Changes were similar between placebo and vibegron, with differences of less than 1 mmHg. The change in P category was similar between placebo and vibegron, with 100 mg vibegron subjects There was a small increase in the proportion of 1.3% vs. 0.5% with placebo. The mean maximum change over 8 weeks was 1.3% vs. 0.5% with placebo (<2 bpm). No dose-dependent pattern of HR was detected because of the comparable HR. The small differences in the percentage of subjects exceeding the number and blood pressure thresholds were similar to those in the tolterodine group. It was.

[0254] [Table 17]

[0255] More intensive assessment of heart rate and blood pressure was performed in healthy volunteers in some Phase 1 trials. The safety of vibegron in healthy subjects, including specific analysis of heart rate, was A six-part, double-blind, randomized, placebo-controlled study to evaluate efficacy, tolerability, and multiple-dose PK. Depending on the cohort, doses ranged from 25 to 400 mg once daily for 7 to 28 days. Least-squares fit of maximum change from baseline in moving average heart rate over 4 hours post-dose (MA4 HR) The means and 90% confidence intervals are shown in Table 18. The effect on heart rate was dose-dependent, with showed a difference from Brasepo of less than 1 bpm.

[0256] [Table 18]

[0257] Cardiovascular safety was evaluated in healthy volunteers in a thorough QT study after single doses of 200 mg and 400 mg. were also evaluated, which approximated the steady-state exposure of vibegron at 100 mg and 200 mg, respectively. As shown in Table 19, the mean maximum effects on blood pressure and RR interval were reduced at lower doses. Using log-log regression analysis from multiple doses of vibegron exposure (from three Phase 1 studies), et al.), calculated mean ± standard deviation C max and the AUC from the 75 mg dose were 120 ± 74.7 ng / kg, respectively. The mean values ​​were 1140 ± 476 ng·h / mL and 1140 ± 476 ng·h / mL. These estimates were significantly lower than those for the 200 mg single dose. C values ​​were approximately 3.3-fold and 2-fold lower, respectively, and 9.2-fold and 6-fold lower, respectively, than the 400 mg single dose. max and A It represents UC.

[0258] [Table 19]

[0259] Example 6 Dose Selection 5.1 Validity of dose comparison

[0260] The Phase 2 study discussed in Example 4 demonstrated a dose-dependent effect on voiding, as seen in Table 20. Conversely, there was a dose-dependent effect on urge incontinence or total incontinence. These data suggest a relatively shallow dose-response relationship in the range of 50 to 100 mg once daily. The efficacy of vibegron begins to plateau at 50 to 100 mg, so 75 mg is mg accounts for the majority of efficacy achieved.

[0261] [Table 20]

[0262] 5.2 Reducing side effects

[0263] Vibegron demonstrated a greater than dose-proportional increase in exposure. In contrast, increasing the dose from 50 mg to 100 mg resulted in max is increased by about four times, which is related to the cardiovascular system. These are the PK parameters that appear to be most closely related to the effects of To illustrate the situation, we use data from a Phase 1 study to compare doses of max and dose AUC model Based on the simulation, the 75 mg dose of vibegron was compared with the 100 mg dose. avoided approximately 29% of the observed exposure and subsequently reduced the upper range of exposure achieved at the 100 mg dose It was found that the outlier C max This decrease in values ​​may have clinically relevant cardiovascular effects. This reduces the possibility of interference.

[0264] In a Phase 1 multiple-dose study, doses up to 100 mg reported no significant adverse events, including postural dizziness, vertigo, and syncope. Adverse events such as dizziness and syncope did not show a clear dose-response relationship. appears to increase at doses of 100 mg or more, and the incidence of the adverse event "symptomatic orthostatic hypotension" The rates of adverse events associated with these doses were higher with vibegron doses above 150 mg. The risk can be disproportionately reduced by reducing the dose from 100 mg to 75 mg, but this , if the dose is reduced by 25%, C max This is due to a decrease of approximately 40% (120 ng / mL at 75 mg vs. 206 ng / mL at 100 mg). Without wishing to be bound by theory, the increase in bioavailability with increasing dose The greater than dose-proportional increase was due to the intestinal saturable P-glycoprotein (P-gp)-mediated This may have been due to a spill.

[0265] The reduced exposure at the 75 mg dose compared with the 100 mg dose may reduce the risk of adverse events in special populations. Subjects with moderate renal impairment should be treated with The mean increase in AUC was 1.6-fold compared with subjects receiving a strong CYP3A / P-gp inhibitor. The subjects' exposure was approximately 2-fold higher at the 75 mg dose. max Assuming that increases by a factor of two, these Special populations observed with vibegron C greater than those observed with 100 mg max The probability of achieving this is 15% (See Figure 1.) Minimizing exposure to extreme collapse subjects is C is about 50-70% higher than in men max This is important for older adults and women who showed

[0266] All patents, patent applications, and other publications cited herein are incorporated by reference in their entirety. The body is incorporated herein.

[0267] Example 7 Overactive Bladder (OAB) Symptoms in the Pharmacological Treatment of Benign Prostatic Hyperplasia (BPH) A Phase 3 Trial to Evaluate the Efficacy, Safety, and Tolerability of Vibegron in Men with A double-blind, randomized, placebo-controlled, multicenter study

[0268] Several beta-3 adrenergic receptor (β3-AR) agonists are available for the treatment of BPH. Improved safety profile compared with anticholinergics in treating persistent OAB symptoms in men with ) efficacy in this subset of the broader OAB population setting. Unique safety needs not adequately assessed in the program (e.g., potential for urinary retention) This study aimed to evaluate the efficacy and safety of cerebrovascular disease in men with OAB symptoms while undergoing pharmacological treatment for BPH. Safety, tolerability, and efficacy of vibegron (75 mg once daily (QD) for 24 weeks) or placebo It is designed to evaluate efficacy.

[0269] The primary study objective was to compare vibegron versus placebo in men with OAB symptoms treated with pharmacologic therapy for BPH. The primary objective of this study was to evaluate the efficacy, safety, and tolerability of Sebo. Based on the 3-day diary, a) the average daily voiding episodes and b) the average daily urgency episodes were recorded. Vibegron and BPH pharmacological therapy were more effective than placebo and BPH pharmacological therapy in reducing both The safety evaluation included evaluating whether the drug was effective in men with BPH who had OAB symptoms. To assess whether vibegron and the pharmacological treatment of BPH are safe and tolerable.

[0270] This study is aimed at evaluating the efficacy and safety of a stable dose of pharmacologic therapy for BPH in men with symptoms of OAB. A Phase 3 Randomized, International Study to Evaluate the Safety, Tolerability, and Efficacy of Vibegron 75mg in Patients with Chronic Illness This is a double-blind, placebo-controlled, two-part, parallel-group, multicenter study. At baseline, all eligibility criteria were met. Subjects who meet the criteria will be randomized 1:1 to receive either vibegron 75 mg or placebo in a double-blind study. Randomization was based on baseline mean number of voiding episodes per day (1 ≤2 or >12), use of alpha blockers with or without 5-ARI (yes or no) ), and stratified based on urinary incontinence (yes or no).

[0271] The study will consist of two parts: Part 1 (approximately 80 subjects) and Part 2 (approximately 1,008 subjects). Part 1 consisted of screening, run-in, baseline, week 2, and week 4. Additional orthostatic blood pressure and heart rate measurements were included to assess potential orthostatic changes (screenshots taken). (From before administration to 6 hours after administration, excluding pre-administration for training and habituation) Part 2 will be conducted by an independent Data and Safety Monitoring Committee (DSMB). Following a review of 4-week safety data from Part 1, including orthostatic blood pressure results, Part 2 will also include a urodynamic substudy (approximately 60 subjects).

[0272] Both study parts included a screening period (weeks 1 to 4), placebo, and BPH pharmacological A single-blind run-in period (2 weeks) was added to the treatment, and a randomized double-blind treatment period (24 weeks) was administered. Subjects who completed the 24 week visit were randomized to the 28 week study, which was conducted under a separate study protocol. You may be offered the opportunity to register for a 2-week extended exam (see Example 8). Subjects who do not receive the study treatment will be assessed for safety approximately 21 days (plus up to 4 days) after the subject's last dose of study treatment. Subjects who completed the 24-week visit (i.e., those who underwent a sex follow-up assessment (by telephone) (For subjects who discontinued the study early, the period was approximately 27 weeks after withdrawal.) , unscheduled visits may be arranged if necessary.

[0273] At Visit 1 (screening) visit, subjects met the following criteria unless otherwise noted: You are eligible to participate in this study only if all of the following apply to you: 1. Be able to give written informed consent, including the following: This includes compliance with requirements and restrictions set forth in the applicable international standard. 2. Male subjects aged 45 years or older. 3.Weight 50kg or more (inclusive). 4. Subjects will be receiving either a) alpha blocker monotherapy or b) alpha blocker and 5ARI. Patients must agree to continue treatment for BPH with a stable dose of either Subjects taking anticancer drugs must have started treatment at least 3 months prior to screening. Patients must have started taking a 5-ARI and be on a stable dose at the start of screening. Subjects on the study were required to have started treatment at least 6 months prior to screening and to have been screened Patients must be on a stable dose at the time of treatment. 5. Have been receiving medication for at least 2 months to treat LUTS due to BPH and have not been hyperactive Active bladder symptoms (frequency of 8 or more voiding episodes per day with or without incontinence and History of urinary urgency (three or more episodes per day). 6. Subjects must have an IPSS total score ≥ 8 at Screening and Visit 3 (Baseline). be. 7.Subject has a prostate-specific antigen (PSA) level less than 4 ng / mL or a PSA level greater than or equal to 4 ng / mL1 <0 ng / mL and prostate cancer has been ruled out to the treating physician's satisfaction. 8. Subject agrees not to participate in a clinical trial of another interventional drug or device during the study. . 9. In the opinion of the investigator, meets the requirements of the protocol, including completion of study questionnaires and bladder diaries are able and willing to comply. 10. At Visit 2 (run-in) and Visit 3 (baseline), subjects will complete a 3-day bladder diary. Must have both of the following additional qualifications based on the period: a) 1 (b) an average of 8 to 20 voiding episodes per day over a 3-day diary period An average of 3 or more urgency episodes per day. 11. Subjects must have a post-void residual (PVR) volume value of less than 100 mL. 12. Visits 2 (run-in) and 3 (baseline), 3-day bladder function at baseline Average of at least 2 nocturia episodes per night based on bladder diary. is defined as waking up to void during the main sleep period.

[0274] At Visit 1 (Screening) visit, if any of the following criteria apply, Subjects are not eligible to participate in this study unless specifically stated in: 1. The subject has had a 24-hour urinary volume of more than 3,000 mL. 2. Subject is a night shift worker or will be a night shift worker during the study. 3. Any urinary disturbance that, in the opinion of the treating physician, may cause urinary urgency, frequency, or incontinence. Low tract disease; this was determined by the treating physician to be due to bladder stones, interstitial cystitis, These include, but are not limited to, prostate cancer, persistent, genitourinary tuberculosis, and urothelial tumors. 4. History of prostate surgery, including minimally invasive transurethral or transrectal procedures, Have had prophylactic treatment for BPH within the past 6 months or have had planned prostate cancer treatment, including minimally invasive prostate procedures The surgery is during the study period. 5. History of pelvic radiation therapy, low anterior resection (LAR), or any abdominoperineal resection (APR) are present or planned for the trial period. 6. Subject had prostatitis within the past 6 months. 7. History of urinary retention requiring intervention (e.g., catheterization) for any reason . 8. Subjects are taking or using any medication to treat erectile dysfunction (ED) I don't use them regularly (sildenafil and vardenafil have long half-lives). Short-term ED medications are permitted if used less than twice a week in the past 3 months and during the study. 9. Subject will undergo treatment to treat ED (e.g., penile device implantation) during the treatment period. A prostate procedure is planned or is being planned. 10. Subjects have had treatment for overactive bladder, lower urinary tract symptoms / BPH symptoms, or erectile dysfunction within the past 3 months. Some herbal medicines are used to treat it. 11. Subjects have started using diuretics within 3 months prior to screening. Subjects were already taking any diuretic at a stable dose for at least 3 months prior to the study. Candidates may register for the exam. 12. Maximum urinary flow rate (Qmax) is less than 5.0 mL / sec and minimum voided volume is 125 mL. 13. Based on a 3-day bladder diary, Visit 2 (run-in) or Visit 3 (baseline) visit and a history or current history of nocturnal polyuria. Nocturnal polyuria is defined as the amount of urine produced per third of the total amount of urine produced per 24 hours. is defined as a nighttime occurrence of more than 1 of the above. 14. Have undergone bladder training or electrical stimulation within 28 days prior to screening or during the study The company plans to start 15. Clinical symptoms or laboratory criteria (≥5 white blood cells (WBC / hpf) with the presence of red blood cells (RBC) and / or positive urine culture, 10 per specimen 5 (defined as ≥ 100 colony-forming units (CFU) / mL) Active or recurrent (>3 episodes per year) urinary tract infection due to Subjects who were diagnosed with a urinary tract infection (UTI) during the study were rescreened once the infection had cleared after treatment. You can receive training. 16. Within 6 months prior to screening, have had exposure to botulinum toxin, resiniferatoxin, or They received either intravesical or intraprostatic treatment with capsaicin. 17. Have a sacral nerve stimulation (SNS) or posterior tibial nerve stimulation (PTNS) device implanted It is used. 18. Uncontrolled hyperglycemia (fasting blood glucose >150 mg / dL or >8.33 mmol / L, or defined as non-fasting plasma glucose >200 mg / dL or >11.1 mmol / L) or In the teacher's opinion, it is not being controlled. 19. Has been diagnosed with diabetes insipidus. 20. You have been diagnosed with sleep apnea. 21. Screening is not required, except for adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical carcinoma. Concurrent malignancy or history of any malignancy within 5 years prior to screening. 22. HIV, AIDS, or unexplained warning signs (anemia, gastrointestinal bleeding, unintentional weight loss, known or suspected to have a cancer (e.g., suspected cancer). 23. History of clinically relevant liver disease or severe liver dysfunction (Child-Pugh classification C) There is. 24. In the opinion of the investigator, participation in the study places the patient at risk, There is a significant electrocardiogram (ECG) abnormality. 25. Uncontrolled hypertension (systolic blood pressure ≥ 180mmHg and / or diastolic blood pressure ≥ 100mmHg) Hg or higher) or a resting heart rate (with pulse) of more than 100 beats per minute. 26. Subjects with a systolic blood pressure of 160mmHg or greater but less than 180mmHg are considered safe to continue in this study. and will be excluded unless the investigator determines that the patient will be able to complete the study according to the protocol. These subjects were taking stable antihypertensive medications for at least 3 months prior to screening. It is necessary to use it. 27. All subjects with signs and symptoms of uncontrolled hypertension, regardless of blood pressure measurement These include neurological symptoms or findings, hematuria, proteinuria, retinopathy, These include, but are not limited to, acute myocardial infarction, unstable angina, and acute heart failure. 28.Having had cerebrovascular accident, transient ischemic attack, or unstable angina within 6 months prior to the screening visit coronary artery bypass graft or percutaneous coronary intervention intervention (e.g., angioplasty, stent insertion), or neurovascular intervention (e.g., carotid stenting) Subjects with these conditions had at least must also have been on stable medical treatment for three months. 29. Injury, surgery, or neurodegeneration that may affect the lower urinary tract or its innervation Have a history of illness (e.g., multiple sclerosis, Parkinson's disease). 30.Has unassessed hematuria, including microscopic hematuria (>5 RBC / hpf). Subjects with benign hematuria as assessed by the urinary tract may participate. Imaging studies of the kidneys and ureters (e.g., computed tomography with or without contrast) (CT scan, renal ultrasound, magnetic resonance imaging (MRI), intravenous pyelogram, etc.) and cystoscopy. Documentation of testing must be obtained. Subjects who have not been previously evaluated for hematuria will not be enrolled. There may not be. 31. Alanine aminotransferase or aspartate aminotransferase Serum levels exceed 2.0 times the upper limit of normal (ULN) or bilirubin (total bilirubin) exceeds 1.5 × ULN (or secondary to Gilbert syndrome or a pattern consistent with Gilbert syndrome) (If >2.0 × ULN) 32. Estimated glomerular filtration rate (eGFR) is 30 mL / min / 1.73 m 2 is less than. 33. Use of prohibited drugs. 34.Has changed the dosage of any medication or study drug within 4 weeks prior to the screening visit The plan is to start or change the administration of these medications during this period. 35. History of sensitivity to any of the study treatments or their components, or any other condition that the investigator believes to be A history of drug or other allergies which, in their opinion, would prohibit their participation. 36. Currently participating in or screening for an investigational compound, device, or procedure. Participated within 28 days prior to training. 37.Currently participating or have participated in a study using vibegron. 38. Any significant drug or alcohol use within 1 year prior to screening, as assessed by the investigator. History of alcohol abuse / dependence. 39. Coronary or neurovascular intervention is planned during the study period. 40. Subjects who, in the opinion of the investigator, may confound the outcome of the study or fail to comply with study procedures conditions that may interfere with the subject's ability to participate in the study or that may not be in the subject's best interest to participate in the study There is history or current evidence of a disease, treatment, laboratory abnormality, or other condition. 41. At Visit 3 (Baseline), subjects are ineligible during the 2-week placebo-controlled run-in period. (taking less than 80% or more than 120% of the study drug).

[0275] The primary and secondary study endpoints were as follows: ("per day" means 24 consecutive days of (Note that this refers to a period of time.) <Co-primary efficacy endpoint> Change from baseline in mean number of voiding episodes per day (CFB) at week 12. Average number of urgency episodes per day (urgency: need to urinate immediately) at 12 weeks CFB in action. <Secondary efficacy endpoints> -CFB at week 12 for the mean number of nocturia episodes per night. Urge urinary incontinence per day in subjects with urinary incontinence at baseline inence) episodes at week 12. Mean International Prostate Symptom Score (IPSS) storage score at 12 weeks of CFB (1 week recall). · CFB at week 12 for mean voided volume per void. <Other endpoints> Average number of voiding episodes per day at weeks 2, 4, 8, 16, 20, and 24 CFB in. The mean number of urgency episodes per day at weeks 2, 4, 8, 16, 20, and 24. CFB in week. The average number of nocturia episodes per night at weeks 2, 4, 8, 16, 20, and and CFB at 24 weeks. IPSS storage score at weeks 4, 8, 16, 20, and 24 CFB (1 week (recall). IPSS quality of life scores at weeks 4, 8, 12, 16, 20 and 24 after CFB (One week recall). Urge urinary incontinence per day in subjects with urinary incontinence at baseline The mean number of incest episodes at weeks 2, 4, 8, 16, 20, and 24 CFB. CFB of mean voided volume per void at weeks 2, 4, 8, 16, 20, and 24 . Mean number of total urinary incontinence episodes per day at week 2 in subjects with urinary incontinence at baseline , CFB at weeks 4, 8, 12, 16, 20 and 24. - Urgency per day in weeks 2, 4, 8, 12, 16, 20, and 24 50% reduction from baseline in urgency episodes (feeling of needing to urinate immediately) Percentage of all subjects. At baseline, at weeks 2, 4, 8, 12, 16, 20, and 24 Subjects with urinary incontinence who achieved a 75% reduction in daily urge incontinence episodes from baseline Percentage of people. <Other / Exploratory Endpoints – Quality of Life> - 12% of symptom anxiety scores assessed by the Overactive Bladder Questionnaire Long Form (OAB-q-LF) CFB at week (1-week recall). Health-related quality of life (HRQL) total score assessed by OAB-q-LF at week 12 CFB. (HRQL includes subscales of coping, concern, sleep and social interaction. A total score is calculated by adding the four subscale scores. HRQL subscale coping scores assessed by OAB-q-LF at 12 and 24 weeks CFB. -HRQL subscale concern scores assessed by OAB-q-LF at weeks 12 and 24 CFB. -HRQL subscale sleep scores assessed by OAB-q-LF at 12 and 24 weeks CFB. HRQL subscale social interaction scores assessed by OAB-q-LF at weeks 12 and 24 CFB in the eye. - EQ-5D-5L, assessed by a health status questionnaire measure developed by the EuroQolGroup CFB at 12 and 24 weeks. Overall bladder symptoms based on Patient Global Impression of Severity (PGI-Severity) at weeks 4, 12 and and CFB at 24 weeks. Overall score of bladder symptoms based on Patient Global Impression of Control (PGI-Control) CFB at weeks 4, 12, and 24 of the control group. Overall symptom frequency based on Patient Global Impression of Symptom Frequency (PGI-Frequency) at weeks 4 and 12 CFB at 1 h and 24 wk. Patient Global Impression of Urgency-Related Leakage (PGI Leakage) for subjects with urinary incontinence at baseline Based on the overall urgency-related leakage for bladder symptoms at weeks 4, 12, and and CFB at 24 weeks. Based on Patient Global Impression of Change (PGI-Change) at weeks 4, 12, and 24 Overall change in bladder symptoms. · International Index of Erectile Function (IIEF) CFB at 12 and 24 weeks.

[0276] Efficacy assessments will be collected in the form of a 3-day subject bladder diary. Information collected in the diary will be , daily urination, urgency, nocturia, number of incontinence episodes, and 24-hour urination volume The IPSS will be used to assess the relevant primary and secondary efficacy endpoints. Quality of life endpoints were assessed by completing assessments, OAB-q LF, EQ-5D-5L and PGI scores. do.

[0277] Subjects will complete a questionnaire on-site at the start of each required study visit (before vital signs and blood draws). Completed, the questionnaire assesses subject-perceived symptom relief and health-related quality of life.

[0278] <Bladder diary> The bladder diary included all voiding, urgency, incontinence, nocturia, and bowel movements during one 24-hour period. Frequency of daily OAB symptoms including urinary volume, primary reason for incontinence, and volume voided per void (one 24-hour period) by selecting the box for each symptom that occurs during a particular day or night. It is therefore used by the subject to record.

[0279] Bladder diaries were completed at Visit 2 (run-in), Visit 3 (baseline), and Visits 2, 4, 8, 12, 16, 20, and Urine volume should be completed by the subject on all 3 days within 7 days prior to visit 1 and 24 weeks. Diary data may be collected on any (1) of the 7 diary days preceding the questionnaire, beginning when the patient wakes up on that day, The recording should last approximately 24 hours, continuing until the patient wakes up the next day.

[0280] "Diary days" are the time when the subject wakes up every morning (i.e., the time when the subject woke up yesterday). The period between the time the subject woke up and the time they woke up today (approximately a 24-hour period).

[0281] To be eligible to participate in the study, subjects must have at least the following: : Three consecutive diary days during the screening period (7 days prior to run-in), and Three consecutive diary days during the run-in period (the seven days prior to the baseline visit), and As needed, in the opinion of the investigator, at baseline and throughout the study It is possible to remain compliant with diary requirements, including measuring and recording urine output.

[0282] At all study visits, site staff asked subjects if they had any difficulties with the diary. and address any questions the subject may have. Instructions for completing the diary correctly Subjects should report data immediately after each event (in real time). They are trained to enter data for "missing" events as quickly as possible. ,Data from all events that occurred within the preceding diary day (approximately 24 hours) are collected at a fixed time every morning. Review and verify that all data has been entered into the

[0283] Responses to the bladder diary will determine whether or not a subject is able to complete the diary and whether or not the subject is able to Reviewed by field staff to assess whether they meet the eligibility criteria The daily averages of voiding, urgency episodes, nocturia episodes, and UUI episodes were Calculated as the average of the total number of events on each day. will be excluded from the study.

[0284] <Results reported by patients> Subjects completed the questionnaire on-site at the beginning of each required study visit (prior to vital signs and blood draws). Completed at study visits, participants assessed symptom relief, symptom bother, and health-related Assessing quality of life. Recommended guidelines for the use of patient-reported outcome measures include: “Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Produ ct Development to Support Labeling Claims,” US Department of Health and Human Services, Food and Drug Administration, December 209, which states: These include the following questionnaires, each of which is incorporated by reference in its entirety:

[0285] The International Prostate Symptom Score (IPSS) is a questionnaire consisting of eight questions (seven about urinary symptoms and one about quality of life). each with responses based on a 6-point scale indicating increasing severity. Urinary symptom responses are assigned a score ranging from 0 to 5. Thus, the total IPSS score is The score ranges from 0 to 35 (asymptomatic to very symptomatic). Points are assigned from 1 to 6.

[0286] Global Impression Items include the patient's overall impression of the severity of their condition. (PGI-Severity), Patient's Global Impression of Control (PGI-Control), Patient's Global Impression of Frequency (P GI-frequency), Patient Global Impression of Leakage (PGI-leakage), and Patient Global Impression of Change (PGI-leakage). GI-changes are included.

[0287] The Overactive Bladder Questionnaire (OAB-q Long Form [OAB-q LF], 1-week recall) was used to assess health-related quality of life (HRQL) The 33-item patient-controlled symptom scale includes the symptom anxiety scale (8 items) and the symptom anxiety scale (25 items). HRQL is a patient-specific questionnaire. HRQL measures the relationship between illness and treatment for physical, psychological and social aspects of life. It is a multi-domain concept that represents the patient's general perception of the impact of To claim a meaningful improvement means: (1) a cure for the disease of interest and its treatment; As a result, there is a lot of uncertainty surrounding how clinical trial populations feel and perform. (1) all important HRQL domains were measured; (2) overall improvement was demonstrated; and and (3) no decline was observed in any of the domains. The scale is divided into four subscales: coping, concerns / worries, sleep, and social interaction. The BRCA scale was a key secondary endpoint, with item scores ranging from 1 (never) to 6 ( A higher score indicates better QoL. The core is calculated by summing the individual HRQL subscale scores. The kale items were scored from 1 (not at all) to 6 (very much) and the symptoms were Higher anxiety scores indicate greater symptom severity. This instrument was administered to both men and women. It has been developed and validated in both controllable and non-controllable OAB patients, including:

[0288] The EQ-5D health questionnaire is a standardized instrument for use as a measure of health outcomes. See abin et al. Value in Health;17(1):70-76 (2014).

[0289] The Internal Index of Erectile Function (IIEF) measures four major areas of male sexual function: erectile function, It is a 15-question assessment of erectile dysfunction that examines sexual function, sexual desire, and sexual satisfaction.

[0290] Applicable to a wide range of health conditions and treatments; simple descriptive profiles and Provides a single index value.

[0291] Safety endpoints included adverse events (AEs), clinical laboratory values, and vital sign assessments. The safety and tolerability parameters of

[0292] AEs are considered to be related to the investigational drug and may be a temporary side effect of the use of the investigational drug. AEs are adverse medical occurrences in clinical trial subjects that are related to the clinical trial. Unwanted and unintended symptoms (including abnormal laboratory findings) temporarily associated with the use of the drug ), a condition, or a disease (new or worsening).

[0293] Example 8 Overactive Bladder (OAB) Symptoms in the Pharmacological Treatment of Benign Prostatic Hyperplasia (BPH) A Phase 3, Open-Label Study to Evaluate the Long-Term Safety and Efficacy of Vibegron in Men with Extension Test

[0294] As an extension of the study described in Example 7 (the "Parent Study"), an international, Phase 3, open-label, 28-week trial A study was conducted to evaluate the efficacy and safety of cyclophosphamide in men with OAB symptoms receiving stable pharmacological treatment for BPH. The safety and efficacy of vibegron 75 mg in patients with bronchitis have been evaluated. Patients with OAB who are currently receiving stable pharmacological therapy for BPH and continue to be eligible for the study Approximately 300 men with symptoms of COVID-19 could be allowed to enroll in the extension study from approximately 60 study sites. It is.

[0295] During this extension study, subjects randomized in the parent study to receive vibegron 75 mg: The same treatment was continued once daily for an additional 28 weeks, and subjects randomized to the placebo group in the parent study During the extension period, patients will receive study treatment with vibegron 75 mg once daily for 28 weeks. Subjects originally randomized to vibegron by participating in both the parent and extension studies The subjects randomized to placebo received vibegron for a total of 28 weeks. The patient will receive vibegron treatment for one week.

[0296] Subjects were randomly assigned to receive either 5α-reductase inhibitor (5-ARI) or 5-ARI-treated subjects in the parent study. The same alpha blockers (e.g., tamsulosin, doxazosin, and alfazosin) Use of antidepressants (e.g., finasteride, dutasteride, and alfatradiol) Continue in extension study.

[0297] The primary and secondary study endpoints are shown below. Evaluations were performed on the first baseline from the parent study. Therefore, the change from baseline (CFB) study endpoint for the extension study is At the 52-week visit, CFB was compared with baseline in the parent study. Subjects randomized to vibegron in the first study were randomized to placebo for 52 weeks. The study consisted of 28 weeks of vibegron exposure for subjects randomized to 100 mg / kg / day.

[0298] For study endpoints, "per day" refers to "diary days" and refers to the subject's bladder The time between when the subject woke up each morning and when they woke up the next morning, as recorded in a diary is defined (approximately a 24 hour period).

[0299] <Primary endpoint - safety> Includes AEs, clinical labs, vital signs assessments, PVR volumes, and total IPSS

[0300] <Secondary endpoint - efficacy> Average number of voiding episodes per day at 52 weeks of CFB Average number of urgency episodes per day (urgency: need to urinate immediately) at 52 weeks CFB in The mean number of nocturia episodes per night at 52 weeks of CFB Urge urinary incontinence per day in subjects with incontinence at baseline in the parent study Mean number of incontinence episodes in the 52nd week of CFB Mean International Prostate Symptom Score (IPSS) quality of life score at 52 weeks of CFB (weekly recall) CFB at week 52 for mean voided volume per void

[0301] <Other endpoints> The mean number of total urinary incontinence episodes per day in subjects with incontinence at baseline in the parent study CFB at 52 weeks of Urgency episodes per day at 52 weeks (urgency: needing to urinate immediately) Percentage of all subjects with a 50% decrease from baseline Patients with urinary incontinence at baseline in the parent study had urgency incontinence episodes per day at week 52 Percentage of subjects achieving a 75% reduction in sword from baseline.

[0302] <Other / exploratory endpoints - quality of life> -CFB at Week 52 of IPSS subscale voiding score (1-week recall) CFB (1-week recall) at week 52 for quality of life scores on the IPSS subscale Symptom anxiety score of 52 was assessed using the Overactive Bladder Questionnaire Long Form (OAB-q-LF). CFB at week (1-week recall) Health-related quality of life (HRQL) total score as assessed by OAB-q-LF at week 52 CFB in the context of mental health. (HRQL includes subscales of coping, concern, sleep, and social interaction. A total score is calculated by adding the four subscale scores. HRQL subscale coping scores assessed by OAB-q-LF at 52 and 24 weeks CFB HRQL subscale concern scores assessed by OAB-q-LF at 52 and 24 weeks CFB -HRQL subscale sleep scores assessed by OAB-q-LF at 52 and 24 weeks CFB HRQL subscale social interaction scores assessed by OAB-q-LF at 52 and 24 weeks CFB in the eye - EQ-5D-5L, assessed by a health status questionnaire measure developed by the EuroQolGroup CFB at 52 weeks Overall bladder symptoms based on Patient Global Impression of Severity (PGI-Severity) at Week 52 CFB Overall symptom severity based on Patient Global Impression of Control (PGI-Control) CFB in controls at week 52 Overall symptom frequency based on Patient Global Impression of Symptom Frequency (PGI-Frequency) at Week 52 CFB in Overall patient prevalence of urgency-related leakage in subjects with urinary incontinence at baseline in the parent study At week 52, the overall urgency to bladder symptoms leakage was based on the overall impression (PGI leakage) CFB - Overall bladder symptom improvement at week 52 based on Patient Global Impression of Change (PGI-Change) change

[0303] Example 9. Phase 3 Randomized, Double-Blind, Placebo- and Active (Tolterodine)-Controlled Clinical Trial

[0304] An international, phase 3, randomized, double-blind study in men and women with overactive bladder. A sevoflurane-controlled and active-controlled (tolterodine) parallel-group multicenter study was conducted. There are two types of OAB: wet (patients with UUI, involuntary urinary incontinence with urgency) and dry (patients with UUI) A total of 1,518 patients were randomly recruited across 215 study sites. Patients were standardized and assigned to one of three groups for a 12-week treatment period.

[0305] The study consisted of a screening period (weeks 1 to 5), a single-blind run-in period (weeks 2), and a randomized It consisted of a double-blind treatment period (12 weeks) and a follow-up period (4 weeks).

[0306] The study evaluated the safety, tolerability, and efficacy of 75 mg of vibegron versus placebo. Tolterodine ER 4 mg was the active control. Patients were randomized to receive either 100 mg or 150 mg of ER in a double-blind 5:5:4 ratio. Patients were randomized to one of three treatment arms: vibegron 75 mg, placebo, or tolterodine ER 4 mg. All were administered once daily for 12 weeks of treatment. Between visits, patients underwent study evaluations at weeks 4 and 8.

[0307] 8.1. Eligibility Criteria

[0308] To be eligible for participation in this study, patients must meet all of the following inclusion criteria prior to enrollment: Participants must meet the following criteria and not meet any of the following exclusion criteria:

[0309] 8.1.1 Inclusion criteria

[0310] 1. Willing and able to provide written informed consent. 2. Male or female, aged 18 years or older. Note: Up to 15% of patients may be male. 3. History of OAB (physician-diagnosed) for at least 3 months prior to the screening visit Note: OAB is usually characterized by frequency and nocturia, with or without urge urinary incontinence (UUI). Defined as associated urgency. Urodynamic evaluation not required. 4. Based on the patient voiding diaries returned at both the run-in and baseline visits, Meet the criteria for either OAB wet or OAB dry (all completed (You must use the diary date that you completed.) Diaries returned for training must have at least 5 completed diary dates. Days (not necessarily consecutive) are required and are returned in the diary at the baseline visit requires 4 completed diary days. Averages should not be rounded up to an integer: a. OAB Wet Criteria: i. An average of 8.0 or more voids per diary day; and ii. An average of ≥ 1.0 UUI episodes per diary day; and iii. If stress urinary incontinence is present, the total number of UUI episodes should be recorded from the previous visit diary. The number of stress urinary incontinence episodes must be greater than the total number of stress urinary incontinence episodes reported by all patients. b. OAB Dry Standard: i. An average of 8.0 or more voids per diary day; and ii. An average of 3.0 or more urgency episodes per diary day; and iii. An average of <1.0 UUI episodes per diary day; and iv. If stress urinary incontinence is present, the total number of UUI episodes will be recorded from the last visit diary. should be greater than the total number of stress incontinence episodes in the first 12 months. 5. For women of reproductive potential: From the screening visit to the completion of the follow-up visit Continue abstinence or use an acceptable method of contraception (as defined in section 5.2.1) each time the patient engages in sexual intercourse. ) 6. For females of reproductive potential: Remain oocyte-fertile until at least 1 month after the last dose of study treatment. Agree not to donate offspring (eggs). 7. Demonstrated 80% or greater compliance with self-administration of study treatment during the run-in period. . 8. Able to walk and generally in good physical and mental health according to the treating physician Thus, it is judged. 9. In the opinion of the treating investigator, the subject is Completion (including collection, measurement, and step-by-step urine collection and measurement containers (as required by sponsor) Ability to self-record voiding using the provided device) and comply with protocol requirements Able and willing to comply.

[0311] 8.1.2 Exclusion criteria

[0312] <Urological history> 1. Patients have a history of 24-hour urinary volume of >3,000 mL in the past 6 months or are in the run-in phase. Have a daily urine volume measurement of more than 3,000 mL during the period. 2. In the opinion of the treating physician, urolithiasis, interstitial cystitis, prostate cancer, gastrointestinal (GI) cancer, or Nucleus, lithiasis, urothelial tumors, prostatitis, and clinically relevant benign prostatic hyperplasia (BPH) or causes of urinary urgency, frequency, or incontinence, including, but not limited to, bladder outlet obstruction. Lower urinary tract pathology that may be a contributing factor. Note: No evidence of bladder obstruction as determined by the investigator. Men with mild to moderate BPH who had not been taking medication for BPH for at least 1 year prior to screening If you have taken any of the following drugs within 3 months prior to screening: herbal medicines, alpha antagonists, or other No change in symptomatic treatment or medication dosage and no change in any of the 5 ataxias within 6 months of screening May be included as long as there is no change in the dose of the sulfa reductase inhibitor. 3. Procedural treatment for stress urinary incontinence, pelvic organ prolapse, or BPH within 6 months of screening have had surgery to correct 4. Current history or evidence of stage 2 or higher pelvic organ prolapse (prolapse extending beyond the hymenal ring) (I am.) 5. The patient is currently using a pessary to treat pelvic organ prolapse. 6. Have a known history of high post-void residual volume, defined as greater than 150 mL. 7. Has undergone bladder training or electrical stimulation within 28 days prior to screening or will begin during the study It is planned. 8. Clinical symptoms or laboratory criteria (≥5 white blood cells (WBC) or positive urine culture, ≥105 colonies in one specimen) Active or recurrent (>3 times per year) urinary Patients diagnosed with a urinary tract infection (UTI) at the screening visit were Once the infection has cleared, patients can be rescreened. 9. Requires indwelling or intermittent catheterization. 10. Have received internal detrusor injections of botulinum toxin within 9 months prior to screening.

[0313] <Other medical history> 11. Uncontrolled hyperglycemia (fasting blood glucose >150 mg / dL or >8.33 mmol / L and / or non- defined as fasting plasma glucose >200 mg / dL or >11.1 mmol / L) or If not managed. 12. There is evidence of diabetes insipidus. 13. Pregnant, breastfeeding, or planning to become pregnant during the planned period of the study. 14. Infopathic uterine cancer, except for basal cell carcinoma, squamous cell carcinoma, or in situ cervical carcinoma that has been treated thoroughly. Concurrent malignancy or history of any malignancy within 5 years prior to signing informed consent There is. 15. Uncontrolled hypertension (systolic blood pressure ≥ 180mmHg and / or diastolic blood pressure ≥ 100mmHg) Hg or higher) or a resting heart rate (with pulse) of more than 100 beats per minute. 16. Patients with a systolic blood pressure of 160 mmHg or greater and less than 180 mmHg will be It is safe for the patient to proceed with this study and they will be able to complete the study according to protocol. These patients were excluded unless the investigator determined that they were receiving stable antihypertensive medication for at least 90 days. You must be taking the medication. 17. All patients who exhibit signs and symptoms of uncontrolled hypertension, regardless of blood pressure measurement, These include neurological symptoms or findings, hematuria, proteinuria, retinopathy, These include, but are not limited to, unstable angina, and acute heart failure. 18. Have narrow-angle glaucoma (primary open-angle glaucoma is not excluded). 19. Cerebrovascular accident, transient ischemic attack, unstable angina, myocardial infarction, coronary intervention (e.g. , coronary artery bypass grafting or percutaneous coronary intervention (e.g., angioplasty, stent insertion) ), or neurovascular intervention (e.g., carotid artery stenting) within 6 months prior to the screening visit Patients with these conditions were randomized to receive a 2-month follow-up visit at least 3 months prior to the screening visit. Patients must be receiving stable medical treatment for at least 24 hours. 20. Have a history of liver disease. 21. Injury, surgery, or neurodegeneration that may affect the lower urinary tract or its innervation Have a history of illness (e.g. multiple sclerosis, Parkinson's disease, etc.).

[0314] 8.2 Test evaluation and procedures

[0315] The treating physician or qualified designee shall review any protocol-specified washout procedures. Review prior medication use, including any medication requirements, within 28 days prior to completion of the screening electronic diary Previous medications taken by the patients were recorded.

[0316] All medications taken for the treatment of OAB within 1 year of the screening visit were recorded. The medication history of male patients with a history of mild to moderate BPH was evaluated to determine whether they met the eligibility criteria. A stable treatment regimen was ensured.

[0317] Concomitant medications will be reviewed at each study visit from screening through week 12, as well as at any unscheduled visits. Viewed and recorded.

[0318] Men with mild to moderate BPH without evidence of bladder obstruction as determined by the treating physician were Taking medication for BPH for at least 1 year prior to baseline and within 3 months prior to baseline Unless you have changed the dose of herbal medicines, alpha antagonists, or other symptomatic treatments or medications, To be eligible for the study, these BPH medications must be included in the screening The study participants should be stable from the study visit to the baseline visit.

[0319] Patients with a history of hypertension were required to have been on a stable blood pressure treatment regimen for 90 days prior to the baseline visit. must have received the required medical certification and be deemed safe to proceed with this study and be tested per protocol. must be deemed by the treating physician and / or medical monitor to be able to complete There is.

[0320] 8.2.1 Post-void residual volume

[0321] The risk of acute urinary retention or morbidity associated with increased post-void residual (PVR) is Antimuscarinic therapy promotes smooth muscle relaxation by inhibiting muscarinic acid-induced smooth muscle contraction During contractions, the detrusor muscle may be poorly contractile or may have a severe obstruction (most commonly The inability of the bladder to generate enough pressure to overcome the outlet resistance of the urethra (due to BPH) In such cases, acute urinary retention or incomplete emptying of the bladder may occur.

[0322] The volume of urine remaining in the bladder after voiding (PVR) may serve as a surrogate for impaired voiding ability. It is an objective measurement.

[0323] PVR was performed via ultrasound at the visits indicated in the schedule of activities.

[0324] 8.3 Statistical analysis

[0325] Co-primary endpoint analysis (baseline mean number of daily voids at 12 weeks) Change from baseline in daily urge urinary incontinence episodes at 12 weeks Maximum likelihood estimates of mean change from baseline in number of A mixed model for repeated measures with restricted variables (MMRM) was used. This model excluded dropouts. Adjusting for the covariate distribution and using all available information on patients within the same set of covariates This accounts for the fact that measurements made over time in the same patient tend to correlate. , to derive estimates of the treatment effect in the non-dropout population. The analytical models included treatment duration, visit, OAB type (wet vs. dry), and gender (female vs. male). sex), region (USA vs. other countries), baseline score, and visit-by-treatment interaction Includes:

[0326] Primary inference is treatment versus change from baseline derived from the MMRM model at week 12 As part of the secondary objectives, treatment differences at each post-baseline visit were also The estimated treatment differences at each visit were derived using the same MMRM model. The results are presented in a summary of statistical analyses with associated p-values.

[0327] Correlations between repeated measurements were modeled using an unstructured covariance matrix. Statistical inference was performed using restricted (or residual) maximum likelihood (REML) for the unstructured data. If the weighted covariance model does not converge with the default Newton-Raphson algorithm, try Fisher Using a scoring algorithm or other suitable method, the initial values ​​of the covariance parameters are calculated. In the unlikely event that none of the above methods result in convergence, ,Structured covariance is used to model the correlation between repeated,measurements.

[0328] Changes from baseline efficacy endpoints were assessed for coprimary endpoints. The analyses were performed using the same MMRM model as described in

[0329] Percentage of patients with at least a 75% reduction in the mean number of daily UUI episodes at 12 weeks and The efficacy endpoint was the proportion of patients who achieved a 50% reduction in the average number of daily urgency episodes. Analyses were performed using Cochran-Mantel-Haenszel risk difference estimates. Week data were analyzed using multiple imputation. Estimated differences in proportion of responders and the mean of those differences The 95% confidence intervals are calculated for OAB type ( Cochran-Mantel-Haensze stratified by sex (female vs male) and wet vs dry. l Risk difference estimates were calculated using

[0330] The co-primary and secondary efficacy endpoints were analyzed The same statistical methods as those used in the exploratory analyses were used for the exploratory responder analyses. - The same Cochran-Mantel-Haenszel model as described above was used for the endpoints. was used and analyzed.

[0331] Safety analyses were performed using the SAF and summarized by treatment group as treated. The period is from the first dose of double-blind study treatment to 28 days after the last dose of study treatment. or the start date of a rollover to another investigational drug, surgical intervention, or extension study. Safety was assessed by a summary of adverse events, treatment-related adverse events, and The patients were evaluated through the frequency of withdrawal and clinical laboratory evaluation.

[0332] The results or effects reported herein are statistically significant based on the above statistical analysis. It should be understood that the level of statistical significance is, for example, at least p<0.05, at least Both may be p<0.01, at least p<0.005, or at least p<0.001. When a result or effect is stated or identified herein, said result or effect will generally occur in the setting of It is understood that the efficacy and safety of the treatment can be evaluated based on its statistical significance compared to a sebum-based baseline. Let it be.

[0333] 8.4 Clinical Trial Data and Results

[0334] In this study, vibegron 75 mg taken once daily achieved three key secondary endpoints: was significantly superior to placebo across all primary endpoints (and two coprimary endpoints) The study showed improved efficacy and further improved efficacy of vibegron in patients with UUI and total urinary incontinence episodes. The results showed significant benefits (see Table 21).

[0335] [Table 21]

[0336] Vibegron 75 mg demonstrated a statistically significant reduction in total urinary incontinence by week 2 and after 12 weeks of treatment This significance was maintained throughout the study period. Vibegron 75 mg significantly reduced the amount of urine excreted per urination. The study showed an increase in bladder capacity, which is a relatively objective measure of increasing bladder capacity. Episodes were reduced by half in the vibegron group versus baseline, and UUI was Nearly half of vibegron-treated patients with UUI episodes reported no improvement after 12 weeks of vibegron therapy. The incidence of pesticide use was reduced by at least 75%. Vibegron was well tolerated with few adverse events. The mean mean mean ≥ 2% was higher than placebo.

[0337] Daily urge urinary incontinence (UU) in all subjects and in men with and without a history of BPH The changes in UI) episodes are shown in Table 22.

[0338] [Table 22]

[0339] Table 23 shows changes in voiding in all subjects and in men with and without a history of BPH. Descriptive statistics are shown in Table 24.

[0340] [Table 23]

[0341] [Table 24]

[0342] For all subjects and for men with and without a history of BPH, the frequency of urgency episodes was The attrition data are shown in Table 25.

[0343] [Table 25]

[0344] Additionally, there was a statistically significant difference in postvoid residual volume (PVR) in all men and in men with a history of BPH. The data are presented in Tables 26 and 27, respectively.

[0345] [Table 26]

[0346] [Table 27]

[0347] By comparison, the PVR in the entire study population is shown in Table 28.

[0348] [Table 28]

[0349] Having now fully described the present invention, it is apparent to those skilled in the art that the present invention or its embodiments may be of any kind that may affect the scope of the present invention or its embodiments. can be performed within a broadly comparable range of conditions, formulations, and other parameters without It is understood that this is possible.

[0350] Other embodiments of the invention may be contemplated in light of the specification and practice of the invention disclosed herein. It will be apparent to one skilled in the art that the present specification and examples are to be considered as illustrative only. It is intended that the true scope and spirit of the invention be indicated by the following claims. .

Claims

1. Methods for treating overactive bladder symptoms in a subject with benign prostatic hyperplasia in need of such treatment orally administering to said subject an amount of about 60 mg to about 90 mg of vibegron per day. A method comprising:

2. 2. The method of claim 1, wherein said amount of vibegron is from about 65 mg to about 85 mg.

3. 2. The method of claim 1, wherein said amount of vibegron is from about 70 mg to about 80 mg.

4. 2. The method of claim 1, wherein said amount of vibegron is about 75 mg.

5. The subject is diagnosed with urge urinary incontinence, urge urinary incontinence, incontinence, urgency, frequency, nocturia, or any combination thereof The method according to any one of claims 1 to 4, wherein the patient has a condition selected from the group consisting of:

6. The subject is diagnosed with urge urinary incontinence, urgency, and frequency. The method of claim 5 having a urinary symptom.

7. The method of claim 1 , wherein the subject is a human.

8. The method of claim 7, wherein the human is a male.

9. 9. The method of claim 7 or 8, wherein the human is over 45 years of age.

10. The method according to any one of claims 1 to 9, wherein the subject suffers from severe renal dysfunction. Law.

11. The method according to any one of claims 1 to 9, wherein the subject suffers from moderate renal impairment. method.

12. 12. The method of claim 1, wherein the subject is concurrently receiving pharmacological therapy for BPH. The method described above.

13. 13. The method of claim 12, wherein the pharmacological therapy for BPH is a 5-alpha reductase inhibitor. method.

14. 13. The method of claim 12, wherein the pharmacological therapy for BPH is an alpha blocker.

15. The pharmacological treatment of BPH consists of a combination of 5-alpha reductase inhibitors and alpha blockers. The method of claim 12, wherein the

16. 16. The method of any one of claims 1 to 15, wherein vibegron is administered once daily.

17. 17. The method of claim 16, wherein vibegron is administered with a meal.

18. 17. The method of claim 16, wherein vibegron is administered without food.

19. 19. The method of any one of claims 1 to 18, wherein vibegron is administered as a free base. 。

20. 19. The method of claim 1, wherein vibegron is administered as a pharma- ceutically acceptable salt thereof.

13. The method according to claim 1.

21. The subjects experienced a mean maximum change from baseline in systolic blood pressure over the treatment period. said mean maximum change being less than 1 mm / Hg from the mean maximum change in subjects taking a placebo 21. The method of claim 1, wherein

22. The subject will have a mean maximum decrease in systolic blood pressure from baseline to less than 8 mm / Hg over the treatment period.

21. The method of any one of claims 1 to 20, wherein the method undergoes a change.

23. The subjects experienced a mean maximum change from baseline in diastolic blood pressure over the treatment period. and the mean maximum change was less than 1 mm / Hg from the mean maximum change in subjects taking placebo.

21. The method according to claim 1 ,

24. The subject will have a mean maximum decrease in diastolic blood pressure from baseline to less than 5 mm / Hg over the treatment period.

21. The method of any one of claims 1 to 20, wherein the method undergoes a change.

25. The subject will have a decrease in the average number of urinations per 24 hours from baseline to approximately -1 21. The method of any one of claims 1 to 20, experiencing a change of from .0 to about -2.

5.

26. The subject will achieve a 50% reduction in daily urgency episodes from baseline over the treatment period.

21. The method of claim 1 , wherein the method experiences a decrease in

27. The subject will achieve a 75% reduction in daily urgency episodes from baseline over the treatment period.

21. The method of claim 1 , wherein the method experiences a decrease in

28. The subjects will achieve at least a 30% increase from baseline in mean voided volume (mL) per micturition.

28. The method of claim 1 , wherein the subject is exposed to a pulmonary circulation.

29. The subjects will have a baseline mean International Prostate Symptom Score (IPSS) score over the treatment period.

29. The method according to claim 1 , wherein the composition experiences a change from about -2.5 to about -5.0 from the line. method.

30. The subjects were randomly assigned to receive a randomized controlled trial based on their mean International Index of Erectile Function (IIEF) domain scores over the treatment period.

30. The method of claim 1, wherein the method undergoes a change from the line.

31. The subject will have a baseline post-void residual urine volume of about 10 mL to about -20 mL over the treatment period.

31. The method of claim 1 , wherein the method experiences a change from the line.

32. The treatment period is selected from the group consisting of 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 weeks; 32. The method of any one of claims 21 to 31.

33. Reducing urination in subjects with benign prostatic hyperplasia who are in need of a method to reduce or decrease urination or reducing the amount of EDTA administered to a subject in an amount of about 60 mg to about 90 mg per day. orally administering vibegron.

34. 34. The method of claim 33, wherein said amount of vibegron is from about 65 mg to about 85 mg.

35. 34. The method of claim 33, wherein said amount of vibegron is from about 70 mg to about 80 mg.

36. 34. The method of claim 33, wherein said amount of vibegron is about 75 mg.

37. The mean number of urinations over a 24-hour period was approximately 0.5 times lower than the mean number of urinations in subjects receiving placebo.

37. The method of any one of claims 33 to 36, wherein the amount is from 5 to about 1.0 less.

38. The reduction or decrease in urination is between about 2.0 and about 2.5 times that achieved with placebo.

37. The method according to any one of claims 33 to 36, wherein the effect is a reduction or decrease in the average number of urinations in a 24-hour period. Method of posting.

39. The reduction or decrease is greater than or equal to that achieved with extended-release tolterodine (ER) 4 mg. and the like. The method of any one of claims 33 to 36.

40. Reducing urination in subjects with benign prostatic hyperplasia who are in need of a method to reduce or decrease urination said method comprising administering to a subject an amount of vibegron of 75 mg per day. orally administering.

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