FIELD OF THE INVENTION

This invention relates to the use of a OXTR antagonist and pharmaceutical formulations containing said OXTR antagonist, for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis.

BACKGROUND TO THE INVENTION

Adenomyosis is an under-diagnosed disease of the uterus defined by the abnormal presence of endometrial glands and stroma in the myometrium accompanied by smooth muscle cell hyperplasia

[Benagiano G, Habiba M, et al. The pathophysiology of uterine adenomyosis: an update Fertil Steril 2012;98:572-579.]. Patients with adenomyosis are primarily pre-menopausal and may experience heavy menstrual bleeding (HMB), severe dysmenorrhea, pelvic pain, and/or dyspareunia [Li X, Liu X, et al. Clinical profiles of 710 premenopausal women with adenomyosis who underwent hysterectomy. J Obstet Gynaecol Res. 2013 2013]. Additionally, the presence of adenomyosis has been implicated in impaired reproductive function including infertility [Campo V and Benagiano G. Infertility and Adenomyosis.

Obstetrics and Gynecology International. 2012;], in vitro fertilization (IVF) failure [Vercellini P, Consonni D, et al. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Human Reproduction, 2014], idiopathic spontaneous abortions [Martinez-Conejero JA1, Morgan M, et al. Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation Fertil Steril. 2011] and other adverse pregnancy outcomes [Mochimaru A, Aoki S, Hirahara F, et. al. Adverse pregnancy outcomes associated with adenomyosis with uterine enlargement. J. Obstet. gynaecol. Res. 2014]. The true incidence of adenomyosis is unknown; reliable epidemiological studies are unavailable because confirmation of the diagnosis of adenomyosis has primarily occurred at the time of hysterectomy.

Adenomyosis diagnosed using transvaginal ultrasonography (TVUS) was present in 20.9% of women attending a gynaecology clinic [(age range not available; [Naftalin J, Hoo W, et al. How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Human Reproduction 2012)] and in 43.3% of women undergoing hysterectomy (age range: 21-55 with a median age of 45 years [Li X, Liu X, et al. Clinical profiles of 710 premenopausal women with adenomyosis who underwent hysterectomy. J Obstet Gynaecol Res. 2013]. Increasing age and gravidity, and the presence of pelvic endometriosis are all significantly associated with the presence of

adenomyosis [Naftalin J, Hoo W, et al. How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Human Reproduction 2012;As the accuracy of imaging modalities such as TVUS and MRI used to detect adenomyosis has improved, diagnosis in women with heavymenstrual bleeding and dysmenorrhea is occurring at an earlier age. Adenomyosis is not a uniform disease but represents a spectrum of lesions, ranging from extensive endometrial invasion of the myometrium and overt diffuse adenomyosis to focal adenomyomas to minimal endometrial invasion with disruption of the junctional zone, the interface between the endometrium and myometrium [Exacoustos C, Brienza L, et al. Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound ' Obstet Gynecoi '2011].

Typically, disease involves the posterior wall of the uterus. The frequency and severity of symptoms appear to correlate with extent [Naftalin J, Hoo W, et al. Is adenomyosis associated with menorrhagia? Hum Reprod. 2014] and depth of disease [Cirpan T, Yeniel O, et al. Clinical symptoms and histopathological findings in subjects with adenomyosis uteri. Clin Exp Obstet Gynecol. 2008] of disease.

There are no drugs approved for the treatment of adenomyosis. Physicians typically prescribe anti-prostaglandins, nonsteroidal anti-inflammatory drugs, tranexamic acid, oral contraceptives, danazol, aromatase inhibitors, gonadotropin-releasing hormone (GnRH) analogs, or a levonorgestrel-releasing intrauterine device system to treat symptoms.

Minimally invasive procedures for therapy such as endometrial ablation, laparoscopic myometrial electrocoagulation and adenomyoma excision are used primarily for focal disease. In the United States, hysterectomy remains the treatment of choice if future fertility is not an issue, if extensive disease precludes a minimally invasive procedure or if other less invasive modalities fail [Levgur M Therapeutic options for adenomyosis: a review. Arch Gynecol Obstet 2007; Cho S, Nam A, et al. Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am J Obstet Gynecol 2008;].

Adenomyosis is considered an oestrogen dependent, proliferative disease of uterine tissues [Kitawaki J. Adenomyosis: the Pathophysiology of an oestrogen-dependent disease. Best Pract Res Clin Obstet Gynaecol. 2006. Oestrogen up-regulates the oxytocin receptor (OXTR) in the uterus with evidence for local synthesis and release of oxytocin by endometrial cells [Zingg HH, Laporte SA. The oxytocin receptor. Trends Endocrinol Metab. 2003;]. Conversely, progesterone inhibits oxytocin receptor signalling [Grazzini E, Guillon G, et al. Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998]. Oxytocin stimulates prostaglandin production in myometrial cells [Zingg HH, Laporte SA. The oxytocin receptor. Trends Endocrinol Metab. 2003;]. In equine endometrial cultures, atosiban (an OXTR and vasopressin 2 receptor antagonist) decreased prostaglandin production [Penrod LV, Allen RE, et al. Oxytocin stimulated release of PGF2a and its inhibition by a cyclooxygenase inhibitor and an oxytocin receptor antagonist from equine

endometrial cultures. Anim Reprod Sci. 2013]. In vitro studies demonstrate that oxytocin promotes cell proliferation in human primary myometrial cells, leiomyomas, human trophoblast, and endothelial neoplastic cells suggesting that the OT/OXTR system may play an important role in regulating uterine cell growth [ Cassoni P, Sapino A, et al. Oxytocin and oxytocin receptors in cancer cells and proliferation. J Neuroendocrine! 2004; Busnelli M, Rimoldi V, et al. Oxytocin-induced cell growth proliferation in human myom etrial cells and leiomyomas. Fertil Steril. 2010].

Oxytocin levels and OXTR expression fluctuate in both endometrium and myometrium during phases of the menstrual cycle suggesting biological functions in the uterus in addition to parturition

[Fuchs F, et al. Oxytocin receptors in nonpregnant human uterus. J Clin Endocrinol Metab.19851; Mechsner S, Grum B, et al. Possible roles of oxytocin receptor and vasopressin-lr receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri. Fertil Steril. 2010]. Oxytocin is linked to uterine peristalsis and contractility in the non-pregnant uterus with studies demonstrating that oxytocin administration at different phases of the human menstrual/oestrous cycle results in differential intrauterine pressure and/or peristaltic response with highest response in the peri- ovulatory interval [Zervomanolakis I, Ott HW, Hadziomerovic D, Mattle V, Seeber BE, Virgolini I, Heute D, Kissler S, Leyendecker G, Wildt L. Physiology of upward transport in the human female genital tract. Ann N Y Acad Sci. 2007].

Several pathways linked to OXTR signaling are implicated in the pathogenesis of adenomyosis including the ERK1/2/MAPK, COX2/prostaglandins, and estrogen biosynthetic/P450 aromatase pathways [Viero C, Shibuya I, et al. REVIEW: Oxytocin: Crossing the bridge between basic science and

pharmacotherapy. CNS Neurosci Ther . 2010; Benagiano G, Brosens I, Habiba M. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. Hum Reprod Update. 2013]. Uterine hyperperistalsis and dysperistalsis has been reported in patients with adenomyosis

[Leyendecker G, Kunz G, et al. Uterine peristaltic activity and the development of endometriosis. Ann N Y Acad Sci. 2004]. Abnormal uterine contractility may play a role in the pathogenesis of both adenomyosis and endometriosis via dislodging of basal endometrium with stem cell potential [Leyendecker G, Kunz G, et al. Uterine peristaltic activity and the development of endometriosis. Ann N Y Acad Sci. 2004]. In patients with adenomyosis, OXTR is up-regulated in the junctional zone [Zhang Y, Yu P, Sun F, Li TC, Cheng MJ, Duan H. Expression of oxytocin receptors in the uterine junctional zone in women with adenomyosis. Acta Obstet Gynecol Scand. 2015\ and OXTR levels correlated with severity of

dysmenorrhea scores in endometrial tissue [Nie J, Liu X, et al. Immunoreactivity of oxytocin receptor and transient receptor potential vanilloid type 1 and its correlation with dysmenorrhea in adenomyosis. Am J Obstet Gynecol. 2010]. In human adenomyosis myometrial strips, increased contractility was associated with increased OXTR [Guo SW, Mao X, et al. Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor in women with symptomatic adenomyosis. Fertil Steril. 2013], and adenomyosis-associated myometrium showed morphological changes consistent with dysperistalsis [Mechsner S, Grum B, et al. Possible roles of oxytocin receptor and vasopressin-lr receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri. Fertil Steril. 2010].

Based on the observations described above, increased OXTR activation and signalling may play a key role in the pathogenesis and progression of adenomyosis. By blocking multiple pathways associated with adenomyosis including pain, proliferation, dysperistalsis and inflammation, treatment with the OXTR antagonist, Epelsiban may have a beneficial effect on the signs and symptoms of adenomyosis.

Epelsiban (3R, 6R)-3-(2, 3-dihydro-l/ inden-2-yl)-l-[(ltf)-l-(2, 6-dimethyl-3-pyridinyl)-2- (4-morpholinyl)-2-oxoethyl]-6-[(15)-l-methylpropyl]-2, 5-piperazinedione is a potent and selective OXTR antagonist in development for enhanced implantation rates during IVF. Epelsiban has nanomolar affinity for the oxytocin receptor and >27,000-fold selectivity over the closely related vasopressin receptors. In nonclinical pharmacology studies, Epelsiban demonstrated competitive antagonism to exogenous oxytocin administered in rat in vitro and in vivo models of myometrial contractility. Epesiban has demonstrated an adequate safety and tolerability profile in completed toxicology studies of up to 13 weeks duration in addition to female fertility, embryofetal and pre-and postnatal development studies in rats and/or rabbits.

WO2006/000399A describes diketopiperazine derivatives including Epelsiban derivatives said to have an antagonist action at the oxytocin receptor.

SUMMARY OF THE INVENTION

In a first aspect the present invention provides a compound which is (3R _r 6>?)-3-(2, 3-dihydro- l inden-2-yl)-l-[(ltf)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(15 )-l- methylp

or a pharmaceutically acceptable salt thereof for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated for use with adenomyosis, the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis.

In a one embodiment of the first aspect the present invention there is provided a compound which is (3R, 6fl)-3-(2, 3-dihydro-l/ inden-2-yl)-l-[(ltf)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4- morpholinyl)-2-oxoethyl]-6-[(15)-l-methylpropyl]-2,5-piperaz inedione:

or a pharmaceutically acceptable acid addition salt thereof, in which the acid is selected from hydrochloric, hydrobromic, nitric, phosphoric, sulphuric, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesu I phonic, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric and maleic acid for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated for use with adenomyosis, the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis

In another embodiment of the present invention there is provided (3/?, 6 ?)-3-(2, 3-dihydro- l/ inden-2-yl)-l-[(l/7)-l-(2, 6-dimethyl-3-pyridinyl) -2-(4-(morpholinyl)-2-oxoethyl]-6-[(15)-l- methylpropyl]-2, 5-piperazinedione for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis.

In another embodiment of the present invention there is provided (3/?, 6 ?)-3-(2, 3- dihydro-lH-inden-2-yl)-l-[(l/?)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(15 )- l-methylpropyl]-2, 5-piperazinedione benzenesulfonate salt, for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis

In second aspect the invention provides a pharmaceutical composition comprising a compound which is (3/?, 6 ?)-3-(2, 3-dihydro-l/-£inden-2-yl)-l-[(l/?)-l-(2, 6-dimethyl-3-pyridinyl)-2- (4-morpholinyl)-2-oxoethyl]-6-[(15)-l-methylpropyl]-2,5-pipe razinedione or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis

In one embodiment of the second aspect the invention there is provided a pharmaceutical composition comprising a compound which is (3/?, 6 ?)-3-(2, 3-dihydro-l inden-2-yl)-l-[(l ?)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(15 )-l-methylpropyl]-2,5-piperazinedione or a pharmaceutically acceptable acid addition salt thereof in which the acid is selected from: hydrochloric, hydrobromic, nitric, phosphoric, sulphuric, methanesulphonic, ethanesu I phonic, benzenesulphonic, p-toluenesu I phonic, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric and maleic acid together with one or more pharmaceutically acceptable carriers for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis

In a third aspect the invention provides the use of a compound which is (3/?, 6 ?)-3-(2, 3- dihydro-l/ inden-2-yl)-l-[(l/?)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(15 )- l-methylpropyl]-2,5-piperazinedione or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis

In one embodiment of the third aspect the invention provides the use of a compound which is (3/?, 6/7)-3-(2, 3-dihydro-l inden-2-yl)-l-[(l ?)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(15)-l-methylpropyl]-2,5-piperazinedione or a pharmaceutically acceptable acid addition salt thereof in which the acid is selected from: hydrochloric, hydrobromic, nitric, phosphoric, sulphuric, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesu I phonic, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric and maleic acid in the manufacture of a medicament for use in the treatment of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, the symptomatic relief of dysmenorrhea associated with adenomyosis, for use in the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis

In a fourth aspect there is provided a method of treating adenomyosis, a method for relieving the symptoms of menorrhagia associated with adenomyosis, a method for relieving the symptoms of dysmenorrhea associated with adenomyosis, a method for relieving the symptoms of dysmenorrhea and menorrhagia associated with adenomyosis, or a method for modification of adenomyosis which method comprises administering a therapeutically effective amount of a compound which is (3/?, 6/?)- 3-(2, 3-dihydro-l/ inden-2-yl)-l-[(l/7)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]- 6-[(15)-l-methylpropyl]-2,5-piperazinedione or a pharmaceutically acceptable salt thereof to a subject in need thereof. In one embodiment of a fourth aspect of the present invention there is provided a method of treating adenomyosis, a method for relieving the symptoms of menorrhagia associated with adenomyosis, a method for relieving the symptoms of dysmenorrhea associated with adenomyosis, a method for relieving the symptoms of dysmenorrhea and menorrhagia associated with adenomyosis, or a method for modification of adenomyosis which method comprises administering a therapeutically effective amount of a compound which is (3/?, 6 ?)-3-(2, 3-dihydro-l inden-2-yl)-l- [(l ?)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(15 )-l-methylpropyl]-2,5- piperazinedione or a pharmaceutically acceptable acid addition salt thereof in which the acid is selected from: hydrochloric, hydrobromic, nitric, phosphoric, sulphuric, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric and maleic acid to a subject in need thereof.

In a fifth aspect there is provided a combination of a compound which is (3/?, 6 ?)-3-(2, 3- dihydro-l/ inden-2-yl)-l-[(l/?)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(15 )- l-methylpropyl]-2,5-piperazinedione or a pharmaceutically acceptable salt thereof with another therapeutic agent suitable for the treatment of of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, the symptomatic relief of dysmenorrhea associated with adenomyosis, the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis.

In one embodiment of a fifth aspect there is provided a combination of a compound which is

(3/?, 6 ?)-3-(2, 3-dihydro-l/ inden-2-yl)-l-[(l/7)-l-(2, 6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(15)-l-methylpropyl]-2,5-piperazinedione or a pharmaceutically acceptable acid addition salt thereof in which the acid is selected from: hydrochloric, hydrobromic, nitric, phosphoric, sulphuric, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric and maleic acid with another therapeutic agent suitable for the treatment of of adenomyosis, for use in the symptomatic relief of menorrhagia associated with adenomyosis, the symptomatic relief of dysmenorrhea associated with adenomyosis, the symptomatic relief of dysmenorrhea and menorrhagia associated with adenomyosis, or for use in modification of adenomyosis.

In some embodiments, the use is in the treatment of adenomyosis.

In other embodiments, the use in the symptomatic relief of dysmenorrhea associated with adenomyosis.

In other embodiments, the use in the symptomatic relief of menorrhagia associated with adenomyosis.

In other embodiments, the use is in the symptomatic reieft of dysmenorrhea! and menorrhagia associate with adenomyosis. In other embodiments, the use is in the modification of adenomyosis. As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. Salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.

The compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.

When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. The compounds of the present invention may be used in combination with tocolytics or prophylactic medicines. These include, but are not limited to, beta-agonists such as terbutaline or ritodrine, calcium channel blockers, e.g. nifedepine, non-steroidal anti-inflammatory drugs, such as indomethacin, salts of magnesium, such as magnesium sulphate, other oxytocin antagonists, such as atosiban, and progesterone agonists and formulations. In addition the compounds of the present invention may be used in combination with antenatal steroids including betamethasone and dexamethasone, prenatal vitamins especially folate supplements, antibiotics, including but not limited to ampicillin, amoxicillin/clavulanate, metronidazole, clindamycin, and anxiolytics.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

The compounds of formula (I) have a high affinity for the oxytocin receptors on the uterus of rats and humans and this may be determined using conventional procedures. For example the affinity for the oxytocin receptors on the rat uterus may be determined by the procedure of Pettibone et al, Drug Development Research 30. 129-142 (1993). The compounds of the invention also exhibit high affinity at the human recombinant oxytocin receptor in CHO cells and this may be conveniently demonstrated using the procedure described by Wyatt et al. Bioorganic & Medicinal Chemistry Letters, 2001 (1 1 ) p1301-1305.

The compounds of the invention exhibit an advantageous pharmacokinetic profile including good bioavailability coupled with good aqueous solubility. In one aspect, the compounds of the invention exhibit good potency and low intrinsic clearance. In another aspect, the compounds of the invention exhibit low intrinsic clearance.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.

It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 1000 mg per day, dependent upon the route of administration.

Thus for parenteral administration a daily dose will typically be in the range 2 to 50mg, preferably 5 to 25mg per day. For oral administration a daily dose will typically be within the range 10 to 1000 mg, e.g. 50 to 500 mg per day.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) and/or pharmaceutically acceptable derivatives thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflation, implant, vaginal or rectal administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tablets or lozenges formulated in the conventional manner.

The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compositions according to the invention may contain between 0.1 -99% of the active ingredient, conveniently from 1 -50% for tablets and capsules and 3-50% for liquid preparations. The advantageous pharmacokinetic profile of the compounds of the invention is readily demonstrated using conventional procedures for measuring the pharmacokinetic properties of biologically active compounds.

The compounds of the invention and pharmaceutically acceptable derivatives thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups are as defined above for compounds of the invention unless otherwise stated.

Compounds of formula (I) may be prepared by reaction of the carboxylic acid (II), wherein Ri , R2 and R3 have the meanings defined in formula (I), and the chirality at R3 is either R or S, or a mixture thereof,

or an activated derivative thereof with the amine HNR4R5, wherein R ₄ and R5 have the meaning defined in formula (I), under standard conditions for preparing amides from a carboxylic acid or an activated derivative thereof and an amine.

It will be appreciated that the mixture of diastereomers of compounds of formula (I) obtained from the above reaction may be separated using standard resolution techniques well known in the art, for example column chromatography.

Thus the amide of formula (I) may be prepared by treating the carboxylic acid of formula (II) with an activating agent such as BOP (benzotriazol-l -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), TBTU (2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate), BOP-CI (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), oxalyl chloride or 1 ,1 '- carbonyldiimidazole in an aprotic solvent such as dichloromethane optionally in the presence of a tertiary amine such as triethylamine and subsequent reaction of the product thus formed, ie the activated derivative of the compound of formula (II), with the amine HNR4R5.

Alternatively the amide of formula (I) may be prepared by reacting a mixed anhydride derived from the carboxylic acid (II), wherein Ri , R2 and R3 have the meanings defined in formula (I) with the amine HNR4R5 in an aprotic solvent such as tetrahydrofuran. Conveniently the reaction is carried out at low temperatures, for example 25 ^° C to - 90 ^° C, conveniently at approximately - 78 ^° C. The mixed anhydride is conveniently prepared by reacting the carboxylic acid (II) with a suitable acid chloride e.g. pivalolyl chloride in an aprotic solvent such as ethyl acetate in the presence of a tertiary organic base such as a trialkylamine e.g. triethylamine and at low temperatures, for example 25 ^° C to - 90 ^° C, conveniently at approximately -78 ^° C.

Compounds of formula (I) may also be prepared by reacting a compound of formula (III)

wherein Ri , R2 and R3 have the meanings defined in formula (I) and R6 is 2-hydroxyphenyl, with 1 ,1 '-carbonyldiimidazole or 1 ,1 '-thiocarbonyldiimidazole in a suitable solvent such as dichloromethane and subsequent reaction of the products thus formed with the amine HNR4R5.

Compounds of formula (II) may be prepared from a compound of formula (III) wherein R6 is 2-hydroxyphenyl by reaction with 1 ,1 '-carbonyldiimidazole or 1 ,1 '-thiocarbonyldiimidazole in a suitable solvent such as dichloromethane and subsequent reaction of the product thus formed with aqueous acetone.

Compounds of formula (III) wherein R6 is 2-hydroxyphenyl may be prepared from the corresponding compounds of formula (III) wherein R6 is a 2-benzyloxyphenyl group by hydrogenolysis using hydrogen and a palladium catalyst.

Alternatively compounds of formula (III) wherein R6 is a 2-hydroxyphenyl may be prepared from the compound of formula (IV)

(IV)

wherein R^ R2 and Rs have the meanings defined in formula (I), R6 is 2-benzyloxyphenyl,

R7 is benzyloxycarbonyl and Re is Ci-6alkyl, by the reaction with hydrogen in the presence of a palladium on charcoal catalyst and acetic acid. This reaction is conveniently carried out in a solvent such as ethanol, trifluoroethanol or mixtures thereof.

Compounds of formula (IV) may be prepared by reacting the amino ester hydrochloride

(V)

wherein Ri has the meaning defined in formula (I) and Re is Ci-6alkyl, with an aldehyde R3CHO (VI) wherein R3 has the meaning defined in formula (I), in the presence of triethylamine and in a solvent such as trifluoroethanol and then reacting the resultant product with a compound of formula (VI I)

wherein Ri has the meaning defined in formula (I) and R7 is t-butyloxycarbonyl or benzyloxycarbonyl and the isocyanide CNR6 (VI I I) wherein R6 is a 2-benzyloxyphenyl group, in a solvent such as trifluoroethanol.

Compounds of formula (I II) wherein R6 is a 2-benzyloxyphenyl group may be prepared from a compound of formula (IV) wherein Ri , R2 and Rs have the meanings defined in formula (I), R6 is 2-benzyloxyphenyl and R7 is t-butyloxycarbonyl by the reaction with hydrogen chloride in dioxan followed with triethylamine in a solvent such as dichloromethane.

The compound of formula (IV) wherein R ₇ is t-butyloxycarbonyl may be prepared by the route described above using a compound of formula (VI I) wherein R ₇ is t-butyloxycarbonyl.

The R2 substituent is a 1 -methylpropyl group and the compound of formula (I) wherein R2 is a 1 -methylpropyl group having an (S) or (R) configuration may be prepared by starting with the aminoester hydrochloride (V) wherein the R2 group has the required (S) or (R) configuration.

Aminoester hydrochloride (V), wherein Ri has the meaning defined in formula (I) and Re is C1-6 alkyl, may be prepared from the corresponding commercially available amino acids, D- alloisoleucine or D-isoleucine, by the method of Schmidt, U; Kroner, M; Griesser, H. Synthesis (1989), (1 1 ), 832-5.

Aldehydes R3CHO (VI), wherein R3 has the meaning defined in formula (I), are either commercially available or may be prepared by literature methods (Comins, Daniel L; Weglarz, Michael A.; J.Org.Chem.; 53; 19; 1988; 4437-4442).

The aminoacid derivative (VI I) wherein Ri has the meaning defined in formula (I) and R7 is t-butyloxycarbonyl is commercially available; the aminoacid derivative (VI I) wherein Ri has the meaning defined in formula (I) and R7 is benzyloxycarbonyl may be prepared from the corresponding commercially available amino acid (/?)-Ri CH(N H2)CC>2H (IX), wherein Ri has the meaning defined in formula (I), by treatment with N-(benzyloxycarbonyloxy)succinimde and triethylamine in a solvent such as dioxane in water. The isocyanide CNR6 (VIII) may be prepared according to literature methods (Obrecht, Roland; Herrmann, Rudolf; Ugi, Ivar, Synthesis, 1985, 4, 400-402).

Acid addition salts of the compound of formula (I) may be prepared by conventional means, for example, by treating a solution of the compound in a suitable solvent such as dichloromethane or acetone, with a suitable solution of the appropriate inorganic or organic acid.

Further details relevant to the manufacture and use of Epelsiban may be found in WO2006/000399A.

Based on the observations described above, increased OXTR activation and signalling may play a key role in the pathogenesis and progression of adenomyosis. By blocking multiple pathways associated with adenomyosis including pain, proliferation, dysperistalsis and inflammation, treatment with the OXTR antagonist, Epelsiban may have a beneficial effect on the signs and symptoms of adenomyosis.

In vitro receptor binding and functional assays have demonstrated that Epelsiban is a potent oxytocin receptor antagonist with nanomolar or lower affinity for rat, baboon and human (Ki of 0.09 nM to 11 nM) oxytocin receptors, and approximately 183X greater potency than its major metabolite. Epelsiban is highly selective (>27000-fold) for the human oxytocin receptor versus human Via, Vlb and V2 vasopressin receptors. In vitro, Epelsiban competitively antagonized the effects of oxytocin on rat myometrial tissue contractility with a pA2 value (the negative logarithm of the molar concentration of antagonist required to produce an agonist dose ratio equal to 2) of 6.53. In vivo in nulliparous rats, intravenous administration of Epelsiban significantly inhibited oxytocin-induced uterine contractility in a dose-dependent manner with an inhibitory dose ID50 of 0.29 mg/kg and the plasma inhibitory concentration IC50 value of 100 ng/mL Similarly, Epelsiban produced significant inhibitory effects following oral administration to nulliparous rats on oxytocin-induced uterine contractions following both single and repeat doses. The high affinity and selectivity of Epelsiban for the oxytocin receptor suggests that it will interact with endogenous human oxytocin receptors with little or no effects on closely related vasopressin receptors.

To date Epelsiban has been administered to 173 subjects: 38 healthy male volunteers in a first time in human (FTIH) trial, 50 men with premature ejaculation in a phase II proof of concept (POC) trial, and 85 healthy females of child bearing potential in three pharmacokinetic (PK) studies. No clinically relevant risks were identified when taking Epelsiban at doses up to 450 mg two times daily for 14 days that would preclude dosing for 12 weeks.

The objectives of the IND-opening study, a Phase 2 randomised, double-blind, placebo- controlled, parallel group, proof of concept study are to assess, tolerability and effect of Epelsiban compared to placebo on the change in monthly menstrual blood loss (MBL) from baseline to menstrual cycle 3 In women with adenomyosis, and will be the first dosing experience of Epelsiban in this study population. Data from this Phase 2a study will be used to inform the range of doses to be evaluated in the Phase 2b dose ranging study. By blocking OXTR signalling of pathways associated with adenomyosis including pain, proliferation, dysperistalsis, and inflammation, treatment with Epelsiban may reduce MBL and dysmenorrhea in subjects with adenomyosis.

Table 1. Objective(s)/Endpoint(s)

Objectives Endpoint

Primary

To assess the effect of Epelsiban on the MBL measured from blood collected from percent menstrual cycle by-products and recovered by change in monthly menstrual blood loss (MBL) alkaline hematin methodology during each from baseline to menstrual cycle 3 compared to menstrual cycle.

placebo in women with adenomyosis

To assess the safety and tolerability of Safety parameters include adverse events (AE); Epelsiban in women with adenomyosis. clinical laboratory tests; thyroid stimulating

hormone (TSH); iron; ferritin; total iron binding capacity (TIBC); serum progesterone, estrogen and prolactin levels; urine specific gravity;

concomitant medications; electrocardiograms; vital signs; and menstrual blood loss.

Secondary

To assess the effect of Epelsiban on the change Average daily dysmenorrhea score from Day -1 from baseline in dysmenorrhea score at to Day 2 of menses captured daily via menstrual cycles 1, 2 and 3 compared to Menstrual

placebo. Diary in the Adenomyosis Symptoms and

Impacts electronic Patient Reported Outcomes [(e)PRO] measure).

To assess the effect of Epelsiban on the change MBL measured from blood collected from from baseline in MBL at menstrual cycles 1, 2, menstrual cycle by-products and recovered by and 3 compared to placebo alkaline hematin methodology during each

menstrual cycle

To characterize the pharmacokinetics (PK) of Plasma Epelsiban and GSK2395448

Epelsiban and its metabolite, GSK2395448 in an concentrations.

adenomyosis population.

Exploratory

Number of subjects achieving a 25% MBL measured from blood collected from or greater reduction in MBL. menstrual cycle by-products and recovered by alkaline hematin methodology during each menstrual cycle.

Change from baseline in adenomyosis Adenomyosis Symptoms and Impacts (e)PRO symptoms and impacts measure to menstrual measure that will capture symptoms throughout cycle 3. each menstrual cycle (on menses and off menses) for cycles 1, 2, and 3.

To explore the ability of magnetic resonance Maximal junctional zone thickness at a region of imaging (MRI) of the uterus to measure interest, uterine volume, bright foci on T2.

different

features of adenomyosis at baseline and 12

wks

in Epelsiban and placebo-treated women with

adenomyosis.

Change from baseline in analgesic usage for High, medium and low total analgesic use control of dysmenorrhea symptoms at during

menstrual menses.

cycles 1, 2 and 3 compared to placebo.

This is a 12-week, randomized, double-blind, placebo-controlled, parallel group study with an interim utility analysis in women with adenomyosis. The study will be composed of three periods: Screening, Treatment, and Follow-up. A subject's total time involved in the study will be approximately 6 months. There will be three treatment arms with approximately 24 subjects per arm randomized 1: 1: 1 to receive 75 mg of Epelsiban three times daily, 200 mg of Epelsiban three times daily, or placebo three times daily. After at least 10 patients in each arm have been evaluated, a futility check will be made on the low and high dose primary efficacy endpoint, MBL. Failure of the low dose to achieve a predictive probability of success of 0.2 will result in discontinuation of enrolment into the low dose arm. Failure of the high dose to achieve a predictive probability of success of 0.2 will result in discontinuation of enrolment into the high dose arm. If the study is fully enrolled at the time of the futility analysis, the futility analysis will not be conducted. Each subject will be enrolled in only one treatment arm.

A screening number of subject with suspected adenomyosis complaining of heavy menstrual bleeding will be screened for the study to obtain approximately 24 subjects per treatment arm. Screening assessments will consist of two menstrual periods to determine eligibility and will be performed within 120 days prioer to enrolment.

For this study, three screening assessments will be performed:

• Screening A (Visit 1) is the initial screening. Subjects will be instructed on how to collect and store menstrual cycle by-products for their upcoming cycle.

· During screening B (Visit 2), menstrual cycle by-products will be returned to the clinic and subjects will be given additional menstrual cycle products for their next menses. Subjects will be shown a demonstration of how to utilize the (e)PRO device and receive the device to be completed daily beginning approximately 1 week before their next menses. Subjects will be scheduled for a MRI and endometrial biopsy.

The MRI must be conducted 7 to 10 days following Day 1 of the next menses. • Screening C (Visit 3) is the final screening assessment. Subjects will return their menstrual cycle by-products to the clinic and be given additional menstrual cycle products for their next menses. Study personnel should ensure that the information collected in the (e)PRO is being entered completely. Subjects who meet all the inclusion criteria (including MBL ectsmL total blood loss per menstrual cycle on either Screening B or Screening C alkaline hematin test) and none of the exclusion criteria will be randomized and return to the clinic to receive their first dose of study treatment at Visit 4 Visit 4 may be postponed for one menstrual cycle, and the first dose of study treatment will be scheduled 12 to 16 days after Day 1 of the next menses.

Table 2 Regimen Descriptions

Subjects will be discharged from the clinic after the initial dosing and will continue to

take the study medication as directed. Subjects should continue to enter information into the (e)PRO device daily. Subjects will return to the clinic with their menstrual byproducts approximately four days after their menstrual period ends for each cycle for a total of three menstrual cycles while in the treatment phase. Subjects will receive their morning dose of study medication in the clinic on these visits and will receive additional study medication to take as directed. The total daily dose of Epelsiban to be administered to any subject in any cohort will not exceed a total daily dose of 600 mg Subjects will receive a follow up telephone call from the clinic approximately seven to ten days post-last dose for follow up assessments

Approximately 600 subjects will be screened to randomize 72, with approximately 24 randomized subjects per treatment arm.

Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose levels with a protocol amendment.

This study is a Phase 2a, randomized, double-blind, placebo-controlled study using a standard parallel group study design.

As there are no validated experimental animal models of adenomyosis to generate data on target Epelsiban therapeutic exposures that can be used to extrapolate to an exposure response prediction in patients, exposures from a rodent model evaluating the effect of Epelsiban to inhibit oxytocin-induced uterine contractions adjusted for interspecies differences in protein binding and potency was used. The target exposures derived from the IC50 and IC90 in the rodent model reflect the ability of Epelsiban to inhibit the oxytocin signaling pathway(s) for stimulating myometrial contractility in a non-pregnant uterus. It is unknown if the target therapeutic exposure should be adjusted for increased oxytocin receptor expression in the adenomyotic uterus [Zhang Y, Yu P, Sun P, Li TC, Cheng J, Duan H. Expression of oxytocin receptors in

the uterine junctional zone in women with adenomyosis. Acta Obstet Gynecol Scand.

2015] and/or if a higher target exposure is required to inhibit the alternative oxytocin signaling pathways for proliferation and inflammation, which may play a role in the development and progression of adenomyosis. Therefore, higher target concentrations of Epelsiban may be necessary to elicit an effect.

The term "study treatment" is used to describe any combination of products received by the subject as per the protocol design. Study treatment may therefor refer to the individual study treatments or the combination of those study.

Table 3. Study Treatment

randomized 1: 1: 1 to receive Epelsoban 200 mg TID, Epelsiban75 mg TID, or placebo TID. Each subject will be enrolled in ony ne treatment arm, and will take a total of three tablets times per day. Study treatment should be taken with food or immediately after a meal. The total daily dose of Epelsiban to be administered to any subject in any cohort will not exceed a total daily dose of 600 mg.

After the initial screening visit (Screening A), subjects will be given menstrual cycle collection products with detailed instructions on the collection process (details are in the SRM or the laboratory manual) Subjects will return to the clinic seven to ten days after the beginning of their menses to return al used products (Screening B). Additional screening activities will be completed, and they will be given additional menstrual cycle roducts for the next mnth. Subjects will return to the clinic seven to ten days after the beginning of their menses to return all used products (screening C). Additional screening activities will be completed, and they will be given additional menstrual products for the next month.

If the alkaline hematin results of Screening B are >60ml_, the subject continues with Screening C. If the alkaline hematin results of Screening B are<60ml_, the subject is considered a screen failure.

Subjects will return to the clinic seven to ten days ater the beginning of their next menses to return all used products for Screening C. Subjects with alkaline hematin results >80ml_ on either the Screening B or Screening C collection, who meet all other incusion criteria and none of the exclusion criteria, will return to the clinic between 12 and 16 days from when their last cycle started for randomization and for their first day to receive study treatment.

Subjects will be required to have their MBL measured from menstrual cycle by-products and recovered by alkaline hematin testing for 2-3 menstrual cycles during screening and each menstrual cycle until the end of the study treatment period. Subjects are required to use only the menstrual cycle products (pads, tampons and liners) provided by the sponsor. No other brand or product should be utilized. All used products should be returned to the clinic preferably within four days fromt he end of the menses.

Subjects will utilize the (e)PRO device measure to record dysmenorrhea scores in addition to other symptoms and macts associated with adenomyosis at baseline and during each menstrual cycle.

Magnetic Resonance Imagine (MRI)

MRI is being used because its properties (reproducibiity, increased resolution, and reduced operator variability) are expected to provide an advantage over use of TVUS [Champaneria R, Abedin P, Daniels J, et. al. Ultrasound scan and magnetic resonance imaging for the diagnosis of

adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010]

Bowel motility influences the image quality of MRI of the pelvic region and is often the cause for movement artifacts. Thus, anti-peristaltic agents such as glucagon are routinely used to improve the quality of images and pelvis. Administration of glucagon l.Omg intramuscularly immediately prior to the MRI is intended to reduce movment artifacts that may interfere with measurements of junctional zone thickness [Froehlich IM, Daenzer M, von Weymarn C et al. Aperistaltic effect of hyoscine Nbutylbromideversus glucagon on the small bowel assessed by magnetic resonance imaging. Eur Radiol. 2009.

Transvaginal Ultrasound (TVUS)

A TVUS will be conducted. The imagine is to identify subjects that may have findings suggestive of adenomysis defined as globular or asymmetric uterus with lack of contour abnormality or mass effect, obscured endometrial-myomerial interface, or hypo or hyperechoic areas with or without subendometrial or myometrial cysts on imaging [Reinhold C, Tafazoli P, Wang L. Hum Reprod Update. 1998]. If other imaging (i.e. MRI) has been performed with the previous 12 months of screening suggestive of adenomyosis, this may be utilized in place of the TVUS.

Pharmacokinetics

Blood Sample Connection

Blood samples for pharmacokinetic (PK) analysis of Epelsiban and its major metabolite will be collected and detailed. PK sampling should only be collected at either the end of cycle one or end of cycle two visit (Visit 5 or Visit 6). The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring.

Blood Sample Analysis

Plasma analysis will be performed. Concentrations of Epelsiban and its major metabolite will be determined in plasma samples using the currently approved bioanalytical methodology.

Bioma rketf s) / Pha rmacodvna mic Ma rkers

CA125 is a high molecular weight glycoprotein present in the epithelium of the

endometrium. CA125 concentrations have been reported to be elevated in patients with

adenomyosis [Kil K, C JE, Pak HJ, et. al. Usefulness of CA125 in the differential diagnosis of uterine adenomyosis and myoma. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2015\.

Adenomyosis Symptoms and Impacts Electronic Patient Reported Outcome Measure rfe)PRQ1

The signs and symptoms of adenomyosis and the impact of Epelsiban on both the signs and symptoms during menses and throughout the entire menstrual cycle will be assessed using the daily (e)PRO measure. The (e) PRO is a multi-item self-reported daily

assessment of symptoms and patient impact of adenomyosis. The development of

the ePRO was based on patient interviews and existing questionnaires (e.g. the Pfizer

Endometriosis Pain and Bleeding Diary [Deal, 20 I 0] and the Menorrhagia Impact

Questionnaire [Busnelli M, Rimoldi V, et al. Oxytocin-induced cell growth proliferation in human myom

etrial cells and leiomyomas. Fertil Steril. 2010). The (e)PRO will be completed on a daily basis once the subject meets the Screening B MBL criteria and continue through the collection of the 3rd menstrual cycle by-products on treatment (approximately week 12). Clinics will provide

adequate training to subjects on the completion of the (e) PRO during the Screening B

clinic visit. Subjects will be asked to bring the (e) PRO device to the clinic at each visit to ^■ be reviewed with the study site staff.

Subjects must return the (e )PRO device to the clinic during their end of Cycle 3 visit or at the follow up visit if they are withdrawn early from the study.

Dysmenorrhea Dysmenorrhea scores will be collected in a daily Menstrual Diary via the (e) PRO device. Additional details regarding the questionnaire administration, recording of data, and

collection and storage of the information are provided in the SRM.

The hypothesis tested is whether the mean percent change from baseline to end of cycle 3 ~ MEL on treatment is greater for active treatment than placebo.

Listings will be provided for non-quantitative exploratory end points.

The proportion of patients estimated from linear regression of log MBL that meet or exceed 25% along with 90% credible intervals by treatment arm.

Adenomyosis symptoms and impacts will be summarized by frequency of categories of descriptors.

Junctional zone thickness measurements and change from baseline in junctional zone thickness measurements will be described by means, standard deviations, and 90%

confidence interval estimates by treatment arm.

Uterine volume and change from baseline measurements of uterine volume will be described by means, standard deviations, and 90% confidence intervals by treatment arm.

T2 foci will be characterized by a five number summary (min, first quartile, median, third quartile, max) by treatment arm.

High, medium and low total analgesic use will be summarized by mean, standard deviation and 90% confidence interval by treatment arm.

Haemoglobin, haematocrit, erythrocyte count, and iron metabolism parameters (serum ferritin, iron and total iron binding capacity levels) and change from baseline hemoglobin, hematocrit, erythrocyte count, and iron metabolism parameters (serum, ferritin, iron and total iron binding capacity levels) will be summarized by mean, standard deviation, and 90% confidence intervals by treatment arm.

Menstrual cycle frequency and regularity, and duration of menses will be summarized by mean, standard deviation, and 90% confidence intervals by treatment arm.

Daily pad/tampon count and change from baseline daily pad/tampon count via (e)PRO will be summarized by mean, standard deviation, and 90% confidence intervals by treatment arm.

Serum CA 125 levels and change from baseline CAI25 levels will be summarized by mean, standard deviation and 90% confidence intervals by treatment arm.

Scatter plots and all pair-wise correlations, along with 90% confidence intervals will be used for the correlation between various changes from baseline MRI imaging features

with percent change from baseline MBL, change from baseline dysmenorrhea and change from baseline CA125 levels.

Scatter plots and all pair-wise correlations, along with 90% confidence intervals will be used for the correlation between change from baseline CA 125 levels with percent change from baseline MBL and change from baseline dysmenorrhea. Scatter plots will be used for the correlations between the change from baseline CA125 levels, percent change from baseline MBL and change from baseline dysmenorrhea with

trough epelsiban and GSK2395448 plasma concentrations as data allow.

Assessment of Menstrual Diary and Adenomvosis Svmptons and Impacts (e)PRO

Exit interviews will be conducted as the final procedure at visit 7 shown in the Time and

Events table to explore subjects' experience with the (e)PRO at specified study sites. Pre-selected sites will conduct one-on-one interviews with a total of approximately 30-40 study participants. Study participants at these defined sites will be asked to pallid pate in this assessment. Subjects will be asked to consent to the exit interview within the context of study consent. Specifically, the interviews will assess the patient's experience with study questionnaires including: 1) interpretation of items; 2) thoughts about the relevant recall period; 3) feedback on the content in relation to their most important symptoms and overall symptoms and impacts; and 4) for any symptoms or impacts not included. In addition, usability of the (e)PRO, will be assessed (e.g. ease

of navigation, readability of text, and use of response options, etc).

The interviews will follow a semi-structured interview guide to be administered by clinic site staff. Site staff will be trained in conducting qualitative research interviews. The exit interview will be conducted, transcribed, and analysed in English. Exit interviews will be audio-taped for subsequent transcription and qualitative analysis. The Exit interview procedures, questions, and data

management of recordings will be described in the training materials and provided to site personnel who will administer the Exit interviews. Details will be included the SRM.

Electronic PRO data capture during the study as well as information captured in the exit interviews will be used to further evaluate the content validity and psychometric

performance of the questionnaire and relevant scoring of the instrument.