Methods of treating heavy menstrual bleeding

Abstract

The present invention relates to the method of treating heavy menstrual bleeding in a subject with or without uterine fibroids and in need of treatment by administering an effective amount of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof, in combination with estrogens and progestogens.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. patent application Ser. No. 14 / 211,096, filed on Mar. 14, 2014, which claims priority to U.S. patent application Ser. No. 61 / 788,821, filed on Mar. 15, 2013, the entire contents of which are fully incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention pertains to the use of GnRH receptor antagonists for the treatment of heavy menstrual bleeding in a subject with or without uterine fibroids.BACKGROUND OF THE INVENTION[0003]Uterine fibroids (leiomyomata) are the most common benign tumors in women. Uterine fibroids are highly prevalent in women of reproductive age and are identified in more than 50% of women between 35 and 50 years of age. The incidence increases with age and is the most common reason for hysterectomy (Buttram V C Jr, Reiter R C. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981;36(4):433-45; Day Baird D, Dunson D B, Hill M C, et a...

AI Technical Summary

Problems solved by technology

Obstetric outcomes attributed to fibroid tumors result in a cost of $238 million to $7.76 billion annually.

Symptoms associated with fibroids most commonly include heavy or prolonged menstrual bleeding, pelvic pressure and pelvic organ compression, back pain, and adverse reproductive outcomes.

2004;6:88-92) is inconvenient and may lead to iron-deficiency anemia, a key symptom of uterine fibroids and the leading cause of surgical interventions that may include hysterectomy.

However, surgery is also associated with risks such as infections, bleeding complications, thromboembolic effects, scarring / adhesions, and even increased mortality (Maresh M J A, Metcalfe M A, McPherson K, et al.

Of note, none of these uterus-sparing methods provide definitive cure, as fibroids often recur following treatment.

Unfortunately, currently available medical options provide only short-term improvement of symptoms, and as such, are only indicated prior to surgery or their side-effects limit their long-term use.

Currently there are no chronic treatments approved for the long term management of heavy menstrual blood loss associated with symptomatic uterine fibroids.

Although combined oral contraceptives (OCs) are widely used for the treatment of women complaining of anovulatory bleeding, to date, there are no high-quality comparative studies supporting their use in heavy menstrual bleeding associated with uterine fibroids.

However, LNG-IUS may only be used in women who have no distortion of the uterine cavity.

However, little evidence supports the use of progestins in the presence of uterine fibroids and high-dose progestin may stimulate fibroid growth when used continuously as a monotherapy, or in conjunction with a GnRH agonist as add-back therapy (Carr B R, Marshburn P B, Weatherall P T, et al.

In addition, continuous use of progestins may actually induce breakthrough bleeding and spotting via negative effects on normal endometrial angiogenesis (Hickey M, Dwarte D, Fraser I S. Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding.

In addition, the side effects of estrogen deprivation, primarily bone mineral density (BMD) loss and severe hot flushes, limit the use of GnRH agonists.

High-dose progestin treatment is also associated with uterine bleeding abnormalities such as breakthrough bleeding and spotting, and systemic side effects, including weight gain and metabolic effects (Hickey M, Dwarte D, Fraser IS.

However, the chronic use of estrogen alone (without a progestin) as add-back therapy is not feasible because of the risk of unopposed estrogen effect on the endometrium that may lead to endometrial hyperplasia.

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