Compositions and methods for the treatment of adenomyosis and rectovaginal endometriosis
Inventors
Gotteland, Jean-Pierre • Loumaye, Ernest
Assignees
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Publication Number
US-12280052-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The present disclosure provides compositions and methods for treating endometrial growth disorders in a patient, such as a human patient, and particularly pre-menopausal female human patients. Exemplary disorders that may be treated using the compounds and therapeutic regimens described herein include adenomyosis and rectovaginal endometriosis. The compounds described herein that may be used to treat such indications include gonadotropin-releasing hormone (GnRH) antagonists. Suitable GnRH antagonists useful in conjunction with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid and the choline salt thereof, among others.
Core Innovation
The disclosure relates to administering a GnRH antagonist for treating adenomyosis in a human patient in need thereof. The treatment is carried out by administering a therapeutically effective amount of a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable choline salt form.
The document also describes alternative compound formula sets, including formulas (I) through (XIV), and identifies the specific compound 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid. Related structural characterization includes XRPD, solid-state NMR, HPLC-MS, and 1H NMR, together with crystalline state characterization for the choline salt.
The disclosure associates adenomyosis treatment with reductions in FSH, LH, and E2, reduction of uterine volume and rectovaginal endometriosis node volume, and improvements in pelvic pain and related symptoms including dysmenorrhea, dyspareunia, dyschezia, and uterine bleeding. It also references amenorrhea measures, EHP-30 and PGIC scores, bone mineral density stability, add-back therapy, and kit embodiments with package insert instructions.
Claims Coverage
The consolidated claim coverage centers on one independent method claim directed to treating adenomyosis in a human patient by administering a therapeutically effective amount of formula (VI) compound or a pharmaceutically acceptable salt. The combined dependent features refine the method with a choline salt form, oral administration, once-daily dosing, an example daily dose around 100 mg/day, and assessment of uterine volume reduction by MRI or TVUS.
Treating adenomyosis with formula (VI) compound or salt
Administering to a human patient a therapeutically effective amount of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid represented by formula (VI), or a pharmaceutically acceptable salt thereof, for treating adenomyosis.
Use of a pharmaceutically acceptable choline salt form
Treating adenomyosis using the method in which the compound is provided as a pharmaceutically acceptable choline salt form of compound (VI).
Oral administration of compound (VI) or salt
Administering the compound (VI) or a pharmaceutically acceptable salt thereof orally to the patient.
Once-daily dosing schedule
Administering the compound to the patient once daily.
Example daily dosage around 100 mg/day
Administering the compound at an amount of about 100 mg per day.
Uterine volume reduction assessed by MRI or TVUS
Assessing reduction in uterine volume using MRI or transvaginal ultrasound (TVUS) as an outcome within the treating method.
The claim set consolidates around treatment of adenomyosis with formula (VI) or a pharmaceutically acceptable salt, including a choline salt embodiment. The dependent refinements consistently specify oral, once-daily administration, an example daily dosage around 100 mg/day, and imaging-based assessment of uterine volume reduction.
Stated Advantages
Reduced serum FSH, LH, and E2.
Reduced uterine volume.
Reduced myometrial/junctional zone thickness.
Reduced rectovaginal endometriosis node volume.
Reduced pelvic pain and related symptoms, including dysmenorrhea, dyspareunia, dyschezia, and uterine bleeding.
Achievement of amenorrhea.
Improved Endometriosis Health Profile (EHP-30) and Patient Global Impression of Change (PGIC) scores.
Bone mineral density stability.
Diminution of lesions.
Sustained reduction in adenomyosis-associated pain.
Documented Applications
Treating adenomyosis in a human patient in need thereof using a GnRH antagonist compound of formula (VI) or a pharmaceutically acceptable salt, including a choline salt form.
Treating rectovaginal endometriosis as a female endometrial growth disorder.
Use in a kit with package insert instructions for treating adenomyosis.
Evaluating therapeutic response in adenomyosis patients using imaging-based assessment of uterine volume by MRI or transvaginal ultrasound (TVUS) and assessing pelvic pain and related symptoms.
Assessing rectovaginal endometriosis and rectovaginal endometriosis nodes using GnRH antagonists, including use of EHP-30 and PGIC.
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