Gonadotropin-releasing hormone antagonist dosing regimens for treating uterine fibroids and reducing menstrual blood loss
Inventors
Loumaye, Ernest • Gotteland, Jean-Pierre • Pohl, Oliver
Assignees
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Publication Number
US-11759464-B2
Publication Date
2023-09-19
Expiration Date
Abstract
The invention provides compositions and methods for reducing the volume of menstrual blood loss in a patient, such as a human patient, for instance, that has uterine fibroids, by administration of a gonadotropin-releasing hormone (GnRH) antagonist. 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-methoxypheny I]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid and the choline salt thereof.
Core Innovation
The disclosure relates to GnRH antagonist thieno[3,4d]pyrimidine derivative compounds, including 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 pharmaceutically acceptable salts thereof, including a choline salt. The document describes using these compounds in therapeutically effective amounts to treat uterine fibroids and to reduce menstrual blood loss volume in a female human patient.
The methods further include administering add-back therapy comprising about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate. The disclosure associates suppression of β17-estradiol to estradiol serum concentration thresholds, including <50 pg/mL and lower thresholds, with attenuation of bleeding, and links the add-back therapy to prevention of bone mineral density loss and mitigation of hypoestrogenemia-related concerns.
The disclosure describes dosing regimens in which the compound is administered at about 100 mg per day or about 200 mg per day, including oral administration and multiple dose/frequency options. It also reports clinical outcome expectations such as amenorrhea and reduced menstrual blood loss volume.
Claims Coverage
The provided claim set includes two independent claims. Each independent claim defines a method that combines administration of a specific thieno[3,4d]pyrimidine derivative or pharmaceutically acceptable salt with add-back therapy comprising about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.
Reducing the volume of menstrual blood loss with daily compound dosing plus add-back therapy
A method of reducing the volume of menstrual blood loss in a female human patient by administering 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 or a pharmaceutically acceptable salt at about 100 mg per day or about 200 mg per day, together with add-back therapy comprising about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.
Treating uterine fibroids with daily compound dosing plus add-back therapy
A method of treating uterine fibroids in a female human patient in need thereof by administering 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 or a pharmaceutically acceptable salt at about 100 mg per day or about 200 mg per day, together with add-back therapy comprising about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.
Both independent claims cover co-administration of a specific GnRH antagonist compound or pharmaceutically acceptable salt at about 100 mg/day or about 200 mg/day with add-back therapy containing about 1.0 mg β17-estradiol and about 0.5 mg norethindrone acetate, for reducing menstrual blood loss or treating uterine fibroids.
Stated Advantages
Mitigation of hypoestrogenemia-related bone mineral density loss during GnRH antagonist treatment through add-back therapy.
Reduction of menstrual blood loss with associated clinical responses including amenorrhea.
Increase in serum hemoglobin.
Attenuates bleeding associated with suppression of β17-estradiol to estradiol serum concentration thresholds, including <50 pg/mL and lower thresholds.
Supports menstrual and amenorrhea outcomes during treatment.
Documented Applications
Methods for reducing the volume of menstrual blood loss in a female human patient, including contexts involving heavy menstrual bleeding/menorrhagia and uterine fibroids.
Methods of treating uterine fibroids in a female human patient in need thereof using the specified compound and add-back therapy.
Reducing the volume of menstrual blood loss in a female human patient.
Treating uterine fibroids in a female human patient in need thereof.
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