A COMPOSITION FOR TREATING ONE OR MORE ESTROGEN RELATED DISEASES
20210052692 ยท 2021-02-25
Inventors
Cpc classification
A61K38/09
HUMAN NECESSITIES
International classification
Abstract
The present invention relates to treating one or more estrogen related diseases while preventing or reducing the likelihood of developing estrogen deficiency related side effects, wherein said composition comprises administering a therapeutically effective amount of a Gn RH antagonist to a patient in need of said treatment, and wherein said amount of Gn RH antagonist is sufficient for providing a mean endogenous serum estradiol level of between about 20 pg/ml and 60 pg/ml, preferably between 30 pg/ml and 50 pg/m, in said patient in a treatment period of at least four weeks, without relying on add-back therapy. Said composition and method is simple, effective and will accordingly both increase patient acceptance and compliance of therapy.
Claims
1-12. (canceled)
13. A pharmaceutical composition for the treatment of an estrogen related disease while preventing or reducing the likelihood of developing estrogen deficiency related side effects, said composition comprises a therapeutically effective amount of at least one GnRH antagonist administered in a sustained release formulation in the form of a microcrystalline aqueous suspension, and wherein said therapeutically effective amount is sufficient for providing a mean endogenous serum estradiol level of between about 20 pg/ml and 60 pg/ml in a patient in a treatment period of at least four weeks, and wherein an add-back therapy is not administered to the patient during the treatment period.
14. The composition according to claim 13, wherein the mean endogenous serum estradiol level is between about 30 pg/ml and 50 pg/ml in a patient in a treatment period of at least four weeks.
15. The composition according to claim 13, wherein the mean endogenous serum estradiol level between about 20 pg/ml and 60 pg/ml, preferably between 30 pg/ml and 50 pg/ml, is maintained for treatment period of at least eight weeks or longer.
16. The composition according to claim 15, wherein the mean endogenous serum estradiol level is between 30 pg/ml and 50 pg/ml.
17. The composition according to claim 13, wherein the mean endogenous serum estradiol level between about 20 pg/ml and 60 pg/ml is provided by administrating a single dosage of a therapeutically effective amount of GnRH antagonist.
18. The composition according to claim 17, wherein the mean endogenous serum estradiol level is between 30 pg/ml and 50 pg/ml.
19. The composition according to claim 13, wherein the GnRH antagonist or salt thereof is NAc-d-Nal.sup.1,d-pCl-Phe.sup.2,d-Pal.sup.3,d-(Hci).sup.6,Lys(iPr).sup.8,d-Ala.sup.10 trifluoro-acetate (Teverelix TFA).
20. The composition according to claim 13, wherein the GnRH antagonist is selected from the group consisting of Azaline B, Abarelix, Antide, Cetrorelix acetate, and Ganirelix
21. The composition according to claim 13, wherein the GnRH antagonist is Teverelix TFA and the therapeutically effective amount comprises between 25 and 80 mg of Teverelix TFA, preferably between 30 and 60 mg of Teverelix TFA, and even more preferred about 45 mg Teverelix TFA.
22. The composition according to claim 13, wherein the estrogen-related disease is endometriosis.
23. The composition according to claim 13, wherein said estrogen-related diseases are uterine fibroids or uterine leiomyomas.
24. The composition according to claim 13, wherein said estrogen-related diseases are endometrial cancer, uterine cancer, uterine leiomyosarcomas, ovarian cancer or breast cancer.
25. The composition according to claim 13, wherein said estrogen-related diseases are dysfunctional uterine bleeding, vaginal bleeding, menorrhagia, cervical intraepithelial neoplasia, or adenomyosis.
26. A method of treating one or more estrogen related diseases while preventing or reducing the likelihood of developing estrogen deficiency related side effects, wherein said method comprises administering a single dosage of between 25 and 80 mg of the GnRH antagonist, Teverelix TFA administered in a sustained release formulation in the form of a microcrystalline aqueous suspension, to a patient in need of said treatment thereby initiating a treatment period of at least four weeks, and wherein a mean endogenous serum estradiol level of between about 20 pg/ml and 60 pg/ml is obtained in said patient during the treatment period, without relying on add-back therapy.
Description
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0031]
[0032]
[0033]
[0034]
[0035]
[0036]
[0037]
DETAILED DESCRIPTION OF THE INVENTION
[0038] The composition for treating the estrogen related disease comprises administering a therapeutically effective amount of a GnRH antagonist to a patient in need of said treatment, said amount of GnRH antagonist is sufficient for providing a mean endogenous serum estradiol level of between about 20 pg/ml and 60 pg/ml, preferably between about 30 pg/ml and 50 pg/ml, in said patient for at least four weeks, without relying on add-back therapy.
[0039] Even though it is known that lowering the serum estradiol level below 50 pg/ml has the desired effect of inhibiting proliferation of endometrial tissue in a menstruating female, there is a coincident problem of possibly not providing enough estrogen to mitigate, avoid or protect against the menopausal-like symptoms associated with a castrate-like estrogen level. For instance, when the mean endogenous estrogen level falls below about 15 pg/ml, estrogen depletion side-effects occur.
[0040] However, in contrast to the treatments known in the art were the side-effects of endogenous estrogen depletion has been prevented by adding back estrogen, i.e. the so add-back therapy as suggested by Barberi 1992, the composition of the present invention is capable of not only obtaining a mean endogenous serum estradiol level of between about 30 pg/ml and 50 pg/ml but also maintaining said serum level for at least four weeks without simultaneously administration of small amounts of estrogen.
[0041] Thereby is obtained a very effective, simple and inexpensive composition for treating estrogen related diseases. Since, the composition according to the invention does not rely on add-back therapy, the composition will furthermore be more acceptable to patients and more efficient to administer.
[0042] An ideal treatment for endometriosis would be a single composition that suppresses estradiol production sufficiently to alleviate the symptoms of endometriosis and other estrogen dependent disorders ideally for a prolonged period of time of at least four weeks, preferable at least eight weeks or even longer, but not to such an extent that serious and irreversible bone loss occurs.
[0043] While the amount of GnRH antagonist provided in the regimen of the present invention and the dose may vary in accordance with the particular patient and/or GnRH antagonist, the inventors have found that a single dosage of GnRH antagonist can be sufficient for maintaining a mean endogenous serum estradiol level of between about 30 pg/ml and 50 pg/ml in the patient for a treatment period of at least four weeks, preferably at least eight weeks or even longer, such as up to twelve weeks.
[0044] In a preferred embodiment according to the invention the GnRH antagonist is NAc-d-Nal.sup.1,d-pCl-Phe.sup.2,d-Pal.sup.3,d-(Hci).sup.6,Lys(iPr).sup.8,d-Ala.sup.10 trifluoroacetate (Teverelix TFA), however other GnRH antagonist, such as Azaline B, Abarelix, Antide, Cetrorelix acetate, and Ganirelix are also contemplated within the scope of the present invention.
[0045] The GnRH antagonist is administered in a microcrystalline aqueous suspension, i.e. in a sustained release formulation, thereby allowing a more uniform and optimal plasma drug profile, and a smoother therapeutic response over the dosage interval. Clinically, this offers the potential to optimise drug therapy and decrease the occurrence of concentration-related adverse effects, reduce the exposure to drug and reduce the cost of drug therapy. In addition, sustained release formulations may increase patient acceptance and compliance of therapy.
[0046] In a preferred embodiment the microcrystalline aqueous suspension is preferably one or more of the suspensions disclosed in WO 2003/022243. Said document discloses a method in which the GnRH antagonist, (which is a hydrophobic peptide) is contacted with a counter-ion in an amount and at a molar ratio sufficient to provide a fluid, milky microcrystalline aqueous suspension of the GnRH antagonist without formation of a gel. The specific ratios etc. in order to prepare the suspensions are disclosed in details in WO 2003/022243 (the disclosures of which are hereby incorporated by reference) and will not be discussed in further details in this application.
[0047] The inventors have found that such a microcrystalline aqueous suspension, is advantageously in maintaining the mean endogenous serum estradiol level of between about 30 pg/ml and 50 pg/ml in a patient for a prolonged period of time of at least four week and even longer, i.e. for at least eight weeks, without relying on add-back therapy, thereby not only allowing regression of endometriotic lesions but also substantially limit the side-effects of hypoestrogenemia.
[0048] Thus, a patient in need of treatment only needs to administer a single dosage of GnRH antagonist, e.g. 45 mg Teverelix TFA, every four weeks (i.e. about once a month) or in an even more preferred embodiment a single dosage every eight weeks, (i.e. once every other month).
[0049] The single dosage of GnRH antagonist preferably comprises an amount of Teverelix TFA between 25 and 60 mg, preferably between 30 and 45 mg. Dosages above this level has not been shown to be associated with further suppression of the patients serum estradiol level.
[0050] Since body mass does not influence GnRH activity and thus ovulatory function, the single dosage of GnRH antagonist is considered to be universal for all women. The exact dosage of the GnRH antagonist in the formulation will among others depend on the GnRH antagonist used, and/or if more than one GnRH antagonist is present in the composition.
[0051] Since the composition according to the present invention ensures that a patients mean endogenous serum estradiol level is maintained between about 20 pg/ml and 60 pg/ml, preferably between about 30 pg/ml and 50 pg/ml, for at least four weeks without simultaneously administration of small amounts of estrogen, said composition provides a superior treatment method compared to the known GnRH antagonist treatments. Not only is a very simple dosage regime provided but the treatment need not be limited to the six months period, which is the standard for the known GnRH antagonist treatments. Accordingly, the present invention provides a composition for effectively treating estrogen related diseases and at the same prevents the risk of relapse.
[0052] It will be understood that the composition of the present invention can be used for treating all kinds of estrogen related diseases, and is not limited to endometriosis. Said disease could also be selected from one or more of uterine fibroids, uterine leiomyomas, endometrial cancer, uterine cancer, uterine leiomyosarcomas, ovarian cancer, breast cancer, polycystic ovary syndrome, dysfunctional uterine bleeding, vaginal bleeding, menorrhagia, premenstrual syndrome, migraine headache, cervical intraepithelial neoplasia, adenomyosis and Alzheimer's disease.
[0053] Accordingly, the composition according to the present invention allows for a practical administration wherein estrogen levels are low enough to achieve therapeutic benefits from reduced estrogen supplies, but high enough to minimize or avoid the consequences of long-term estrogen deprivation, especially loss of bone mineral density.
EXAMPLES
[0054] A number of examples were conducted in order to substantiate that patients can obtain a mean endogenous serum estradiol level of between about 30 pg/ml and 50 pg/ml in a treatment period of at least four weeks, without relying on add-back therapy.
Example 1
[0055] The Teverelix TFA formulations were manufactured as followed. 0.8 ml or 0.6 ml 5% mannitol were added to the relevant dosage of 60 or 45 mg of the LHRH antagonist teverelix@ trifluoroacetate, respectively. The mixture was stirred using vortex during one minute providing two dosage formulations of Teverelix TFA in a flowing milky pearly microcrystalline aqueous suspensions. The suspensions are made of microcrystals of about 10 m length. Corresponding placebo formulations, without Teverelix TFA was also prepared
[0056] Formulation A: 60 mg Teverelix TFA in 0.8 ml 5% mannitol
[0057] Formulation B: 45 mg Teverelix TFA in 0.6 ml 5% mannitol
[0058] Formulation A placebo: 0.8 ml 5% mannitol
[0059] Formulation B placebo: 0.6 ml 5% mannitol
[0060] A phase I clinical trial with formulation A and B (and placebo) was conducted in order to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of Teverelix TFA.
[0061] The formulations were each injected subcutaneous (s.c.) as follows: [0062] A single dosage of formulation A (60 mg Teverelix TFA) administered s.c. on day 31 of the menstrual cycle, to 8 healthy female subjects [0063] A single dosage of formulation A placebo was administered s.c. to on day 31 of the menstrual cycle, to 4 healthy female subjects [0064] Two dosages of formulation B (45 mg Teverelix TFA) administered s.c. to 8 healthy female subjects. The first dosage on day 31 of the menstrual cycle and a second dosage administered on day 101 of the menstrual cycle, and [0065] two dosages of formulation B placebo was administered s.c. to 4 healthy female subjects. The first dosage on day 31 of the 25 menstrual cycle and a second dosage administered on day 101 of the menstrual cycle.
[0066] The mean estradiol concentration in the respective subjects was measured. The results are shown in table 1 and 2, respectively and is depicted in
TABLE-US-00001 TABLE 1 Formulation A - 60 MG TEVERELIX TFA (N = 8) Mean Median SD Min Max Timepoint (ng/L) (ng/L) (ng/L) (ng/L) (ng/L) N PREDOSE 39.98 36.69 22.87 12.88 76.26 8 6 H p.f.a. 22.18 19.75 10.76 9.03 39.35 8 12 H p.f.a. 20.27 16.67 13.23 9.57 50.15 8 24 H p.f.a. 14.36 12.22 7.26 8.14 29.66 8 48 H p.f.a. 9.86 7.99 4.93 5.66 19.71 8 72 H p.f.a. 9.30 9.97 3.66 4.25 15.65 8 96 H p.f.a. 8.20 8.76 2.65 4.00 12.50 8 120 H p.f.a. 8.33 8.20 2.30 4.25 12.26 8 144 H p.f.a. 8.60 7.39 3.21 5.67 15.74 8 168 H p.f.a. 9.08 7.94 3.72 5.55 15.57 8 216 H p.f.a. 9.88 7.73 4.87 6.40 20.02 8 264 H p.f.a. 8.76 7.71 3.77 3.74 14.90 8 312 H p.f.a. 11.09 8.44 8.38 4.84 29.78 8 360 H p.f.a. 12.29 9.80 11.22 4.75 38.92 8 408 H p.f.a. 21.76 9.01 36.14 4.07 110.42 8 456 H p.f.a. 38.94 9.32 84.43 3.27 247.63 8 504 H p.f.a. 55.78 9.26 129.03 4.06 374.76 8 672 H p.f.a. 43.63 11.22 61.51 6.30 184.91 8 840 H p.f.a. 28.49 17.09 25.25 10.87 76.27 8 1008 H p.f.a. 34.09 19.60 30.97 13.90 93.94 6 1176 H p.f.a. 32.93 36.46 19.42 11.38 60.71 5
TABLE-US-00002 TABLE 2 Formulation B - 2 45 MG TEVERELIX TFA (N = 8) Mean Median SD Min Max Timepoint (ng/L) (ng/L) (ng/L) (ng/L) (ng/L) N PREDOSE 22.88 21.08 8.44 11.54 38.40 8 6 H p.f.a. 14.85 14.11 3.83 8.37 19.94 8 12 H p.f.a. 12.08 11.47 2.99 8.42 17.07 8 24 H p.f.a. 9.83 9.90 1.97 7.45 13.19 8 48 H p.f.a. 8.32 8.73 2.24 5.26 11.35 8 72 H p.f.a. 9.44 9.01 3.87 5.27 14.44 8 96 H p.f.a. 11.41 12.50 6.34 4.92 23.81 8 120 H p.f.a. 10.50 10.83 4.71 3.58 17.57 8 144 H p.f.a. 13.12 14.09 6.00 3.10 21.21 8 168 H p.f.a. 12.91 12.10 6.49 3.51 22.12 8 180 H p.f.a. 8.84 8.83 4.00 3.69 16.10 8 192 H p.f.a. 8.25 7.78 4.28 4.34 17.30 8 216 H p.f.a. 8.74 7.46 5.71 4.12 22.00 8 264 H p.f.a. 11.01 7.94 9.33 4.56 32.92 8 312 H p.f.a. 8.69 7.76 4.12 4.01 14.02 8 360 H p.f.a. 12.93 8.17 14.50 3.52 47.16 8 408 H p.f.a. 18.58 7.72 25.59 3.77 78.47 8 456 H p.f.a. 22.63 7.40 41.97 3.59 125.98 8 504 H p.f.a. 42.11 8.25 90.09 3.04 264.18 8 672 H p.f.a. 23.85 9.13 30.82 3.23 90.19 8 840 H p.f.a. 23.25 15.38 25.74 3.51 79.57 8 1008 H p.f.a. 34.84 15.43 43.08 4.06 130.66 8 1176 H p.f.a. 37.35 15.62 39.41 4.00 109.82 7
[0067] As can be seen in
[0068] Furthermore, total systemic exposure was approximately 1.5-fold greater following two injections of 45 mg Teverelix TFA administered one week apart compared with a single 60 mg injection, see table 3. Based on these results, a single injection of Teverelix TFA is preferred.
TABLE-US-00003 TABLE 3 Total systemic exposure Geometric Mean (CV %) Cmax.sub.Init1 Cmax.sub.Init2 Cmax.sub.Late AUC(0t) AUC(0cq) Treatment n (fmol/mL) (fmol/mL) (fmol/mL) (fmol.h/mL) (fmol.h/mL) 60 mg 8 10900 N/A 2630 1907000 1592000 Teverelix (29.3) (28.8) (39.5) (27.1) (Treatment Group 1) N = 8 2 45 mg 8 6030 7030 3630 2833000 2323000 Teverelix (22.3) (25.3) (17.8) (28.8) (18.9) (Treatment Group 2) N = 8
[0069] Not only did the estradiol concentration decreased after administration of Teverelix TFA, also the concentrations of progesterone, LH and FSH decreased following dosing with Teverelix TFA, see
[0070] As is evident from
[0071] A similar trend was apparent following two injections of 45 mg Teverelix TFA administered one week apart. Following the first 45 mg Teverelix TFA injection, estradiol concentrations decreased and remained suppressed until 48 h p.f.a. where the mean (SD) concentration was 14.56 (9.95) ng/L below baseline. Concentrations then began to rise but remained below baseline until the second injection was administered at 168 h p.f.a. After the second 45 mg Teverelix TFA injection, estradiol concentrations decreased and remained suppressed until 312 h p.f.a. Where the mean (SD) concentration was 14.20 (10.85) ng/L below baseline. Thereafter, estradiol concentrations began to rise until they returned to near baseline and menses reoccurred in at least one subject at 1008 h p.f.a.
Example 2
[0072] A second randomized, single blind, single-center phase I study was conducted.
[0073] Two formulations comprising either 45 mg or 30 mg Teverelix TFA and a placebo formulations, were prepared as described in example 1, i.e. the following formulations were prepared
[0074] Formulation B: 45 mg Teverelix TFA in 0.8 ml 5% mannitol
[0075] Formulation C: 30 mg Teverelix TFA in 0.4 ml 5% mannitol
[0076] Formulation B placebo: 0.8 ml 5% mannitol
[0077] Formulation C placebo: 0.4 ml 5% mannitol
[0078] The respective formulations were each injected subcutaneous (s.c.) to 24 subjects12 per group i.e. 8 on active drug 4 on placebo per group. All subjects received a dose on either the active or placebo s.c. on day 31 of the menstrual cycle, i.e. [0079] A single dosage of formulation B (45 mg Teverelix TFA) administered s.c. on day 31 of the menstrual cycle, [0080] A single dosages of formulation C (30 mg Teverelix TFA) administered s.c. on day 31 of the menstrual cycle, and [0081] A single dosage of formulation B placebo or formulation C placebo administered s.c. on day 31 of the menstrual cycle.
[0082] The concentration of Teverelix TFA, and Estradiol was measured over a period of 63 days. Additionally, the effect on Teverelix TFA on two bone markers was measured.
[0083] Teverelix TFA Concentrations in Serum
[0084] The mean Teverelix TFA concentration in the serum of the respective subjects was measured.
[0085] The results are shown in table 4 and
TABLE-US-00004 TABLE 4 Mean Teverelix TFA concentrations Mean (ng/L) Mean (ng/L) Mean (ng/L) Mean (ng/L) Time (h) Placebo 30 mg 45 mg 30 + 45 mg 0 0.00 0.00 0.00 0.00 0.5 0.00 6.52 5.43 5.79 1 0.00 8.20 8.17 8.18 1.5 0.00 9.29 8.38 8.73 2 0.00 9.64 7.61 8.39 4 0.00 7.86 7.42 7.59 6 0.00 6.28 6.40 6.36 12 0.00 4.00 3.92 3.95 24 0.00 3.10 2.60 2.79 48 0.00 1.89 1.61 1.70 72 0.00 1.29 1.38 1.35 96 0.00 1.50 1.46 1.48 120 0.00 1.57 1.46 1.49 144 0.00 1.30 1.50 1.42 168 0.00 1.74 1.69 1.70 216 0.00 2.00 1.52 1.68 264 0.00 1.87 1.43 1.58 312 0.00 1.64 1.32 1.43 360 0.00 1.44 1.34 1.37 408 0.00 1.35 1.18 1.23 456 0.00 1.02 1.09 1.06 504 0.00 0.95 1.13 1.07 672 0.00 0.71 0.97 0.85 840 0.00 0.60 0.72 0.67 1008 0.00 n.a. 0.84 0.84 1176 0.00 n.a. 0.77 0.77 1344 0.00 n.a. 0.70 0.70 1512 0.00 n.a. 0.57 0.57
[0086] Estradiol Concentrations in Serum
[0087] The mean estradiol concentration in the respective subjects was measured as described in example 1.
[0088] The results are shown in table 5 and
TABLE-US-00005 TABLE 5 Mean Estradiol concentrations Time Mean (ng/L) Mean (ng/L) Mean (ng/L) Mean (ng/L) (days) Placebo 30 mg dosage 45 mg dosage 30 + 45 mg 0 30.6 27.7 21.5 24.6 0.25 25.5 16.1 16.3 16.2 0.5 25.8 13.8 11.5 12.7 1 28.5 12.3 8.4 10.4 2 31.0 11.2 7.5 9.4 3 41.8 13.7 11.4 12.6 4 59.2 19.4 12.3 15.8 5 75.6 22.6 13.3 17.9 6 109.3 24.4 17.5 20.9 7 155.0 31.0 17.8 24.4 9 213.8 50.2 22.6 36.4 11 99.7 46.5 36.4 41.8 13 104.5 59.9 54.9 57.2 15 127.6 36.3 91.6 64.0 17 140.2 38.7 105.9 72.3 19 130.4 51.4 115.1 83.3 21 94.6 64.5 126.1 95.3 28 66.5 67.4 80.9 74.1 35 135.1 60.7 41.6 51.1 42 82.9 58.6 67.4 63.0 49 81.1 60.5. 92.4 76.4 56 95.3 105.1 104.9 105.0 63 132.1 90.7 47.1 68.9
[0089] Women in the 45 mg group had mean estradiol baseline levels of 21.5 ng/L and this was reduced to a nadir of 7.5 ng/L on day 2. Estradiol levels returned to baseline by day 8 in the 30 mg group and day 9 in the 45 mg group. All women in the placebo group had estradiol peaks consistent with ovulations during the study period (64 days).
[0090] Based on peak estradiol levels it appears that only one of the 8 women in the 30 mg and 5 of the 8 women in the 45 mg group ovulated during the study period. This observation is highly correlated with peak LH data. In only two of the 24 women did there appear to be a discrepancy between a lack of peak estradiol levels and an LH surge. Progesterone measurements were generally consistent with the above.
[0091] As is evident from
[0092] Thus, the mean concentrations of estradiol using the composition according to the present invention is below 50 pg/mL, i.e. below the estradiol concentrations which according to the estrogen threshold hypothesis are needed to support the growth of endometrial lesions, and high enough to minimize or avoid the consequences of long-term estrogen deprivation, especially loss of bone mineral density, (Barbieri 1992).
[0093] As is evident from this example said preferred concentration regime of estradiol was maintained for about 60 days, i.e. about four weeks without relying on add-back therapy.
[0094] CTX and DPD Concentrations.
[0095] In order to evaluate the effect of the treatment with Teverelix TFA on the bone mineral density, two biochemical bone mineral markers was measured in the subjects. Telopeptides type I collagen, cross-linked, N-terminal (CTX) was measured in serum of the treated subjects, and deoxypyridinoline (DPD) was measured in the subjects urine.
[0096] Said bone markers were measured on the following days in the test period: 1 (pre-dose), 15, 29, 43, 57, 64
[0097] DPD is a dynamic biochemical marker of bone loss. An increase in DPD levels in an early morning urine specimen is a reliable indicator of increased bone loss. The CTX test measures for the presence and concentration of a crosslink peptide sequence of type I collagen, found, among other tissues, in bone. This specific peptide sequence relates to bone turnover because it is the portion that is cleaved by osteoclasts during bone resorption, and its serum levels are therefore proportional to osteoclastic activity at the time the blood sample is drawn.
[0098] The concentration of DPD and CTX test were carried out at MOS Pharma Services, Central Lab GmbH, Grossmoorbogen 25, 21079 Hamburg, Germany by means of highly sensitive and specific validated chemi-luminescent (CUA) and enzyme-linked immuno-sorbent (ELISA) methods. The results are shown in
TABLE-US-00006 TABLE 6 CTX data Mean (ng/L) Mean (ng/L) Mean (ng/L) Day Placebo 30 mg 45 mg 1 19.6 16.7 22.6 15 19.6 17.1 22.4 29 20 17 21.6 43 18.7 16.7 22 57 17 16.5 19.3 64 18.2 16.2 17.3
[0099] As is evident from table 6, and
[0100] In accordance with the present invention, a regimen or dose of GnRH antagonist is provided which is effective to inhibit proliferation of endometrial tissue in a menstruating female but is ineffective to substantially stop production of endogenous estrogen.
[0101] The formulations used in the present invention is inexpensive to manufacture, and due to the ease of use it provides a very simple dosage regime.
[0102] Modifications and combinations of the above principles and combinations are foreseen within the scope of the present invention.