Progesterone Receptor Modulators for Use in the Therapy of Uterine Fibroids

Abstract

The present invention relates to a long-term therapy including repeated treatment courses of ulipristal acetate or any metabolite thereof for treating uterine fibroids. The present invention also relates to a combined therapy applying ulipristal acetate with a progestin in order to improve the currently used treatment for uterine fibroids.

Claims

1-10. (canceled)

11. A method of treating uterine fibroids in a patient in need thereof, comprising administering to the patient ulipristal acetate or a metabolite thereof in a therapeutically effective amount in sequential treatment periods, wherein each treatment period lasts 2-6 months and each treatment period is followed by a drug-free period.

12. The method of claim 11 wherein each treatment period lasts 2-4 months.

13. The method of claim 11, wherein each treatment period lasts 12 weeks.

14. The method of claim 11, wherein the drug-free period comprises at least one menstruation cycle.

15. The method of claim 11, wherein the drug-free period comprises at least two menstruation cycles.

16. The method of claim 11, wherein the drug-free period comprises at least three menstruation cycles.

17. The method of claim 11, wherein the drug-free period is not more than 6 months.

18. The method of claim 11, wherein the ulipristal acetate or a metabolite thereof is administered daily.

19. The method of claim 18, wherein the daily amount is 5-15 mg ulipristal acetate or a metabolite thereof.

20. The method of claim 19, wherein the daily amount is 10 mg ulipristal acetate.

21-50. (canceled)

Description

LIST OF FIGURES

[0117] FIG. 1: Median return to menstruation following end of UPA treatment and PBAC assessment on intensity of menstrual bleeding of first menstruation after end of treatment

[0118] FIG. 2: Percentage of subjects in amenorrhea at the end of each treatment courses

[0119] FIG. 3: Percentage of subjects with spotting or no bleeding at the end of each treatment courses

[0120] FIG. 4: Median percent change showing efficacy of fibroid volume reduction after UPA treatment

[0121] FIG. 5. Median return to menstruation following end of UPA treatment

[0122] FIG. 6. Median PBAC assessment on intensity of menstrual bleeding of first menstruation after end of treatment

[0123] FIG. 7: Endometrial histology (bening endometrium, hyperplasia, polyps) after UPA treatment

[0124] FIG. 8: Endometrial histology (PAEC) after UPA treatment

EXAMPLES

Example 1

[0125] Multicenter, Phase III Study to Investigate the Efficacy and Safety of 3-Months of Treatment with UPA Followed by 10 Days of Treatment with NETA or Placebo

[0126] All patients received a 3-month treatment course of UPA 10 mg once-daily followed by randomized oral NETA 10 mg once-daily or matching placebo for 10 days. UPA treatment was started during the first 4 days of menstruation. NETA or placebo was taken daily for the first 10 days following the cessation of UPA. The schedule incorporated the potential for women to enter an extension study involving repeated intermittent courses of UPA 10 mg.

Parameters Assessed

[0127] In the clinical trial the effect of treatment of uterine fibroids have been assessed by means of parameters such as uterine bleeding using the pictorial blood-loss assessment chart (PBAC), condition of the uterus using transvaginal ultrasound (TVUS) and endometrial biopsy, endometrial histology using endometrial biopsy and pain using the Short-Form McGill Pain Questionnaire (SF-MPQ and quality of life using the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) questionnaire.

[0128] The efficacy end points were: percentage of amenorrheic patients at the end of UPA treatment; change from baseline in the volume of the three largest myomas to end of UPA treatment and 2 weeks after menstruation following end of NETA/placebo treatment, and change from baseline in pain and QoL to end of UPA treatment.

[0129] The safety endpoints included the number and proportion of patients experiencing treatment-emergent adverse events (TEAEs), including clinically significant changes in vital signs, physical examination, gynecological or breast examination, electrocardiogram (ECG), ovarian ultrasound, changes from baseline in endometrial thickness and clinically significant changes in endometrium biopsy. Other safety endpoints were change from baseline in hematology, coagulation, biochemistry, lipids, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH) and prolactin, as well as serum levels of estradiol (E2).

[0130] Exploratory endpoints included assessment of the strength of the first menstruation after UPA treatment (using PBAC), time to return of menstruation following treatment end, and frequency of post-treatment PAEC observed in the endometrial biopsy after return of menstruation.

Results

Efficacy Endpoints

Amenorrhea

[0131] At the end of UPA treatment, 164 women (78.5%) were amenorrheic (95% CI, 72.4 to 83.5%). The mean and median time from first day of menstruation on, or just prior to, first dose of UPA to amenorrhea were 10.6 and 5.0 days respectively, with a range of 2 to 60 days. From day 10 until end of treatment <5% of patients on any particular day reported any bleeding, and <2% reported heavy bleeding.

Fibroid Volume

[0132] The median change in the combined volume of the largest three fibroids between baseline and end of UPA treatment was 45.1% (interquartile range [IQR], 66.1 to 24.9%). This decrease was maintained after UPA treatment and return of menstruation (median change, 45.8%; IQR, 63.3 to 13.0%). In 74.7% of the women there was a 25% reduction in the volume of the three largest fibroids.

Pain Relief and Quality of Life

[0133] An improvement in pain was recorded with median change from baseline scores at Weeks 5, 9 and end of UPA treatment of 5.0 (IQR, 12.0 to 1.0), 6.0 (IQR, 14.0 to 1.6) and 6.0 (IQR, 14.0 to 2.0) respectively. Similarly, pain assessed by the VAS showed a decrease (improvement) in score, from a median baseline level of 38 (IQR, 17 to 63). Median change was 21 (IQR, 39 to 2), 26 (IQR, 54 to 7) and 25 (IQR, 54 to 6) at Weeks 5, 9 and at end of UPA treatment respectively. Patients had moderately severe symptoms and moderately impaired QoL at baseline. After UPA treatment, women showed an improvement in QoL, defined by a median change from baseline score of 34.4 (IQR, 46.9 to 21.9) for symptom severity and a median increase of 28.5 (IQR, 11.6 to 44.0) for the health-related QoL (HRQL) total score compared to baseline.

Safety Endpoints

[0134] Three serious adverse events (SAEs) were reported for two patients during the study. All occurred post-treatment and were considered not related to study medication. One subject was hospitalized due to two episodes of excessive uterine bleeding 28 days after completion of double-blind treatment. The other subject had right lobular breast cancer and was withdrawn from the study.

[0135] During UPA treatment, 318 TEAEs occurred in 120 women (57.4%), with 3.8% classified as severe. One hundred and twelve TEAEs in 62 women (29.7%) were considered to be UPA related. No SAE occurred during the UPA treatment phase. Only one TEAE (continuous headache of moderate intensity) led to treatment withdrawal. TEAEs occurring in >3%/o of women were headache (16.3%), nasopharyngitis (6.7%), hot flushes (4.8%0/), fatigue (4.3%), breast discomfort/tenderness (3.8%), pelvic pain (3.8%), vertigo (3.8%), nausea (3.8%) and lower abdominal pain (3.3%).

[0136] In the double-blind treatment phase 18 events were reported by 11 women (11.2%) in the NETA group and two events by two women (1.9%) in the placebo group. In the post-treatment phase, TEAEs were reported in 26.5% and 27.2% of women in the NETA and placebo groups respectively.

[0137] During UPA treatment, E2 levels were generally at mid-follicular phase levels. The mean E2 level was 149.9pg/mL (median, 120.0pg/mL) at screening and at Visit 5 the mean E2 level was 81.6pg/mL (median, 55.0pg/mL). No significant changes in ACTH, TSH, or prolactin were recorded. A small number of patients had a marginal increase in hepatic transaminases which all resolved during continued treatment and/or by the time of the follow-up visit.

Exploratory Endpoints

Menstrual Bleeding

[0138] Median return to menstruation following end of UPA treatment was 14.0 days (range, 2 to 42 days) for the NETA treatment group compared to 25 days in those receiving placebo (range, 1 to 62 days) (p0.001) (FIG. 1)

[0139] The overall total median change in PBAC score of the first menstruation following treatment completion compared to that at baseline was 91.5 (IQR, 220 to 23), with a median baseline score of 216. The median change in PBAC score for the NETA treatment group was 122 (IQR, 229 to 9) compared to 69 (IQR, 167 to 40) for the placebo group (p=0.012). (FIG. 1)

Endometrial Histology Following Double-Blind Treatment

[0140] Endometrial histology was benign in all cases. The percentage of non-physiological endometrial features was higher after UPA treatment than at screening (10.9% at screening vs. 25.6% after UPA treatment) with no significant difference between NETA and placebo groups (28.3% in the placebo group and 22.6% in the NETA group). However, after NETA treatment extensive cyst formation (one of the features of PAEC) was less frequent compared to placebo (2.4% in the NETA group vs. 12.0% in the placebo group).

[0141] The biopsy 12 weeks after UPA treatment confirmed benign endometrial histology in all biopsies (n=38); one benign endometrial polyp was reported in the NETA group. At this time in this subgroup, there was no case of PAEC in the NETA group and only one case in the placebo group which comprised epithelial changes and extensive cystic formation.

Endometrial Thickness

[0142] There was a small increase in the percentage of women with endometrial thickness >16 mm by the end of UPA treatment (9.1% vs. 1.5% at screening). Results for the double-blind treatment groups show small increases after NETA (3.5% vs. 0% at screening) and placebo (9.5% vs. 3.0% at screening). Endometrial thickness was comparably influenced by NETA and placebo. Three months later, none of the patients assessed had a thickness >16 mm.

Example 2

[0143] Long-Term Extension of a Multicenter, Phase III Study to Investigate the Efficacy and Safety of 3-Months of Treatment with UPA Followed by 10 Days of Treatment with NETA or Placebo in Subjects with Myomas and Heavy Uterine Bleeding

[0144] The study consisted of three periods of 3 months open-label UPA treatment, each followed by 10 days of double-blind treatment with NETA or placebo and then a drug-free period. Subjects were randomly assigned to a NETA or matching placebo arm with a 1:1 ratio.

[0145] In study described in Example 1, 251 subjects were screened at 21 sites and 209 subjects started treatment with UPA of which 202 attended the end of UPA treatment visit. Of those that completed study of Example 1 (190 subjects), 132 subjects from 19 sites opted to continue in to the extension study.

[0146] In the study of Example 1 and for each present study courses, UPA 10 mg was orally administered once daily for a period of 90 days, followed by 10 mg NETA or matching placebo once daily for a period of 10 days. The first treatment course in the present study consisted of 90 days UPA 10 mg treatment followed by 10 days of double-blind treatment (same as in Example 1 study) started between the first and fourth day of menstruation (inclusive) following visit after the end of treatment, or one month later if uterine sparing surgery had been performed and myomas were still present. The second and third treatment courses of the present study started on the first day of menstruation following visits after ends of each treatment courses, respectively.

Parameters Assessed

[0147] Parameters assessed are the same as it was described in Example 1.

Results

Efficacy Endpoints

Amenorrhea

[0148] The study demonstrated that intermittent courses of UPA 10 mg daily oral treatment for 3 months were effective in the reduction of uterine bleeding, although there was evidence that the effectiveness of 1 st treatment course was lower than for 2nd-4th courses. Of the 132 subjects in the ITT Population, the percentage of subjects in amenorrhea at the end of 1, 2, 3 and 4 treatment courses were 79.5%, 88.5%, 88.2% and 89.7%, respectively (see FIG. 2), and the mean (median) time to amenorrhea (time from the first dose of UPA in each treatment course to the start of amenorrhea) was 9.4 days (4.0 days), 3.3 days (2.0 days), 5.3 days (3.0 days) and 4.2 days (3.0 days), respectively. Over days 9-90, more than 9 days of any level of bleeding (heavy bleeding, bleeding or spotting) were reported by 21 (15.9%), 8 (6.3%), 4 (3.4%) and 4 (3.9%) subjects (ITT Population) (see FIG. 3). The results for the individual placebo and NETA treatment groups were relatively similar.

Fibroid Volume

[0149] The total volume of the 3 largest myomas identified at screening was shown to decrease following each treatment course, with a maximum decrease seen at the end of 4th treatment course when a mean (median) percent change from screening of 53.53% (72.08%) was observed. This decrease was maintained, although reduced, up to the follow-up visit (approximately 2 weeks after the third menstruation following 4th treatment course), when a mean (median) percent change from screening of 33.68% (58.84%) was reported (FIG. 4). The uterine volume measured by US also decreased during the study and similarly maintained after end of treatment, even so due to the focused mechanism of action of ulipristal acetate, the reduction was less than seen for the volume reduction of the 3 largest myomas.

Pain Relief and Quality of Life

[0150] The reduction in uterine bleeding and volume of the myomas was accompanied by a reduction in patient-reported pain, as measured by the Short-Form McGill Pain Questionnaire (SF-MPQ), the 3 SF-MPQ Parts demonstrated improvement from baseline at all visits. The results were similar for the placebo and NETA treatment groups, as for the overall treatment group. Quality of life was measured using the specific Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) symptom severity and health-related QoL (HRQL) scales, and also by the general EuroQoL-5 Dimensions (EQ-5D) questionnaire. In the UFS-QoL the average symptom severity score showed an improvement (decrease) from baseline, there was also an improvement (increase) on average for the HRQL total score compared to baseline. In the ED-5D questionnaire the most common problems reported at baseline and throughout the study were in the pain/discomfort and anxiety/depression dimensions, and for both of these measures improvement was sustained throughout the study.

[0151] Following the end of each treatment course al but 4 subjects with available data returned to menstruation. As anticipated, median times to return of menstruation following discontinuation of UPA 1-4 treatment courses were significantly shorter for subjects from the NETA group compared to those from the placebo group (p<0.001) (FIG. 5). In addition, the heaviness of bleeding as measured by the PBAC score (days 1-8), was greater in subjects from the placebo group after each treatment course. Bleeding for both groups appeared to decrease after each subsequent treatment course, although this was most noticeable in subjects from the NETA group (FIG. 6).

[0152] One demonstration of the efficacy, safety and acceptability of UPA treatment in this patient population is the change in surgery undertaken at the end of the study compared to that initially planned. At the start of study of Example 1, surgery was planned for 66 (50%) of the 132 subjects in the ITT population, but by the end of present study surgery was not performed for 125 (94.7%) subjects; only 7 subjects underwent surgery.

Safety Endpoints

[0153] Safety assessments including vital signs, laboratory and endocrine measurements, as well as reported treatment-emergent adverse events (TEAEs) and Serious Adverse Event (SAEs) demonstrated that this intermittent repeated administration schedule is well tolerated and did not lead to the identification of any new safety concerns. As might be expected, the number of TEAEs reported during the first UPA treatment course, was greater than seen in subsequent treatment courses, no increase in frequency for any TEAE could be observed. Overall, few TEAEs were reported during double-blind treatment; the addition of NETA 10 mg for 10 day after each treatment course of UPA did not raise any safety concerns.

[0154] As reported in previous studies, following treatment with a single treatment course of 3 months UPA, an increase in endometrium thickness was observed. However, the increase in endometrium thickness were monitored after each treatment courses and endometrium thickness data for the 2 treatment groups were compared. Thickness data for subjects from the placebo group were higher compared to those for the NETA group, and more subjects from the placebo group had endometrium thickness >16 mm at each of these visits.

[0155] Endometrium biopsy samples were evaluated by 3 independent pathologists. All biopsy samples had a diagnosis of benign endometrium by consensus review (FIG. 7). Observations of non-physiological changes in endometrium biopsy samples suggested that the incidence was highest in samples taken following first treatment course and second treatment course, including epithelial changes, unusual vascular changes and extensive cyst formation (FIG. 8). At the follow-up visit, the non-physiological changes were similar to observations seen at screening, suggesting rapid reversal of changes once treatment had ended.