Fibristal
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Fibristal - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Uterine Fibroids
Class: Progesterone receptor modulators
Form: Tablets
Ingredients: ulipristal acetate, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and talc

Pharmaceutical information

Drug Substance

Proper Name:ulipristal acetate
Chemical name(s):17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione;
19-Norpregna-4,9-diene-3,20-dione, 17-(acetyloxy)-11-[4-(dimethylamino)phenyl]-,(11β)-
11β-[4-(dimethylamino)phenyl]-3,20-dioxo-19-norpregna-4,9-dien-17-yl acetate
Molecular formula and molecular mass:C30H37NO4; 475.6
Structural formula:



Physiochemical properties:Ulipristal acetate is a white to yellow crystalline powder. Micronized ulipristal acetate is freely soluble in methylene chloride, soluble in methanol, acetone and ethanol, and insoluble in water.

Clinical Trials

Study Demographic and Trial Design

The efficacy of ulipristal acetate 5 mg once daily was evaluated in two Phase 3 randomized, double-blind, 13 week studies recruiting subjects with heavy menstrual bleeding associated with uterine fibroids and at least one myoma measuring 3 cm or more in diameter. Both studies also evaluated a higher 10 mg daily dose of ulipristal acetate. This higher dose is investigational and not approved for use in Canada. Study 1 was double-blind placebo controlled and recruited subjects with fibroid related anemia at study entry. Study 2 contained the GnRH agonist active comparator/leuprolide 3.75 mg (not approved in Canada for the treatment of uterine fibroids) given once per month by intramuscular injection. In Study 2, a double-dummy method was used to maintain the blind.

In both studies menstrual blood loss was assessed using the Pictorial Bleeding Assessment Chart (PBAC). The PBAC was initially developed as a screening tool to discriminate between menorrhagia and normal blood loss and has been extensively used as a tool to describe the reduction of menstrual blood loss in clinical trials. In this context, a PBAC score of 100 corresponds to approximately 80 mL of blood loss which is considered the threshold for heavy menstrual bleeding.

Study 1

This study was a multicenter, double-blind, placebo-controlled trial. Subjects were enrolled at 38 sites in six countries in Europe. Pre-menopausal women with symptomatic uterine myoma(s), excessive uterine bleeding (a PBAC >100 within the first 8 days of menses is considered to represent excessive menstrual blood loss) and anemia (hemoglobin [Hb] <10.2 g/dL) who were eligible for surgery (N=241) with a mean age of 42 years received a dose of 5 mg (n=95) or 10 mg (n=98) ulipristal acetate (Fibristal) or placebo (n=48). All subjects received 80 mg elemental iron (Fe2+) orally once daily in addition to study drug or placebo. The mean BMI for the study subjects was 25.3 and ranged from 18.0 to 40.1.

The primary endpoints were the percentage of subjects with reduction in uterine bleeding defined as a PBAC score <75 at end-of-treatment visit (Week 13) and the change in total myoma volume assessed by magnetic resonance imaging (MRI) from screening to end-of-treatment visit (Week 13). Secondary endpoints were the following: change from baseline to Week 5, Week 9, and Week 13 visits in bleeding pattern recorded by subjects using the PBAC; change from baseline to Week 5, Week 9 and Week 13 visits in Hb, hematocrit (Hct) and ferritin; percentage of subjects with Hb >12 g/dL and Hct >36% at Week 5, Week 9 and Week 13 visits; percentage of subjects in amenorrhea at Week 5, Week 9, and Week 13 visits; percentage of subjects with a volume reduction of ≥25% of the total myoma volume assessed by MRI at Week 13 visit; percentage of subjects with a reduction of ≥25% of uterine volume assessed by MRI at Week 13 visit; change from screening to Week 13 visit in uterine volume assessed by MRI; change from baseline to Week 5, Week 9, and Week 13 visits in global pain score (Short Form McGill Pain Questionnaire [SF-MPQ]); and change from baseline to Week 13 visit in symptoms related to uterine myomas (measurement of discomfort due to uterine fibroids questionnaire).

Study 2

This study was a multicenter, double-blind, active comparator-controlled comparison of the efficacy and safety of ulipristal acetate (Fibristal) to active comparator. Subjects were enrolled at 32 sites in seven countries in Europe. Pre-menopausal women with symptomatic uterine myoma(s) and excessive uterine bleeding who were eligible for surgery (N= 301) with a mean age of 40 years were randomly allocated to receive Fibristal 5 mg (n=97) or 10 mg (n=103) or active comparator (n=101). Subjects were not required to be anemic to be enrolled in this study. The mean BMI for the study subjects was 25.5 and ranged from 18.1 to 39.8.

The primary endpoint was the percentage of subjects with reduction of uterine bleeding defined as a PBAC score < 75 at end-of-treatment visit (Week 13 visit). The secondary endpoints were the following: change from baseline to Week 5, Week 9 and Week 13 visits in Hb, Hct, and ferritin; percentage of subjects in amenorrhea at Week 5, Week 9, and Week 13 visits; change from screening to Week 13 visit in the total volume of the three largest myomas assessed by ultrasound (US); change from screening to Week 13 visit in uterine volume assessed by US; change from baseline to Week 5, Week 9, and Week 13 visits in global pain score (SF-MPQ); and change from baseline to Week 13 visit in Uterine Fibroid Symptom and health-related Quality of Life (UFS-QOL) score. The co-primary safety objectives were to show a superior side-effect profile for ulipristal acetate versus active comparator in terms of serum estradiol levels at Week 13 and the proportion of subjects with moderate-to-severe hot flashes during treatment. Secondary safety end points included hematologic and other laboratory assessments, including bone-turnover markers (urinary N-terminal propeptide of type 1 procollagen [P1NP], type I collagen C-telopeptide [CTX], and bone-specific alkaline phosphatase [BSAP] and deoxypyridinoline [DPD]).

The results in Table 1 reflect Fibristal 5 mg vs. placebo and Fibristal 5 mg vs. active comparator.

Study Results

Table 1: Results of Primary and Selected Secondary Efficacy Assessments in Phase 3 Studies
ParameterStudy 1Study 2
Placebo
N = 48
Ulipristal acetate 5 mg/day
N = 95
Active comparator 3.75 mg/ month N = 93Ulipristal acetate 5 mg/day
N = 93
Subjects whose menstrual bleeding became normal (PBAC < 75) at Week 139 (18.8%)86 (91.5%)182 (89.1%)84 (90.3%)
Median change in myoma volume from baseline to Week 13a+3.0%-21.2%2-53.5%-35.6%
Menstrual bleeding
Median PBAC at baseline376386297286
Median change at Week 13-59-329-274-268
Subjects in amenorrhea at Week 133 (6.3%)69 (73.4%)174 (80.4%)70 (75.3%)
Median change in uterine volume from screening to Week 13a+5.88%-12.1%-47.1%-20.4%
Hemoglobin change from baseline to Week 13 (g/dL) (adjusted mean)+3.13+4.051+0.53+0.51
Pain Assessment (SF-MPQ) change from baseline to Week 13 (median)-2.5-5.03-5.5-5.0

a In Study 1, change from baseline in total myoma and uterine volume was measured by MRI. In Study 2, change in the volume of the three largest myomas and uterine volume were measured by ultrasound.

p-values (relative to placebo): 1 = <0.001, 2= 0.002, 3=0.101.

Study 1

Bleeding Symptoms

At Week 13, the percentage of subjects with PBAC score <75 was far greater with ulipristal acetate 5 mg (91.5%) than with placebo (18.8%) (p < 0.001). In addition, the decrease in mean PBAC at study Weeks 9 and 13 was statistically significant; p < 0.001) compared to placebo. Significantly more subjects were in amenorrhea with ulipristal acetate 5 mg compared to placebo at both Weeks 9 and 13 (p < 0.001). At Week 13, the percentage of subjects in amenorrhea was 6% with placebo, and 73% with ulipristal acetate.

Approximately 50% of the subjects in the ulipristal acetate 5 mg group became amenorrheic within the first 10 days of treatment as shown in Figure 1.

Figure 1: Time to No Bleeding (Persistent Amenorrhea) (ITT Population)



A return to normal bleeding (as defined by subsequent PBAC scores that were always <75) was achieved by Week 13 in the majority of subjects who were treated with ulipristal acetate 5 mg as shown in Figure 2.

Figure 2: Time to PBAC <75 (ITT Population)



Of the subjects who had not undergone hysterectomy or endometrial ablation, a total of 55 (72.4%) subjects from the ulipristal acetate 5 mg group returned to menstruation by Week 13. For those subjects, the mean time to return to menstruation after end of treatment was 19.9 days (median = 21.0 days).

Hemoglobin and Hematocrit Values

The mean increase in Hg at Week 13 with ulipristal acetate 5 mg was 4.1 g/dL compared with 3.1 g/dL for placebo (p<0.001). In addition, there was a mean increase of Hct at Week 13 of 10.0% with ulipristal acetate 5 mg versus 7.4% for placebo (p<0.001). Anemia was corrected by Week 13 in over 80% of subjects with anemia who received 5 mg ulipristal acetate. In addition, fewer subjects were anemic (defined as Hb ≤ 10.2 g/dL) at Week 13 with ulipristal acetate (4.0%) compared to placebo (11.4%).

Fibroid and Uterine Volume

A significantly greater proportion of subjects had a reduction in total fibroid volume ≥ 25% at Week 13 with ulipristal acetate 5 mg/day (41%) compared with placebo (18%) (p=0.014). Also, change in uterine volume from screening to Week 13 was statistically significant with a median % change of +5.9 cm3 with placebo and -12.1 cm3 with ulipristal acetate 5 mg (p=0.001).

Serum Estradiol

For the safety population (N=95), the mean serum estradiol value was 92.4 pg/mL in the ulipristal acetate 5 mg group at Week 13, which corresponds to mid-follicular phase levels for a pre-menopausal woman, and was 119.6 pg/mL in the placebo group.

Pain and Discomfort

There was a greater improvement in levels of pain as assessed by the Visual Analog Scale (VAS) from baseline to Week 9 between the ulipristal acetate 5 mg group (-31.23) and the placebo group (-18.42) (p=0.048).

A significantly greater improvement in discomfort measurements due to uterine fibroids, as determined using the Discomfort Due to Uterine Fibroids Questionnaire was seen for subjects in the ulipristal acetate 5 mg group versus placebo at Week 13 (median change from Baseline of -9.0 for ulipristal acetate vs. -6.0 for placebo; p=0.001).

Hot Flashes

The number and percentage of subjects reporting at least one episode of a moderate to severe hot flash during the treatment period was 2 (2.1%) (no hot flashes were reported in subjects in the placebo group).

Endometrial Changes

At Week 13, 10 subjects (10.5%) in the ulipristal acetate 5 mg group and one subject (2.1%) in the placebo group had endometrial thickness > 16 mm. At Week 13, endometrial-biopsy samples that were assessed centrally revealed no malignant or premalignant lesions or hyperplasia. However, non-physiological progesterone receptor modulator associated endometrial changes (PAEC) were observed more frequently in the ulipristal acetate 5 mg group than in the placebo group (41.6% and 7.9%, respectively). The results of the endometrial biopsies 6 months after the end of treatment showed that the non-physiological changes seen on treatment were generally reversible with only 1 subject (1.3%) in the ulipristal acetate 5 mg group and 1 subject (2.6%) in the placebo group with non-physiological changes at that timepoint.

Study 2

Bleeding Symptoms

Excessive bleeding was controlled more rapidly in subjects who received ulipristal acetate 5 mg than those who received active comparator, with the majority of ulipristal acetate 5 mg subject achieving persistent amenorrhea within 10 days, as shown in Figure 3.

Figure 3: Time to No Bleeding (Persistent Amenorrhea) (ITT Population)



A return to normal bleeding (as defined by subsequent PBAC scores that were <75 for the preceding 4 weeks) was achieved at Week 13 by 90% of the subjects receiving ulipristal acetate 5 mg and 89% of subjects receiving active comparator as shown in Figure 4.

Figure 4: Time to PBAC <75 (ITT Population)



Of the subjects who had not undergone hysterectomy or endometrial ablation, a total of 49 (63.6%) subjects from the ulipristal acetate 5 mg group returned to menstruation by Week 13, and a total of 22 (28.9%) of those treated with active comparator returned to menstruation by Week 13.

Following completion of treatment, the median time to return to menstruation was 25 days for subjects treated with ulipristal acetate 5 mg and 43 days for subjects treated with active comparator.

Hemoglobin Values

At Week 13, subjects treated with ulipristal acetate 5 mg had an adjusted mean change from baseline of +0.51 g/dL in Hg.

Fibroid and Uterine Volume

The volume of the three largest myomas was assessed by ultrasound at the end of treatment (Week 13) and at Week 26 (without further treatment) in subjects who did not have hysterectomy or myomectomy performed. For these subjects, the median percentage change from screening in the total volume of the three largest myomas in the ulipristal acetate 5 mg treatment group was -45.5% and -50.0% for Weeks 13 and 26, respectively (see Figure 5). This average decrease was generally maintained at Week 38 for subjects treated with ulipristal acetate 5 mg who did not undergo hysterectomy or myomectomy (median of -44.8%). Subjects who did not undergo hysterectomy or myomectomy and received active comparator had median values of -55.7% and -43.3% at Weeks 13 and 26 respectively. For these subjects, fibroids began to enlarge approximately 1 month after the last dose of active comparator acetate (median of -42.4% at Week 17) and continued to increase through week 38. However, fibroid volume reduction in subjects receiving ulipristal acetate appeared to be maintained in the majority of subjects for 6 months after the end of treatment.

Figure 5: Median Percentage Change from Screening to Weeks 13, 17, 26, and 38 in the Volume of the Three Largest Myomas in Subjects who did not have Surgery before Week 38



Serum Estradiol

For the safety population (N=97), the median serum estradiol value was 64.0 pg/mL in the ulipristal acetate 5 mg group and 60.5 pg/mL in the group receiving 10 mg of ulipristal acetate at Week 13, but decreased to postmenopausal levels in the active comparator group (25.0 pg/mL) (p<0.001 for each ulipristal group vs. active comparator). The number, and percentage, of subjects reporting episodes of moderate or severe hot flashes during the treatment period was 11 (11.3%) for subjects treated with ulipristal acetate 5 mg, and 40 (39.6%) for subjects treated with active comparator.

Pain and Discomfort

The median change from baseline to Week 13 for responses to the SF-MPQ and VAS in subjects treated with ulipristal acetate 5 mg were -5.0 and -31.0, respectively. In addition, subjects in the 5 mg ulipristal acetate treatment group showed an improvement (-28.2) on average for the symptom severity score and an improvement (20.3) on average for the quality of life total score at Week 13 compared to baseline.

Endometrial Changes

At Week 13, the histologic specimens from subjects in the ulipristal acetate 5 mg group were all given a diagnosis of benign endometrium except for one who had a diagnosis of simple, non-atypical hyperplasia. Non-physiological endometrial changes at Week 13 were observed in 77.3% of the subjects in the ulipristal acetate 5 mg group, 79.6% of the subjects in the ulipristal acetate 10 mg group, and in 35.6% of subjects in the active comparator group. The results of the endometrial biopsies 6 months after the end of treatment showed that the non-physiological changes seen on treatment were generally reversible with only three subjects (3.9%) in the ulipristal acetate 5 mg group with non-physiological endometrial changes at that timepoint

Bone Resorption

Due to the short duration of the clinical study, meaningful changes in bone markers were not expected. However, subjects treated with active comparator showed a significantly larger increase in median levels from baseline to Week 13 of type 1 CTX (101.5 mcg/mmol to 258.0 mcg/mmol) compared to subjects treated with ulipristal acetate (117.0 mcg/mmol to 175.0 mcg/mmol) (p>0.001).

Detailed Pharmacology

Ulipristal acetate is an orally-active selective progesterone receptor modulator characterized by a tissue-specific partial progesterone antagonist effect.

Endometrium

Ulipristal acetate exerts a direct effect on the endometrium. When daily administration of a 5 mg dose is commenced during a menstrual cycle most subjects (including subjects with myoma) will complete their first menstruation but will not menstruate again until after treatment cessation. Upon ulipristal acetate treatment cessation, menstrual cycles generally resume within 4 weeks.

The direct action on the endometrium results in class-specific benign changes in histology termed, PAEC. Typically, the histological appearance is an inactive and weakly proliferating epithelium associated with asymmetry of stromal and epithelial growth resulting in prominent cystically dilated glands with admixed estrogen (mitotic) and progestin (secretory) epithelial effects. Such a pattern has been observed in approximately 60% of subjects treated with Fibristal for 3 months. These changes are reversible after treatment cessation. These changes should not be confused with endometrial hyperplasia.

About 5% of patients of reproductive age experiencing heavy menstrual bleeding have an endometrial thickness of greater than 16 mm. Endometrial thickening >16 mm was observed in approximately 11% of subjects treated with Fibristal. This thickening disappears after treatment is withdrawn and menstruation occurs. If endometrial thickness persists beyond the 3 months following the end of treatment and return of menstruation then this may need to be investigated as per usual clinical practice to exclude underlying conditions.

Fibroids

Ulipristal acetate exerts a direct action on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis.

Pituitary

A daily dose of ulipristal acetate 5 mg inhibits ovulation in the majority of subjects as indicated by progesterone levels maintained at around 0.3 ng/mL.

A daily dose of ulipristal acetate 5 mg partially suppresses FSH levels but serum estradiol levels are maintained in the mid-follicular range in the majority of subjects and are similar to levels in subjects who received placebo.

Ulipristal acetate does not affect serum levels of TSH, ACTH or prolactin during 3 months of treatment.

Toxicology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.

Most findings in general toxicity studies were related to the action of ulipristal acetate on progesterone receptors, with antiprogesterone activity observed at exposures similar to therapeutic levels. In a 39 week study in cynomolgus monkeys, histological changes resembling PAEC were noted at low doses.

Due to its mechanism of action, ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1 mg/kg), guinea pigs and in monkeys. The safety for a human embryo is unknown. At doses which were low enough to maintain gestation in the animal species, no teratogenic potential was observed.

Reproduction studies performed in rats at doses giving exposure in the same range as the human dose have revealed no evidence of impaired fertility due to ulipristal acetate in treated animals or the offspring of treated females.

Administration of ulipristal acetate at dose levels up to 10 mg/kg/day for at least 99 weeks in female rats and 100 weeks in male rats resulted in significant reductions in bodyweight gain but no evidence of an increase in tumors. In addition, Transgenic Hemizygous CByB6F1-Tg(HRAS)2Jic mice were dosed with ulipristal acetate at 0, 15, 45, or 130 mg/kg/day for 26 weeks. There was no evidence of any test article-induced carcinogenicity. Based on these data, ulipristal acetate is not considered to be carcinogenic up to the highest doses tested.