Esmya ® and the PEARL studies: A review

Abstract

Ulipristal acetate was investigated in four phase 3 trials. In PEARL I, ulipristal produced significant normalisation of blood loss within 1 week and decreased fibroid volume. In PEARL II, ulipristal produced faster and more consistent control of bleeding than leuprorelin acetate and had a more favourable side-effect profile. Ulipristal-induced decreases in fibroid volume persisted for 6 months, whereas fibroids regrew after leuprorelin was stopped. PEARL III showed that ulipristal was effective during long-term treatment, with norethisterone further reducing the magnitude of bleeding in the off-treatment period. PEARL IV investigated ulipristal over four cycles, finding little difference between 5 and 10 mg ulipristal, further changes in menstruation and fibroid volume with repeat courses, and no increase in side effects.

Background

Ulipristal acetate (Esmya^®) is a synthetic progesterone receptor modulator that has predominantly inhibitory effects on the progesterone receptor. ¹ It is increasingly prescribed for the treatment of uterine fibroids in women of reproductive age to alleviate associated symptoms such as menorrhagia or as a pretreatment to assist with surgical removal of fibroids. For women with heavy menstrual bleeding and fibroids ⩾3 cm in diameter, the latest guidance by National Institute for Health and Care Excellence (NICE) recommends that four courses of 5 mg ulipristal acetate are offered to women with haemoglobin <102 g/L and considered for women with haemoglobin >102 g/L. ²

An alternative to ulipristal are the group of drugs called gonadotrophin-releasing hormone (GnRH) analogues (leuprolide, triptorelin, and goserelin). These reduce the size of fibroids by 25%–50% and have been used to make hysterectomies and myomectomies technically easier and also to reduce blood loss. They are also recommended by NICE. ² The drug is administered subcutaneously or via intramuscular injection and can cause marked menopausal symptoms, including osteopenia or even osteoporosis with long-term use if no add back is concurrently given. When the treatment is stopped, the fibroids regrow with the menopausal symptoms regressing.

Ulipristal acetate acts on the progesterone receptors of the myometrium and prevents stimulation of fibroid growth by inhibiting cell proliferation and causing apoptosis.^1,3 It is licensed for preoperative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. ¹ It is prescribed at a dose of 5 mg/day for courses of 3 months each, followed by a minimum break of 2 months. ¹ Esmya was introduced in 2012 and has been the subject of four phase 3 clinical studies in the PGL4001 (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata (PEARL) programme, which have been conducted consecutively over the past 4 years.^4–8

Pearl I

PEARL I was a double-blind, placebo-controlled study, in which women with symptomatic fibroids who were planning to undergo surgery were randomised in a ratio of 2:2:1 to 5 mg/day (n = 96) or 10 mg/day (n = 98) ulipristal acetate or placebo (n = 48) for 12–13 weeks. ⁴ All women in these three groups also received 80 mg/day oral iron. The groups were stratified by haematocrit (Hct) level (⩽28% and >28%) and race (Black African women or other ethnicities).

Women were included if they were aged 18–50 years and had Pictorial Bleeding Assessment Chart (PBAC) score >100 during the first 8 days of menstruation, fibroid uterus of a size equivalent to ⩽16 weeks’ gestation, body mass index (BMI) 18–40 kg/m², haemoglobin (Hb) <10.2 g/dL, and at least one uterine fibroid >3 cm but <10 cm in diameter. ⁴ Exclusion criteria were any previous uterine surgery apart from caesarean section or cervical conisation; previous history of endometrial ablation or uterine artery embolisation (UAE); history of or any current gynaecological cancer, history or current diagnosis of endometrial hyperplasia, ovarian cyst >4 cm, or uterine polyp >2 cm; and previous or current treatment of fibroids with GnRH agonists or other agents such as progestogens, aspirin, mefenamic acid, anti-fibrinolytic drugs, or systemic glucocorticoids. The co-primary endpoints of PEARL I were reduction in uterine bleeding defined as PBAC score <75 and change in fibroid volume from baseline to week 13. Secondary endpoints were amenorrhoea, pain, and quality of life.

At baseline, PBAC scores ranged from 102 to 1645. After 13 weeks, PBAC score <75 was achieved in 19%, 91%, and 92% of women receiving placebo and 5 and 10 mg ulipristal, respectively. ⁴ Median total changes in fibroid volume from baseline were +3%, −21.2%, and −12.3%, respectively. Of the secondary endpoints, amenorrhoea (PBAC < 2%) was achieved within 10 days of taking placebo or 5 or 10 mg ulipristal in 6%, 73%, and 82% of patients, respectively, and self-reported pain and discomfort associated with fibroids improved significantly with ulipristal compared with placebo. Adverse effects with ulipristal were comparable to those with placebo. Reductions in pain from baseline assessed by a visual analogue scale on the Short-Form McGill Pain Questionnaire ⁹ (0 for no pain to 100 for worst pain) were similar for 5 and 10 mg ulipristal, with median reductions of −5.0 and −5.6, respectively.

In summary, PEARL I showed that ulipristal acetate effectively controls excessive bleeding and pain due to fibroids and reduces fibroid size, with a frequency of side effects similar to that with placebo. ⁴

Pearl II

PEARL II was a randomised, parallel-group, double-blind, double-dummy, active-controlled, phase 3 trial. ⁵ The inclusion criteria were virtually identical to those described for PEARL I, except that anaemia was not a prerequisite for inclusion. Women were randomised in a ratio of 1:1:1 to receive 5 or 10 mg/day ulipristal plus an intramuscular saline injection as placebo once a month or placebo tablets plus an intramuscular injection of 3.75 mg leuprorelin acetate once a month. In total, 303 women were randomised to receive 5 mg/day ulipristal plus placebo (n = 97), 10 mg/day ulipristal plus placebo (n = 104), or placebo plus leuprorelin injection (n = 101). The treatment duration was 12–13 weeks. The primary efficacy endpoint was the proportion of patients with control of uterine bleeding (PBAC < 75) at the end of treatment (week 13) and the safety co-primary endpoints were serum oestradiol levels at the end of treatment and the proportion of patients experiencing moderate to severe hot flushes during treatment (not after the return of uterine menses). Secondary endpoints included fibroid volume, pain, quality of life, and haemoglobin levels.

After 13 weeks, uterine bleeding was controlled (PBAC < 75) in 90%, 98%, and 89% of women taking 5 and 10 mg ulipristal and leuprorelin, respectively. ⁵ Reductions in fibroid volume were 36%, 42%, and 53%, respectively, and rates of amenorrhoea were 75%, 89%, and 80%, respectively. Amenorrhoea was achieved relatively faster with ulipristal acetate (about 2 weeks earlier) than leuprorelin. All three groups had improvements in pain and quality of life. Moderate to severe hot flushes were perceived to be experienced by 11%, 10%, and 40% of patients, respectively, with serum oestradiol levels, which act as an objective measure of flushing, of 64, 61, and 25 pg/L. Overall, hot flushes of any severity occurred in 26% (5 mg), 24% (10 mg), and 65% (leuprorelin).

In summary, PEARL II showed that ulipristal is not inferior to leuprorelin in reducing uterine bleeding and fibroid size prior to surgery but has superior tolerability, with a lower incidence of adverse side effects such as hot flushes and low levels of oestradiol. ⁵

Pearl III and Pearl III Extension

PEARL III was a long-term, open-label, phase 3 clinical trial conducted at 21 investigational centres in four European countries from July 2010 to November 2011; 18 centres participated in an extension to the initial phase of the study. ⁶ The study evaluated the continuous efficacy and safety of sustained intermittent treatment with up to four repeated 3-month courses of 10 mg/day ulipristal for the long-term treatment of moderate to severe symptoms of uterine fibroids.

The study included premenopausal women aged 18–48 years who were eligible for fibroid surgery and had BMI of 18–40 kg/m², regular menstruation in cycles of 22–35 days and with follicle-stimulating hormone (FSH) <20 IU/L, at least one fibroid ⩾3 cm and none >10 cm, heavy menstruation (PBAC > 100) during days 1–8, and uterine size equivalent to <16 weeks’ gestation. ⁶ The exclusion criteria were as for PEARL I and II, with the additional condition that women should not previously have been treated with a selective progesterone receptor modulator such as ulipristal.

In total, 209 premenopausal women with menorrhagia and fibroids started 10 mg/day ulipristal within the first 4 days of their period and continued this treatment for 3 months. ⁶ After the first course of treatment, 132 women entered an extension of the study. At the start of the study, the women were randomised in a 1:1 ratio to receive double-blind treatment with norethisterone acetate or placebo for 10 days at the end of each treatment course to explore the reversibility of any progesterone receptor modulator–associated changes in the endometrium due to ulipristal and the timing and magnitude of the next menstruation after treatment.

Efficacy and safety endpoints were measured after the first 3 months of treatment and then after the further three courses in the extension. ⁶ The primary efficacy outcome was the proportion of women who were amenorrhoeic after each course of ulipristal. Bleeding was assessed as no bleeding, spotting, bleeding, or heavy bleeding. Amenorrhoea was defined as no bleeding for a continuous period of 35 days. Secondary efficacy endpoints were reduction in size of the three largest fibroids, pain, and quality of life.

After the first course of 10 mg ulipristal acetate, 164 (78.5%) women became amenorrhoeic, with a median time to amenorrhoea of 3.5 days. ⁶ Of the 132 who entered the extension course, 89.7% were amenorrhoeic at the end of the fourth course. Ulipristal alone reduced the intensity of the bleed, and norethisterone further reduced the magnitude of bleeding in the off-treatment period. Norethisterone induced early return of menstruation, with a median of 15 days compared to 30 days for the placebo group at the end of the fourth cycle. The median reduction in fibroid volume after one treatment was 45%, increasing after four treatments to 72%. This volume reduction was mostly maintained at follow-up 3 months after end of treatment (59%). Improvement in pain scores appeared by the fifth week and was maintained during the four cycles. Quality-of-life scores were considerably reduced at the end of the treatment compared with scores at baseline, with mean scores within the range of healthy participants and maintained throughout and at 3 months after cessation of treatment.

Norethisterone did not affect the incidence of non-physiological changes induced by ulipristal acetate. ⁶ Transient increases in endometrial thickness were seen in <10% of patients after each course. No cases of endometrial adenocarcinoma or endometrial hyperplasia developed at any time. Ulipristal induced high rates of bleeding control even when no significant reduction in the volume of the fibroid was seen. After each treatment, the magnitude of menstruation diminished further. The most common side effect reported in PEARL III was headache. Although progesterone receptor modulator–associated endometrial changes (PAEC) occurred in 25% of patients after treatments 1 and 4, it did not worsen and rapidly reversed in most women after two successive menstruations. Administration of norethisterone had no influence on the incidence of PAEC.

In summary, PEARL III showed that ulipristal was effective during long-term treatment, with no increase in side effects over time. ⁶

Pearl IV Study

PEARL IV also investigated long-term intermittent use of ulipristal. It was a double-blind, parallel-group trial to assess the sustained efficacy, safety, and tolerability of repeated 12-week courses of 5 or 10 mg/day ulipristal acetate for the long-term management of symptomatic fibroids.^7,8 It was conducted at 46 study sites in 11 European countries from June 2012 to December 2014. In total, 451 women of reproductive age (18–50 years) with symptomatic fibroids ⩾3 cm and ⩽12 cm and an overall size of the uterus less than 16 weeks were recruited. They were randomly allocated by web-integrated voice response system in a ratio of 1:1 to 5 or 10 mg ulipristal, which was started during the first 4 days of menstruation and involved a total of up to four courses, each lasting 84 days. Every 12-week course was followed by a drug-free interval until the start of the second menstrual bleed after the course was completed. Endometrial biopsies were taken at baseline, after the second and fourth treatment cycles, and 3 months after the end of the fourth course.

The primary endpoint was the percentage of women who were amenorrhoeic at the end of two courses of ulipristal (part 1 of the study) and at the end of the four courses (part 2 of the study).^7,8 Secondary endpoints were fibroid volume, uterine volume, and reduction in uterine bleeding measured by PBAC score.

Overall, 75% of patients completed all four courses. ⁷ The rate of amenorrhoea after cycle 4 was 69.6% in the 5 mg group and 74.5% in the 10 mg group, which was not statistically significant, while 48.7% of patients who took 5 mg ulipristal and 60.6% who took 10 mg were amenorrhoeic across all four treatment courses. No difference in PBAC scores was seen between the 5 and 10 mg groups at any time point, with mean (median) levels of 139.7 (77.5) and 128.2 (76.0) after four treatment courses. Clinically significant reductions in volume ⩾25% were seen in both groups after each treatment. The percentage of patients who achieved this reduction increased between the first and fourth treatments for 5 mg (62.3% vs 78%) and 10 mg (66.5% vs 80.5%) ulipristal. No significant differences in pain scores or quality of life were seen between 5 and 10 mg ulipristal at any time point.

Non-physiological endometrial changes at screening were seen in 7.8% of patients in the 5 mg group and 8.4% in the 10 mg group. ⁸ After two treatment cycles, this had increased to 16.3% and 19.2%, respectively, decreasing to 16.2% and 10.3%, respectively, after four courses. At 3 months after completion of the fourth course, levels of non-physiological endometrial changes were similar to those during screening (9.0% and 6.3%, respectively). On ultrasound, 7.4% of all patients in the study after the first course had endometrial thicknesses ⩾16 mm; these returned to below screening levels (4.9%) in subsequent treatment courses.

Most side effects (97.6%) were mild to moderate and decreased in frequency from course to course in almost all categories.^7,8 The overall incidences of adverse events considered by the investigator as treatment related during treatment course 4 were 6.1% with 5 mg ulipristal and 8.0% with 10 mg. Headaches and hot flushes were the most commonly reported side effects and occurred in ⩽11% of patients, with the frequency of these events decreasing with each successive treatment course. Breast pain and discomfort occurred in ⩽3% of patients, which decreased to ⩽1% over subsequent treatment courses. Overall, 114 (25.3%) patients in the study withdrew for any reason: 32 due to adverse events, 21 of which were considered to be related to the drug, with no apparent difference between the two doses.

In summary, the results of PEARL IV were comparable with those of PEARL III and its extension. ⁶ This study thus supports the long-term use of intermittent courses of ulipristal.

Strength and weaknesses

The strengths of these studies are the specific primary and secondary endpoints: the reduction in uterine bleeding measured by the percentage of women with PBAC score <75 and amenorrhoea due to the sustained effect of ulipristal acetate.^4–8 The studies showed that ulipristal is non-inferior to leuprorelin in decreasing fibroid and uterine volume but is associated with less severe menopausal side effects than leuprorelin. The higher dose of 10 mg/day ulipristal was not significantly superior to the licensed dose of 5 mg/day. ¹ The PEARL studies showed that ulipristal is effective for treating fibroids preoperatively, as well as for managing symptoms, whether or not surgery is planned.^4–8 Safety assessments showed that intermittent repeated administration of ulipristal is well tolerated.^6–8

In terms of weaknesses, no placebo control was included in the PEARL II, III, or IV studies; however, PEARL I had shown that ulipristal is superior to placebo and PEARL II that it is non-inferior to leuprorelin.^4–8 In the longer PEARL III and IV studies, a placebo comparator would not have been ethical when a treatment had already been shown to be efficacious. The studies included women with a maximum uterine size equivalent to 16 weeks’ gestation and maximum fibroid size of 12 cm, so the effect of ulipristal on fibroids larger than this has not been confirmed. The maximum period for which ulipristal was used was 18 months, with a 2-month gap between each course. The trials were mostly conducted in European countries and did not include significant numbers of black women – a population in whom fibroids are particularly prevalent.

Adverse effects associated with ulipristal are headache, nausea, fatigue, hot flushes, breast pain, and discomfort, which did not increase with more courses or as the dose of drug increased.^4–8 Seven (5.3%) women in PEARL III and 28 (6.1%) in PEARL IV experienced at least one serious adverse event (SAE), the most frequent of which in both studies was excessive uterine bleeding.^6–8 The use of ulipristal is not recommended in women with severe asthma that is insufficiently controlled by glucocorticoids. Concomitant use of progestogen-only pills, progestogen-releasing intrauterine devices, and combined oral contraceptive pills is also not recommended.

Thickening of the endometrium occurs with ulipristal, but the changes reverse after the drug is stopped and there is a return to menstruation.^6–8 The incidence of hyperplasia did not increase with repeated treatment courses, including in those who received up to eight courses of 10 mg ulipristal acetate. The observed frequency of hyperplasia is in line with that in control groups and the prevalence reported in the literature for symptomatic premenopausal women of this age group (mean age, 40 years). ¹ However, investigation is warranted if bleeding patterns change or endometrial thickening persists 3 months after ulipristal is discontinued.

Conclusion

The PEARL studies have shown that ulipristal acetate offers an efficient alternative treatment option for long-term management of uterine fibroids and the associated management of heavy uterine bleeding. Ulipristal has been shown to be effective in reducing pain and fibroid volume, as well as leading to a significant number of patients being amenorrhoeic and control of menstruation in >95% of patients, verified by PBAC scores and data on quality of life in the PEARL studies. As the higher dose of 10 mg/day ulipristal acetate is not significantly superior to the licensed dose of 5 mg/day, ¹ it is not necessary to prescribe 10 mg/day. Clinical commissioning groups (CCGs) are the likely commissioning pathway for ulipristal in the United Kingdom, where it should be categorised as an amber drug, with shared care when used for intermittent treatment of moderate to severe symptoms of uterine fibroids. The drug should be started in a specialist centre and prescribed in secondary care, but subsequent courses could be prescribed by the general practitioner (GP), with patients then returning to secondary care annually with an ultrasound assessment or sooner if menstrual irregularities occur.

In the future, more information will become available on long-term use of ulipristal acetate from a post-authorisation safety study, which is following 1500 patients who intend to have long-term treatment for up to 5 years, and a second extension of the PEARL III study, which will provide more detail on the safety and efficacy data for up to eight courses of 10 mg/day ulipristal. We anticipate that ulipristal will be a proven alternative option to surgery in patients with fibroids and associated menorrhagia.