Drug Evaluation For reprint orders, please contact: [email protected]
Ulipristal acetate for use in moderate to severe symptoms of uterine fibroids
Although it has been known for a long time that uterine fibroids respond to changes in sex steroid concentrations, it is the availability of selective progesterone receptor modulators such as ulipristal acetete that has provided the gynecologist with a novel option for medical management of uterine fibroids. Ulipristal acetate is presently licensed in Europe for use in women with symptomatic fibroids up to 3 months prior to surgery and has demonstrated good clinical efficacy and safety for this indication. Future trials will define the long-term safety of this drug and its role in medical management of uterine fibroids.
Vikram Sinai Talaulikar*,1 & Isaac Manyonda1 1 St George’s Hospital & University of London, Cranmer Terrace, London, SW17 0RE, UK *Author for correspondence: Tel.: +44 20 8725 3695 Fax: +44 20 8725 5958 vtalauli@ gmail.com
Keywords: fibroids • medical • myoma • SPRM • ulipristal acetate
The unmet need for effective medical treatment of uterine fibroids Uterine fibroids (leiomyomas) are the most common benign tumors of the female genital tract, being found in 20–40% of women of reproductive age. These tumors vary in size from seedling to massive and are classified into submucous, intramural or subserous depending on their location in the uterus. Although the exact etiology of fibroids is not well established, point mutations and chromosomal rearrangements have been detected in fibroid cells. It is known that these tumors depend on sex hormones for their growth and several risk factors have been identified such as early menarche, nulliparity, Afro-Caribbean ethnicity and family history. Not all fibroids may be detected because many remain small and/or asymptomatic throughout the life of the woman. Most symptomatic fibroids present during the age range 30–45 years, while rarely some may also give rise to post-menopausal bleeding. The common symptoms include heavy menstrual bleeding (menorrhagia), anemia leading to generalized tiredness, pelvic pain, pressure on bladder or bowel and interference with fertility and pregnancy. Symptomatic fibroids impact negatively on women’s
10.2217/WHE.14.60 © 2014 Future Medicine Ltd
health and quality of life, and have significant cost implications for their management. The current mainstay treatments are surgical (myomectomy and hysterectomy) and more recently radiological (uterine artery embolization and focused ultrasound surgery). However, the surgical modalities carry significant risks such as infection, bleeding, visceral injuries, adhesions, postoperative morbidity and indeed mortality. The radiological treatments are relatively new and may not be suitable for all affected women, and focused ultarsound surgery, for one, requires equipment and facilities that are not always available in resource-limited settings. Traditionally, a few medical treatment options have been available for fibroids but most of these have mainly been utilized to provide temporary symptom control. Gonadotropin-releasing hormone (GnRH) agonists have been used before surgery to achieve amenorrhea and shrink fibroid size in symptomatic women, but their use is restricted due to significant side effects such as bone mineral density loss and vasomotor symptoms. There is at present no fully established effective long-term medical therapy for a disorder so common among women of reproductive age.
Womens Health (2014) 10(6), 565–570
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ISSN 1745-5057
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Drug Evaluation Talaulikar & Manyonda Ulipristal acetate: novel selective progesterone receptor modulator Ulipristal acetate (UA) (Figure 1) belongs to a group of compounds collectively known as selective progesterone receptor modulators (SPRMs) that include CDB4124 (telapristone), CP-8947 and J-867 (asoprisnil). SPRMs are compounds which have mixed agonistic/ antagonistic effects, depending on expression of coactivators and co-repressors, in different tissues as per their differential progesterone receptor expression. The SPRMs reduce luteinizing hormone and folliclestimulating hormone secretion while maintaining mid-follicular estrogen levels. UA reversibly blocks the progesterone receptor in its target tissues (uterus, cervix, ovaries, hypothalamus) and acts as a potent, orally active anti-progestational agent. Most gynecologists will be familiar with UA as it has been on the clinical scene for several years as an efficient emergency contraceptive (as a one-off dose of 30 mg). More recently it has successfully completed Phase III clinical trials for the medical treatment of uterine fibroids. It has been licensed in Europe for short-term clinical use prior to surgery for fibroids, and has shown efficacy with a significant reduction in uterine bleeding, fibroid volume and improved quality of life, without the side effects associated with other medications such as GnRH agonists. Ulipristal & other selective progesterone receptor modulators: mechanism of action in the treatment of fibroids It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids, and this raised the possibility that anti-progestational agents and progesterone receptor modulators could be useful in the medical management of fibroids [1,2] . Fibroid cells demonstrate higher concentration of estrogen receptors, equally higher expression of mRNA and differential expression of progesterone receptors compared with surrounding myometrium. These differences may account for differential action
N
O O H O H
O Figure 1. Chemical structure of ulipristal acetate.
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of SPRMs on fibroids as compared with normal myometrium [3–5] . UA downregulates the expression of angiogenic growth factors such as vascular endothelial growth factor and their receptors in cultured fibroid cells [3–5] . This can result in the suppression of neovascularization, cell proliferation and survival [1] . UA also increases the expression of matrix metalloproteinases and decreases the expression of tissue inhibitor of metalloproteinases and collagens in cultured fibroid cells. This can reduce the collagen deposition in the extracellular spaces of fibroids, impairing tissue integrity [1,3,4] . UA and other SPRMs have been shown to modulate the ratio of progesterone receptor isoforms (PR-A and PR-B) in the cultured leiomyoma cells [5] . They decreased cell viability; suppressed the expression of growth factors, angiogenic factors and their receptors in those cells; and induced apoptosis. Of particular relevance and importance has been the observation that UA and other SPRMs do not affect normal myometrial cells in culture in the way that they affect leiomyoma cells, thus raising the possibility that they could be used to treat fibroids while selectively sparing normal uterine muscle. Evidence for effectiveness of ulipristal in the treatment of uterine fibroids In a number of clinical trials UA has been shown to reduce menstrual loss and fibroid volume and improve quality of life. Unlike GnRH agonists, UA does not have the side effects of inducing profound estrogen deficiency and decrease in bone mineral density. In the first trial in which UA was given at 10 or 20 mg in comparison against placebo for three cycles, UA showed a 92% reduction in bleeding versus 19% with placebo [6] . Leiomyoma volume was significantly reduced with UA (29 vs 6%; p = 0.01). UA eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles 20% on UA vs 83% with placebo; p = 0.001). UA also improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (p = 0.04). One woman on UA developed changes that were described as endometrial cystic hyperplasia without evidence of atypia. However, the numbers studied were small, with 22 patients being allocated and 18 completing the three cycles or 90–120 day trial [6] . A double-blind, placebo-controlled trial of efficacy and tolerability has also demonstrated positive results when UA was administered for 3–6 months, showing good control of bleeding, reduction in fibroid size and improvement in quality of life in the treatment group [7] . The PEARL I [8] trial compared treatment with oral UA for up to 13 weeks at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) with
future science group
Ulipristal acetate for use in moderate to severe symptoms of uterine fibroids
placebo (48 women) in patients with fibroids, menorrhagia and anemia. All patients received iron supplementation. The co-primary efficacy end points were control of uterine bleeding and reduction of fibroid volume at week 13, after which patients could undergo surgery. At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of UA, 92% of those receiving 10 mg of UA and 19% of those receiving placebo (p < 0.001 for the comparison of each dose of UA with placebo). Treatment with UA for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. PEARL II [9] was a double-blind noninferiority trial in which 307 patients with symptomatic fibroids and excessive uterine bleeding were randomly assigned to receive 3 months of daily therapy with oral UA (at a dose of either 5 or 10 mg) or once-monthly intramuscular injections of the GnRH analog leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a pre-specified noninferiority margin of -20%. Uterine bleeding was controlled in 90% of patients receiving 5 mg of UA, in 98% of those receiving 10 mg, while the figure for leuprolide acetate was 89%. Median times to amenorrhea were 7 days for patients receiving 5 mg of UA, 5 days for those receiving 10 mg of UA and 21 days for those receiving leuprolide acetate. There were no significant differences between the ulipristal groups and the leuprolide group in the proportion of patients reporting other adverse events or discontinuing treatment because of adverse events. Both UA doses were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. The proportions of patients reporting moderate-to-severe hot flashes were 11% in the group receiving 5 mg of UA, 10% in the group receiving 10 mg of UA and 40% in the group receiving leuprolide acetate (p < 0.001 for both comparisons). In fact the findings suggested that UA could potentially be superior to GnRH analogs for the treatment of fibroids due to absence of estrogen suppression and a more persistent shrinkage of fibroids at 6 months post-treatment [9] . PEARL III and its extension [10] were long-term, open-label Phase III trials of UA, which were doubleblinded and placebo-controlled toward the administration of progestin after the end of each UA treatment course. Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding were included. Patients received up to four 3-month courses of UA 10 mg daily, immediately followed by 10-day double-blind treatment with norethisteroneacetate (NETA) (10 mg daily) or placebo. After the first ulipristal acetate (UP) course, amenorrhea occurred
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Drug Evaluation
in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2–6 days). Median fibroid volume change was -45% (interquartile range, -66%; -25%). Amenorrhea rates were 89, 88 and 90% for the 131, 119 and 107 women who received treatment courses 2, 3 and 4, respectively. Median times to amenorrhea were 2, 3 and 3 days for treatment courses 2, 3 and 4, respectively. Median fibroid volume changes from baseline were -63, -67 and -72% after treatment courses 2, 3 and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. The authors concluded that repeated 3-month UA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids [10] . Other medical alternatives available GnRH agonists have been used to achieve amenorrhea and shrink fibroid size in symptomatic women, but their use is restricted due to significant side effects such as bone mineral density loss and vasomotor symptoms. They are expensive, render myomectomy more difficult because they destroy tissue planes and are notorious for rebound growth of the fibroids upon cessation of therapy [11] . Progestational agents such as Norethisterone (nonproprietary) 5 mg three-times a day continuously have also been used in poor resourced settings to induce amenorrhea while improving anemia. Their side effects include bloating, fluid retention, breast tenderness, weight change, nausea, headache, drowsiness and mood swings, while there is no significant reduction in uterine or fibroid volume. Selective estrogen receptor modulators such as raloxifene have been shown to induce fibroid regression in post-, but not pre-menopausal women. Tranexamic acid is primarily used to reduce severity of bleeding associated with fibroids and evidence is insufficient to support the use of aromatase inhibitor drugs in the treatment of women with uterine fibroids. Ulipristal acetate: dosage & duration of therapy The treatment consists of one tablet of 5 mg to be taken orally once daily for up to 3 months. Treatment should be started during the first week of a menstrual cycle. PEARL III and PEARL III Extension studies have also demonstrated the effectiveness of repeated 3-month courses (up to four 3-month courses) of oral UA 10 mg once daily in control of bleeding and pain, reduction in fibroid volume and restoration of quality of life over the long term. If a patient misses a dose, the patient should take UA as soon as possible. If the dose was missed by more than 12 h, the patient
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Drug Evaluation Talaulikar & Manyonda should not take the missed dose and simply resume the usual dosing schedule. Contraindications & drug interactions These include hypersensitivity to the drug, pregnancy, breastfeeding, genital bleeding of unknown etiology and uterine, cervical, ovarian or breast cancer. Hormonal contraceptives and progestogens are likely to reduce UA efficacy by competitive action on the progesterone receptor, and are therefore not recommended. UA is not recommended for patients receiving drugs such as dabigatran etexilate, digoxin, moderate or potent CYP3A4 inhibitor or potent CYP3A4 inducer (rifampicin, carbamazepine, phenytoin, St John’s Wort). Adverse effects associated with use of UA The vast majority of adverse reactions are mild, have not led to discontinuation of the medicinal product and resolved spontaneously. These include hot flushes, headache, functional ovarian cysts, vertigo, nausea, acne, sweating, muscle pain and tiredness. Early clinical studies raised concerns about the effect of SPRMs on the endometrium, and this issue was addressed by a NIH sponsored workshop that evaluated endometrial specimens from women receiving the SPRMs mifepristone, asoprisnil and UA [1,12–14] . Pathologists concluded that there was little evidence of mitosis consistent with the anti-proliferative effect of SPRMs. No biopsy demonstrated atypical hyperplasia. There was asymmetry of stromal and epithelial growth and prominent cystically dilated glands with both admixed estrogen (mitotic) and progestin (secretory) epithelial effects. The panel designated these histological changes as PRM-associated endometrial changes (PAECs) [1,12–14] . In the PEARL II study, endometrial biopsy examinations showed no findings of clinical concern in cases receiving UA. At week 13, all histologic specimens showed benign endometrium except for one patient in the group receiving 5 mg of UA, whose specimen showed simple hyperplasia [9] . Overall, only about 10% of women on UA in the PEARL studies had endometrial thickness greater than 16 mm. It is suggested that unlike in the situation where there is unopposed estrogen effect, the endometrial thickening in women on PRMs is related to cystic glandular dilation and not endometrial hyperplasia. The overall evidence emerging from the recent clinical trials regarding the safety of UA therefore appears to be reassuring. However, long-term studies are necessary to evaluate safety and an appropriate follow-up should be recommended for patients receiving UA [15] . This is especially important because progestogen receptors are found on diverse body organs including brain, breast,
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bone and heart: research on the long-term effects of blocking receptors on these organs is clearly imperative. So far current knowledge about SPRMs does not indicate any adverse impact on breast [16] . What are the clinical implications of availability of ulipristal therapy for fibroids? UA is ‘the new kid on the block’ and naturally there is excitement surrounding its potential applications in the treatment of fibroids. The licensed form of UA is called Esmya™ (manufactured by Gedeon Richter Plc, Hungary) and is given as a 5 mg once a day oral tablet, taken for 3 months ahead of surgery. The current license is too limiting, and further research is required, and indeed is already under way, to establish the longer term safety and efficacy of Esmya. However, it is also reasonable to suggest that UA may be less effective in the treatment of massive fibroids as it may achieve a modest reduction in their size. It may act best in a selection of patients with a certain fibroid number and size as compared with others. Future clinical trials with varying dosage and duration of therapy should provide a definite answer to this question [14] . Clinicians detecting endometrial thickening in women treated with UA need to be aware that administration of UA for longer than 3 months may lead to endometrial thickening. This is related to cystic glandular dilation, not endometrial hyperplasia and pathologists need to be aware of PAEC and avoid misclassifying this appearance as hyperplasia. UA is not recommended in patients with severe renal or hepatic impairment unless the patient is closely monitored. In the absence of robust safety data for a period longer than 3 months or on repeat courses of treatment, treatment duration should not exceed 3 months. Clinicians should be aware of the need to investigate, as per usual clinical practice, persistence of endometrial thickening following treatment discontinuation and return of menstruation to exclude underlying conditions [17] . Contraindications for UA therapy include pregnancy and breastfeeding, genital bleeding of unknown etiology or for reasons other than uterine fibroids and uterine, cervical, ovarian or breast cancer. Patients should be informed that treatment with UA usually leads to a significant reduction in menstrual blood loss or amenorrhea within the first 10 days of treatment. Menstrual periods will generally return within 4 weeks after the end of the treatment course. Future perspective Future large prospective trials (clinician rather than industry led) will be able to establish the long-term efficacy and safety as well as definitive role of UA in medical management of uterine fibroids. Trials with
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Ulipristal acetate for use in moderate to severe symptoms of uterine fibroids
different doses and duration of treatment with UA in varying patient populations will be needed to inform the clinician about optimal therapy using UA. Conclusion As women delay childbearing to their 30s and 40s, gynecologists are increasingly likely to treat women with fibroids who wish to retain their fertility potential. Therefore for many women hysterectomy will not be an option, while some may be averse to the invasiveness of myomectomy, while the impact of the less invasive radiological treatments on fertility has yet to be rigorously evaluated. What is urgently needed is a medical therapy for symptomatic uterine fibroids that is simple, effective, safe and leads to a resolution of symptoms without affecting fertility. UA and other SPRMs appear to hold promise, but the present data are limited in relation to their long-term actions and effect on fertility. Further research is therefore required
Drug Evaluation
to inform clinicians about their long-term efficacy and safety, especially with regard to the endometrium, metabolism and reproductive function. In addition to the peer-review process, with the author(s) consent, the manufacturer of the product(s) discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made at the discretion of the author(s) and based on scientific or editorial merit only. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary • Uterine fibroids are the most common benign tumors of the female genital tract. • Symptomatic fibroids impact negatively on women’s health and quality of life, and have significant cost implications for their management. • The current mainstay treatments are surgical or radiological. • Gonadotropin-releasing hormone agonists have been used to achieve amenorrhoea and shrink fibroid size before surgery but their use is limited by significant side effects. • Ulipristal acetate is a selective progesterone receptor modulator which has been licensed in Europe for use prior to surgery for fibroids. • Ulipristal has shown efficacy with a significant reduction in uterine bleeding, fibroid volume and improved quality of life, without the side effects associated with other medications such as gonadotropin-releasing hormone agonists in PEARL I and II randomized controlled trials. • Ulipristal treatment consists of one tablet of 5 mg to be taken orally once daily for up to 3 months. • PEARL III and PEARL III Extension studies have also demonstrated the effectiveness of repeated 3-month courses (up to four 3-month courses) of oral ulipristal 10 mg once daily in control of bleeding and pain, reduction in fibroid volume and restoration of quality of life over the long term. • Endometrial thickening in women treated with ulipristal for longer than 3 months may be related to cystic glandular dilation, not endometrial hyperplasia, and pathologists need to be aware of progesterone receptor modulator-associated endometrial change and avoid misclassifying this appearance as hyperplasia. • Future trials will define the long-term safety of this drug and its role in medical management of uterine fibroids. growth. In: Translational Research In Uterine Biology. Maruo T, Mardon H, Stewart C (Eds). Elsevier, Amsterdam, The Netherlands (2008).
References Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
Spitz IM. Clinical utility of progesterone receptor modulators and their effect on the endometrium. Curr. Opin. Obstet. Gynecol. 21, 318–324 (2009).
•
Provides mechanisms of action of ulipristal and its effects on body tissues.
2
Maruo T, Matsuo H, Samoto T et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 65, 585–592 (2000).
3
Ohara N, Xu Q, Matsuo H, Maruo T. Progesterone and progesterone receptor modulator in uterine leiomyoma
future science group
•
Provides mechanisms of action of ulipristal and its effects on body tissues.
4
Xu Q, Ohara N, Liu J et al. Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells. Mol. Hum. Reprod. 14, 181–191 (2008).
•
Provides mechanisms of action of ulipristal and its effects on body tissues.
5
Yoshida S, Ohara N, Xu Q et al. Cell-type specific actions of progesterone receptor modulators in the regulation of
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uterine leiomyoma growth. Semin. Reprod. Med. 28(3), 260–273 (2010). • 6
7
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Provides mechanisms of action of ulipristal and its effects on body tissues. Levens ED, Potlog-Nahari C, Armstrong AY et al. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. Obstetr. Gynecol. 111, 1129–1136 (2008). Nieman LK, Blocker W, Nansel T et al. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebocontrolled, phase IIb study. Fertil. Steril. 95(2), 767–772, e1–2 (2011).
••
Forms the core clinical evidence for use of ulipristal.
8
Donnez J, Tatarchuk TF, Bouchard P et al. PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N. Engl. J. Med. 366(5), 409–420 (2012).
••
Forms the core clinical evidence for use of ulipristal.
11
Talaulikar VS, Belli A, Manyonda I. GnRH agonists: do they have a place in the modern management of fibroid disease? J. Obstet. Gynecol. India 62(5), 506–510 (2012).
12
Horne FM, Blithe DL. Progesterone receptor modulators and the endometrium: changes and consequences. Hum. Reprod. Update 13, 567–580 (2007).
13
Mutter GL, Bergeron C, Deligdisch L et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod, Pathol. 21(5), 591–598 (2008).
14
Talaulikar VS, Manyonda I. Progesterone and progesterone receptor modulators in the management of symptomatic uterine fibroids. Eur. J. Obstet. Gynecol. Reprod. Biol. 165(2), 135–140 (2012).
15
Talaulikar VS, Manyonda IT. Ulipristal acetate: a novel option for the medical management of symptomatic uterine fibroids. Adv. Ther. 29(8), 655–663 (2012).
••
Forms the core clinical evidence for use of ulipristal.
9
Donnez J, Tomaszewski J, Vázquez F et al. PEARL II Study Group. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N. Engl. J. Med. 366(5), 421–432 (2012).
16
Communal L, Vilasco M, Hugon-Rodin J et al. Ulipristal acetate does not impact human normal breast tissue. Hum. Reprod. 27(9), 2785–2798 (2012).
••
Forms the core clinical evidence for use of ulipristal.
17
10
Donnez J, Vázquez F, Tomaszewski J et al. PEARL III and PEARL III Extension Study Group. Long-term treatment
European Medicines Agency. Esmya – summary of product characteristics. www.ema.europa.eu
Womens Health (2014) 10(6)
future science group
Ulipristal acetate for use in moderate to severe symptoms of uterine fibroids
Although it has been known for a long time that uterine fibroids respond to changes in sex steroid concentrations, it is the availability of selective progesterone receptor modulators such as ulipristal acetete that has provided the gynecologist with a novel option for medical management of uterine fibroids. Ulipristal acetate is presently licensed in Europe for use in women with symptomatic fibroids up to 3 months prior to surgery and has demonstrated good clinical efficacy and safety for this indication. Future trials will define the long-term safety of this drug and its role in medical management of uterine fibroids.
Vikram Sinai Talaulikar*,1 & Isaac Manyonda1 1 St George’s Hospital & University of London, Cranmer Terrace, London, SW17 0RE, UK *Author for correspondence: Tel.: +44 20 8725 3695 Fax: +44 20 8725 5958 vtalauli@ gmail.com
Keywords: fibroids • medical • myoma • SPRM • ulipristal acetate
The unmet need for effective medical treatment of uterine fibroids Uterine fibroids (leiomyomas) are the most common benign tumors of the female genital tract, being found in 20–40% of women of reproductive age. These tumors vary in size from seedling to massive and are classified into submucous, intramural or subserous depending on their location in the uterus. Although the exact etiology of fibroids is not well established, point mutations and chromosomal rearrangements have been detected in fibroid cells. It is known that these tumors depend on sex hormones for their growth and several risk factors have been identified such as early menarche, nulliparity, Afro-Caribbean ethnicity and family history. Not all fibroids may be detected because many remain small and/or asymptomatic throughout the life of the woman. Most symptomatic fibroids present during the age range 30–45 years, while rarely some may also give rise to post-menopausal bleeding. The common symptoms include heavy menstrual bleeding (menorrhagia), anemia leading to generalized tiredness, pelvic pain, pressure on bladder or bowel and interference with fertility and pregnancy. Symptomatic fibroids impact negatively on women’s
10.2217/WHE.14.60 © 2014 Future Medicine Ltd
health and quality of life, and have significant cost implications for their management. The current mainstay treatments are surgical (myomectomy and hysterectomy) and more recently radiological (uterine artery embolization and focused ultrasound surgery). However, the surgical modalities carry significant risks such as infection, bleeding, visceral injuries, adhesions, postoperative morbidity and indeed mortality. The radiological treatments are relatively new and may not be suitable for all affected women, and focused ultarsound surgery, for one, requires equipment and facilities that are not always available in resource-limited settings. Traditionally, a few medical treatment options have been available for fibroids but most of these have mainly been utilized to provide temporary symptom control. Gonadotropin-releasing hormone (GnRH) agonists have been used before surgery to achieve amenorrhea and shrink fibroid size in symptomatic women, but their use is restricted due to significant side effects such as bone mineral density loss and vasomotor symptoms. There is at present no fully established effective long-term medical therapy for a disorder so common among women of reproductive age.
Womens Health (2014) 10(6), 565–570
part of
ISSN 1745-5057
565
Drug Evaluation Talaulikar & Manyonda Ulipristal acetate: novel selective progesterone receptor modulator Ulipristal acetate (UA) (Figure 1) belongs to a group of compounds collectively known as selective progesterone receptor modulators (SPRMs) that include CDB4124 (telapristone), CP-8947 and J-867 (asoprisnil). SPRMs are compounds which have mixed agonistic/ antagonistic effects, depending on expression of coactivators and co-repressors, in different tissues as per their differential progesterone receptor expression. The SPRMs reduce luteinizing hormone and folliclestimulating hormone secretion while maintaining mid-follicular estrogen levels. UA reversibly blocks the progesterone receptor in its target tissues (uterus, cervix, ovaries, hypothalamus) and acts as a potent, orally active anti-progestational agent. Most gynecologists will be familiar with UA as it has been on the clinical scene for several years as an efficient emergency contraceptive (as a one-off dose of 30 mg). More recently it has successfully completed Phase III clinical trials for the medical treatment of uterine fibroids. It has been licensed in Europe for short-term clinical use prior to surgery for fibroids, and has shown efficacy with a significant reduction in uterine bleeding, fibroid volume and improved quality of life, without the side effects associated with other medications such as GnRH agonists. Ulipristal & other selective progesterone receptor modulators: mechanism of action in the treatment of fibroids It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids, and this raised the possibility that anti-progestational agents and progesterone receptor modulators could be useful in the medical management of fibroids [1,2] . Fibroid cells demonstrate higher concentration of estrogen receptors, equally higher expression of mRNA and differential expression of progesterone receptors compared with surrounding myometrium. These differences may account for differential action
N
O O H O H
O Figure 1. Chemical structure of ulipristal acetate.
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of SPRMs on fibroids as compared with normal myometrium [3–5] . UA downregulates the expression of angiogenic growth factors such as vascular endothelial growth factor and their receptors in cultured fibroid cells [3–5] . This can result in the suppression of neovascularization, cell proliferation and survival [1] . UA also increases the expression of matrix metalloproteinases and decreases the expression of tissue inhibitor of metalloproteinases and collagens in cultured fibroid cells. This can reduce the collagen deposition in the extracellular spaces of fibroids, impairing tissue integrity [1,3,4] . UA and other SPRMs have been shown to modulate the ratio of progesterone receptor isoforms (PR-A and PR-B) in the cultured leiomyoma cells [5] . They decreased cell viability; suppressed the expression of growth factors, angiogenic factors and their receptors in those cells; and induced apoptosis. Of particular relevance and importance has been the observation that UA and other SPRMs do not affect normal myometrial cells in culture in the way that they affect leiomyoma cells, thus raising the possibility that they could be used to treat fibroids while selectively sparing normal uterine muscle. Evidence for effectiveness of ulipristal in the treatment of uterine fibroids In a number of clinical trials UA has been shown to reduce menstrual loss and fibroid volume and improve quality of life. Unlike GnRH agonists, UA does not have the side effects of inducing profound estrogen deficiency and decrease in bone mineral density. In the first trial in which UA was given at 10 or 20 mg in comparison against placebo for three cycles, UA showed a 92% reduction in bleeding versus 19% with placebo [6] . Leiomyoma volume was significantly reduced with UA (29 vs 6%; p = 0.01). UA eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles 20% on UA vs 83% with placebo; p = 0.001). UA also improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (p = 0.04). One woman on UA developed changes that were described as endometrial cystic hyperplasia without evidence of atypia. However, the numbers studied were small, with 22 patients being allocated and 18 completing the three cycles or 90–120 day trial [6] . A double-blind, placebo-controlled trial of efficacy and tolerability has also demonstrated positive results when UA was administered for 3–6 months, showing good control of bleeding, reduction in fibroid size and improvement in quality of life in the treatment group [7] . The PEARL I [8] trial compared treatment with oral UA for up to 13 weeks at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) with
future science group
Ulipristal acetate for use in moderate to severe symptoms of uterine fibroids
placebo (48 women) in patients with fibroids, menorrhagia and anemia. All patients received iron supplementation. The co-primary efficacy end points were control of uterine bleeding and reduction of fibroid volume at week 13, after which patients could undergo surgery. At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of UA, 92% of those receiving 10 mg of UA and 19% of those receiving placebo (p < 0.001 for the comparison of each dose of UA with placebo). Treatment with UA for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. PEARL II [9] was a double-blind noninferiority trial in which 307 patients with symptomatic fibroids and excessive uterine bleeding were randomly assigned to receive 3 months of daily therapy with oral UA (at a dose of either 5 or 10 mg) or once-monthly intramuscular injections of the GnRH analog leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a pre-specified noninferiority margin of -20%. Uterine bleeding was controlled in 90% of patients receiving 5 mg of UA, in 98% of those receiving 10 mg, while the figure for leuprolide acetate was 89%. Median times to amenorrhea were 7 days for patients receiving 5 mg of UA, 5 days for those receiving 10 mg of UA and 21 days for those receiving leuprolide acetate. There were no significant differences between the ulipristal groups and the leuprolide group in the proportion of patients reporting other adverse events or discontinuing treatment because of adverse events. Both UA doses were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. The proportions of patients reporting moderate-to-severe hot flashes were 11% in the group receiving 5 mg of UA, 10% in the group receiving 10 mg of UA and 40% in the group receiving leuprolide acetate (p < 0.001 for both comparisons). In fact the findings suggested that UA could potentially be superior to GnRH analogs for the treatment of fibroids due to absence of estrogen suppression and a more persistent shrinkage of fibroids at 6 months post-treatment [9] . PEARL III and its extension [10] were long-term, open-label Phase III trials of UA, which were doubleblinded and placebo-controlled toward the administration of progestin after the end of each UA treatment course. Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding were included. Patients received up to four 3-month courses of UA 10 mg daily, immediately followed by 10-day double-blind treatment with norethisteroneacetate (NETA) (10 mg daily) or placebo. After the first ulipristal acetate (UP) course, amenorrhea occurred
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Drug Evaluation
in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2–6 days). Median fibroid volume change was -45% (interquartile range, -66%; -25%). Amenorrhea rates were 89, 88 and 90% for the 131, 119 and 107 women who received treatment courses 2, 3 and 4, respectively. Median times to amenorrhea were 2, 3 and 3 days for treatment courses 2, 3 and 4, respectively. Median fibroid volume changes from baseline were -63, -67 and -72% after treatment courses 2, 3 and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. The authors concluded that repeated 3-month UA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids [10] . Other medical alternatives available GnRH agonists have been used to achieve amenorrhea and shrink fibroid size in symptomatic women, but their use is restricted due to significant side effects such as bone mineral density loss and vasomotor symptoms. They are expensive, render myomectomy more difficult because they destroy tissue planes and are notorious for rebound growth of the fibroids upon cessation of therapy [11] . Progestational agents such as Norethisterone (nonproprietary) 5 mg three-times a day continuously have also been used in poor resourced settings to induce amenorrhea while improving anemia. Their side effects include bloating, fluid retention, breast tenderness, weight change, nausea, headache, drowsiness and mood swings, while there is no significant reduction in uterine or fibroid volume. Selective estrogen receptor modulators such as raloxifene have been shown to induce fibroid regression in post-, but not pre-menopausal women. Tranexamic acid is primarily used to reduce severity of bleeding associated with fibroids and evidence is insufficient to support the use of aromatase inhibitor drugs in the treatment of women with uterine fibroids. Ulipristal acetate: dosage & duration of therapy The treatment consists of one tablet of 5 mg to be taken orally once daily for up to 3 months. Treatment should be started during the first week of a menstrual cycle. PEARL III and PEARL III Extension studies have also demonstrated the effectiveness of repeated 3-month courses (up to four 3-month courses) of oral UA 10 mg once daily in control of bleeding and pain, reduction in fibroid volume and restoration of quality of life over the long term. If a patient misses a dose, the patient should take UA as soon as possible. If the dose was missed by more than 12 h, the patient
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Drug Evaluation Talaulikar & Manyonda should not take the missed dose and simply resume the usual dosing schedule. Contraindications & drug interactions These include hypersensitivity to the drug, pregnancy, breastfeeding, genital bleeding of unknown etiology and uterine, cervical, ovarian or breast cancer. Hormonal contraceptives and progestogens are likely to reduce UA efficacy by competitive action on the progesterone receptor, and are therefore not recommended. UA is not recommended for patients receiving drugs such as dabigatran etexilate, digoxin, moderate or potent CYP3A4 inhibitor or potent CYP3A4 inducer (rifampicin, carbamazepine, phenytoin, St John’s Wort). Adverse effects associated with use of UA The vast majority of adverse reactions are mild, have not led to discontinuation of the medicinal product and resolved spontaneously. These include hot flushes, headache, functional ovarian cysts, vertigo, nausea, acne, sweating, muscle pain and tiredness. Early clinical studies raised concerns about the effect of SPRMs on the endometrium, and this issue was addressed by a NIH sponsored workshop that evaluated endometrial specimens from women receiving the SPRMs mifepristone, asoprisnil and UA [1,12–14] . Pathologists concluded that there was little evidence of mitosis consistent with the anti-proliferative effect of SPRMs. No biopsy demonstrated atypical hyperplasia. There was asymmetry of stromal and epithelial growth and prominent cystically dilated glands with both admixed estrogen (mitotic) and progestin (secretory) epithelial effects. The panel designated these histological changes as PRM-associated endometrial changes (PAECs) [1,12–14] . In the PEARL II study, endometrial biopsy examinations showed no findings of clinical concern in cases receiving UA. At week 13, all histologic specimens showed benign endometrium except for one patient in the group receiving 5 mg of UA, whose specimen showed simple hyperplasia [9] . Overall, only about 10% of women on UA in the PEARL studies had endometrial thickness greater than 16 mm. It is suggested that unlike in the situation where there is unopposed estrogen effect, the endometrial thickening in women on PRMs is related to cystic glandular dilation and not endometrial hyperplasia. The overall evidence emerging from the recent clinical trials regarding the safety of UA therefore appears to be reassuring. However, long-term studies are necessary to evaluate safety and an appropriate follow-up should be recommended for patients receiving UA [15] . This is especially important because progestogen receptors are found on diverse body organs including brain, breast,
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bone and heart: research on the long-term effects of blocking receptors on these organs is clearly imperative. So far current knowledge about SPRMs does not indicate any adverse impact on breast [16] . What are the clinical implications of availability of ulipristal therapy for fibroids? UA is ‘the new kid on the block’ and naturally there is excitement surrounding its potential applications in the treatment of fibroids. The licensed form of UA is called Esmya™ (manufactured by Gedeon Richter Plc, Hungary) and is given as a 5 mg once a day oral tablet, taken for 3 months ahead of surgery. The current license is too limiting, and further research is required, and indeed is already under way, to establish the longer term safety and efficacy of Esmya. However, it is also reasonable to suggest that UA may be less effective in the treatment of massive fibroids as it may achieve a modest reduction in their size. It may act best in a selection of patients with a certain fibroid number and size as compared with others. Future clinical trials with varying dosage and duration of therapy should provide a definite answer to this question [14] . Clinicians detecting endometrial thickening in women treated with UA need to be aware that administration of UA for longer than 3 months may lead to endometrial thickening. This is related to cystic glandular dilation, not endometrial hyperplasia and pathologists need to be aware of PAEC and avoid misclassifying this appearance as hyperplasia. UA is not recommended in patients with severe renal or hepatic impairment unless the patient is closely monitored. In the absence of robust safety data for a period longer than 3 months or on repeat courses of treatment, treatment duration should not exceed 3 months. Clinicians should be aware of the need to investigate, as per usual clinical practice, persistence of endometrial thickening following treatment discontinuation and return of menstruation to exclude underlying conditions [17] . Contraindications for UA therapy include pregnancy and breastfeeding, genital bleeding of unknown etiology or for reasons other than uterine fibroids and uterine, cervical, ovarian or breast cancer. Patients should be informed that treatment with UA usually leads to a significant reduction in menstrual blood loss or amenorrhea within the first 10 days of treatment. Menstrual periods will generally return within 4 weeks after the end of the treatment course. Future perspective Future large prospective trials (clinician rather than industry led) will be able to establish the long-term efficacy and safety as well as definitive role of UA in medical management of uterine fibroids. Trials with
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Ulipristal acetate for use in moderate to severe symptoms of uterine fibroids
different doses and duration of treatment with UA in varying patient populations will be needed to inform the clinician about optimal therapy using UA. Conclusion As women delay childbearing to their 30s and 40s, gynecologists are increasingly likely to treat women with fibroids who wish to retain their fertility potential. Therefore for many women hysterectomy will not be an option, while some may be averse to the invasiveness of myomectomy, while the impact of the less invasive radiological treatments on fertility has yet to be rigorously evaluated. What is urgently needed is a medical therapy for symptomatic uterine fibroids that is simple, effective, safe and leads to a resolution of symptoms without affecting fertility. UA and other SPRMs appear to hold promise, but the present data are limited in relation to their long-term actions and effect on fertility. Further research is therefore required
Drug Evaluation
to inform clinicians about their long-term efficacy and safety, especially with regard to the endometrium, metabolism and reproductive function. In addition to the peer-review process, with the author(s) consent, the manufacturer of the product(s) discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made at the discretion of the author(s) and based on scientific or editorial merit only. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary • Uterine fibroids are the most common benign tumors of the female genital tract. • Symptomatic fibroids impact negatively on women’s health and quality of life, and have significant cost implications for their management. • The current mainstay treatments are surgical or radiological. • Gonadotropin-releasing hormone agonists have been used to achieve amenorrhoea and shrink fibroid size before surgery but their use is limited by significant side effects. • Ulipristal acetate is a selective progesterone receptor modulator which has been licensed in Europe for use prior to surgery for fibroids. • Ulipristal has shown efficacy with a significant reduction in uterine bleeding, fibroid volume and improved quality of life, without the side effects associated with other medications such as gonadotropin-releasing hormone agonists in PEARL I and II randomized controlled trials. • Ulipristal treatment consists of one tablet of 5 mg to be taken orally once daily for up to 3 months. • PEARL III and PEARL III Extension studies have also demonstrated the effectiveness of repeated 3-month courses (up to four 3-month courses) of oral ulipristal 10 mg once daily in control of bleeding and pain, reduction in fibroid volume and restoration of quality of life over the long term. • Endometrial thickening in women treated with ulipristal for longer than 3 months may be related to cystic glandular dilation, not endometrial hyperplasia, and pathologists need to be aware of progesterone receptor modulator-associated endometrial change and avoid misclassifying this appearance as hyperplasia. • Future trials will define the long-term safety of this drug and its role in medical management of uterine fibroids. growth. In: Translational Research In Uterine Biology. Maruo T, Mardon H, Stewart C (Eds). Elsevier, Amsterdam, The Netherlands (2008).
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Ohara N, Xu Q, Matsuo H, Maruo T. Progesterone and progesterone receptor modulator in uterine leiomyoma
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•
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Xu Q, Ohara N, Liu J et al. Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells. Mol. Hum. Reprod. 14, 181–191 (2008).
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uterine leiomyoma growth. Semin. Reprod. Med. 28(3), 260–273 (2010). • 6
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Communal L, Vilasco M, Hugon-Rodin J et al. Ulipristal acetate does not impact human normal breast tissue. Hum. Reprod. 27(9), 2785–2798 (2012).
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