An Evidence-Based Review of Elagolix for the Treatment of Pain Secondary to Endometriosis

Abstract

Purpose of Review

This is a review of elagolix use for pain related to endometriosis. It summarizes the background and recent data available about the pathogenesis of endometriosis and pain that is secondary to this syndrome. It then reviews the evidence to support the use of elagolix and the indications for use.

Recent Findings

Endometriosis occurs in 10% of reproductive-age women and is a common source of chronic pelvic pain, infertility, and co-morbid disorders. It usually presents with some combination of dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Treatment options may be surgical or hormonal. Traditional treatment is divided into medical and surgical. The latter, though effective, is reserved for surgical emergencies and patients failing medical management. Medical management with NSAIDs is usually limited in efficacy. It is generally based on hormonal suppression leading to atrophy of endometrial lesions. Elagolix (Orlissa) is a GnRH antagonist that suppressed the entire hypophysis-gonadal axis. Reduced levels of estrogen and progesterone lead to involution of the endometrial lesions and improvement in symptoms. Clinical trials showed that elagolix is effective in treating dysmenorrhea and non-menstrual pain that is secondary to endometriosis. It is well tolerated and has a relatively safe usage profile. Studies up to 12 months long showed continued efficacy and reduction in dysmenorrhea of up to 75%, with 50%–60% reduction in non-menstrual pain. Elagolix was found effective when compared to both placebo and alternative treatments.

Summary

Endometriosis is a common syndrome that causes significant pain, morbidity, and disability, as well as financial loss. Elagolix is an effective drug in treating the symptoms of endometriosis and is a relatively safe option. Phase 4 studies will be required to evaluate the safety and efficacy of long term chronic use.

Introduction

Endometriosis is a disease found primarily in women of reproductive age that is generally associated with chronic pelvic discomfort and infertility. It is estimated to affect one in ten women of reproductive age and holds the third-highest rate for gynecologic disorders resulting in hospitalization within this population.^1,2 Endometriosis is difficult to classify, treat, and is known to negatively affect the quality of life.^3,4 Menstrual pain from the condition also impact patients’ psychological health, with patients who suffer from Endometriosis being at higher risk for anxiety, depression, and other psychiatric disorders.^5,6 The impact also extends onto patients’ partners, family, and friends, and may significantly compromise social relationships.^7,8

The cost of illness and economic burden associated with Endometriosis is significant, with one systematic review averaging $12,118 and $15,737 in annual per-person direct and indirect cost, respectively, in the United States.⁹ The options for management of the disease are varied, ranging from pharmacologic therapy to surgical resection of lesions. Treatment choice is based on factors such as age, reproductive plans, the severity of the disease, and adverse effect profile. Pharmacologic management is targeted at the hypothalamic-pituitary-ovarian axis with the goal of suppressing ovarian function.¹⁰ This review will focus on the clinical effectiveness of Elagolix, an oral gonadotropin-releasing hormone (GnRH) antagonist approved by the Food and Drug Administration for the management of pain associated with endometriosis.

Epidemiology

The study of Endometriosis from an epidemiologic standpoint has been historically difficult due to methodologic problems surrounding disease definition. The primary problem has been the inclusion of asymptomatic women who are found to have endometrial glands and stroma outside of the uterus upon receiving surgery for another reason. This complicates estimating a prevalence of symptomatic disease in the population. Nonetheless, the literature states that endometriosis affects an estimated 10% of women of reproductive age, and suggests a complex pattern of disease, including reproductive, hormonal, genetic, constitutional, and environmental factors associated with the development of endometriosis.¹¹

Reproductive and Hormonal Factors

Cramer et al. first described the relationship between shorter cycle lengths (defined as < 27 days) and longer flow (> 1 week) and the risk of endometriosis, showing that after adjusting for confounding factors women with these menstrual characteristics had more than double the risk for the development of endometriosis as compared to women with longer cycles and shorter durations of flow.¹² Many other studies have since observed the same relationship between heavy flow and shorter cycles with Endometriosis.^13,14 Several epidemiological retrospective studies have found early menarche, defined as ⩽ 11 years of age, to increase the risk for endometriosis.^15–18 Additionally, Missmer et al. in a prospective epidemiological survey study, observed a linear decrease in risk observed with a number of live children, with nulliparous women having the greatest risk.¹⁹ These findings are thought to be related, as a short menstrual cycle will usually result in more frequent menstrual cycles. Earlier menarche and nulliparity also lead to higher circulating Estradiol, which may stimulate the growth of ectopic endometrial tissue and explain this relationship. Thus, a woman’s risk for endometriosis increases as the exposure to menstruation increases.¹ Congruent with this theme, a 2011 meta-analysis by Vercellini and his group found a protective effect of oral contraceptive use against the development of endometriosis.²⁰

Genetic Factors

The genetic predisposition to the development of endometriosis has been reported, with different genes and variants proposed as candidates.^21–24 Most recent literature suggests a polygenic etiology as opposed to a Mendelian inheritance pattern. The number and location of these genes is an on-going discovery, recently accelerated by technologies such as gene mapping.

Socioeconomic and Constitutional Factors

Socioeconomically, studies have shown a higher prevalence of the disease among women of higher socioeconomic status, possibly due to the association between socioeconomic status and other well-established risk factors such as reproductive pattern, body habitus, diet, and physical activity.^12,25 The inverse relationship between body mass index and endometriosis was described early by Cramer and has since been confirmed in various studies, most recently with suggestions that this may be due to hormonal differences in the respective populations.^12,26 Lastly, smoking has been associated with a decreased risk of endometriosis, while alcohol has been reported to increase the risk for endometriosis.^12,14,27,28 Interestingly, smoking has been previously described in the literature to have an anti-estrogenic effect, possibly explaining this relationship.²⁹

Risk Factors for Endometriosis

There are a number of factors that are thought to confer the risk of endometriosis. An early study in 1986 published in JAMA researched patients with endometriosis to determine any relation to menstrual characteristics, smoking, and/or exercise. It was determined that women with endometriosis tended to be Caucasian, have significantly earlier menarche compared to controls, shorter menstrual cycles, and longer duration of flow (8 or more days).¹² Amongst these risk factors, cycle length appeared to have a relatively strong association with women having cycles of 27 days or less having a relative risk of 2.1 (95% CI of 1.5–2.9) when compared to women with cycles lasting 28–34 days.¹² Shorter menstrual cycles (typically defined as less than 27 days) has been consistently cited as a risk factor for endometriosis.^30,18,31,32

Aside from menstrual factors, there are a number of environmental and lifestyle factors related to endometriosis. The 1986 JAMA study did not find any consistent trends or correlations between weight, height, and endometriosis. There were significant associations with regard to smoking and exercise. With regard to smoking, patients who smoked at least a pack per day and who had begun smoking before 17 had significantly decreased risk for endometriosis when compared to nonsmokers.¹² This trend of smoking having a protective factor was observed in other studies as well. Still, a 2014 meta-analysis of 13,129 women with endometriosis concluded that there was no evidence of associated tobacco smoking with the risk of endometriosis.³³ With regard to exercise, the 1986 JAMA study found there to be a protective effect of regular exercise.¹² However, this relationship has not been clear or consistent. In one prospective cohort study involving 102,197 premenopausal women, it was determined that there was a slight reduction in endometriosis incidence when comparing women with the highest activity to the women with the lowest activity indicating that the positive benefit is not as profound as once believed and may only occur at high levels of exercise.³⁴ Some additional risk factors mentioned in the literature include a family history of endometriosis as well as alcohol and caffeine use.³⁵ One additional protective factor mentioned in the literature is higher parity.³⁵ While some risk factors are not agreed upon by the research community, some are relatively well established, such as shorter menstrual cycles and early menarche.

Diagnosis, Clinical Presentation, Workup of Endometriosis

The clinical presentation of endometriosis is often vague, and symptoms sometimes mimic the presentation of other disorders. The most common symptoms and later sequela of endometriosis include dysmenorrhea, chronic pelvic pain, dyspareunia fertility issues, or pelvic masses (often adnexal).^36,37 Other conditions that have clinical presentations that can be similar to endometriosis include adenomyosis, IBS, pelvic floor disorders, neuropathy, primary dysmenorrhea, etc. which highlights the need for an extensive workup to be able to confidently diagnose endometriosis.³⁶ The workup to diagnose endometriosis is most simply divided into surgical and non-surgical techniques. A surgical diagnosis in which visualization of endometriosis is made via laparotomy or laparoscopy alongside histologic confirmation is considered to be the only method of definitive diagnosis.^37,38 However, given the risks, costs, and potential adverse effects of surgery, a definite diagnosis is reserved only to a subset of patients.

Other non-surgical techniques have been established that have served to be useful in the workup and diagnosis. The initial workup should always begin with a thorough history and physical exam that assess for other causes of the clinical presentation as well.³⁶ Imaging is particularly important not just for diagnosis but for later management, as well as ruling out alternate diagnoses. Transvaginal ultrasound (TVUS) is thought of as a first-line imaging modality for suspected endometriosis given its availability, safety, and ability to visualize the pelvis.³⁹ In one study, pre-operative TVUS and transrectal ultrasound were found to have sensitivity and specificity of 86% and 82% respectively when predicting for stage 3 endometriosis as well as 75% and 91% respectively when predicting for stage 4 endometriosis confirmed by laparoscopy.³,⁹ Another study calculated the sensitivity and specificity of all types of vaginal ultrasonography in the diagnosis of deep endometriosis to be 79% and 94%, respectively. ⁴⁰ Another technique often used is magnetic resonance imaging (MRI), in which a meta-analysis found the sensitivity and specificity of MRI in the diagnosis of deep endometriosis to be 94% and 77%, respectively.⁴⁰ Another meta-analysis comparing TVUS and MRI in the diagnosis of deep infiltrating endometriosis in various areas (rectosigmoid, uterosacral ligaments, and rectovaginal septum) found that the sensitivity and specificity of each imaging modality were comparable to one another.⁴¹ Other techniques on the horizon include biomarkers of endometriosis; however, more research is needed as none have been validated as a diagnostic tool.⁴²

Pathophysiology

Three primary hypotheses have been elucidated in the literature regarding the pathophysiology of endometriosis. In 1927, Sampson et al. were the first to describe the now more widely accepted hypothesis, whereby pieces of the endometrium may pass retrograde through the fallopian tubes during menstruation and into the peritoneal cavity.⁴³ This etiology has been supported by many studies. Bulun observed that women with imperforate hymen or transverse vaginal septum, both facilitating retrograde menstruation by blocking forward flow from the vagina, are almost certain to develop endometriosis.⁴⁴ Hooghe and Debrock showed that endometriosis is present in other species that undergo menstruation and that the development of endometriosis is associated with the quantity of retrograde menstruation.⁴⁵ Another hypothesis, known as the “embolic hypothesis,” suggests that endometrial tissue reaches the abdominal and pelvic cavity via the lymphatic or venous system.⁴⁶ The third hypothesis, celomic metaplasia, was also first described in the 1920s by Meyer, arguing that endometrial tissue found outside of the endometrium may be a result of cellular metaplasia of normal peritoneal tissue into endometrial tissue, as seen in other diseases such as Barrett’s esophagus.^47,48

Additionally, recent publications suggest another contributing theory, where progenitor cells from either the bone marrow or from the endometrium itself may arrive at the pelvic cavity via retrograde menstruation or the vascular system, implant, and differentiate into endometrial tissue.^49,50 Evidence in the last three decades supports retrograde menstruation hypothesis as most plausible. Little more has been written regarding the embolic hypothesis due to the difficulty in designing robust studies for its investigation.

Once endometrial fragments are displaced into the peritoneal cavity, three steps are necessary for the development of persistent endometrial tissue and the development of symptoms: successful implantation and attachment, evasion of immune clearance, and localized angiogenesis.⁵¹ Regarding endometrial tissue invasion and attachment, a molecular basis surrounding cytokine and the extracellular matrix has been proposed. Cytokines have been demonstrated to facilitate adhesion due to localized mesothelial layer damage, with subsequent exposure of the underlying basement membrane.^52,53 An imbalance of matrix metalloproteinases and their inhibitors in women with endometriosis has also been previously shown in the literature, offering another contributor to extracellular matrix breakdown and subsequent invasion.⁵⁴ Transforming Growth Factor-Beta (TGF-B), Tumor Necrosis Factor-alpha (TNF-a), interleukin-8 (IL-8), and Matrix Metalloproteinase 3 (MMP-3) have all been shown to be upregulated in women with endometriosis.^55–57 Lucidi et al. concluded through an in vitro binding assay study that the ability of endometrial stromal cells (ESC) to bind to peritoneal mesothelial cells (PMC) was dependent on the origin of the ESCs and not on the characteristics of the PMCs.⁵⁸

A recent review by Patel et al. describes in detail the inflammatory and hormonal environment that favors the persistence of endometriosis, noting an increased sensitivity to and excess of estrogen, progesterone resistance, and defective immunosurveilance.⁵⁹ Further studies regarding the immunobiology of endometriosis found evidence of endometrial cell resistance to apoptosis, and have since confirmed increased local chemokine production, and increased expression of growth factors promoting neuroangiogenesis.^56,60,61 Vascular endothelial growth factor (VEGF), specifically, has been consistently shown to be elevated in peritoneal fluid collected from women with endometriosis, suggesting it may be the primary angiogenic factor in endometriosis.⁵⁷ Coxon et al. provides evidence of increased sensory nerve fibre growth in endometriosis, as well as central changes such as the expectation of pain and presence of comorbidities playing a vital role in the development of endometriosis-associated pain.⁶²

Traditional Treatment Options

Treatment choice for endometriosis is based on a complex decision balancing the goals of care (such as pain relief, fertility, etc.) and the risks and side effects of the chosen treatment. The traditional treatment options can be broken down into medical management and surgical management. Surgical management can be considered if a patient fails medical therapy, has an acute surgical emergency related to endometriosis (such as ovarian torsion due to an endometrioma), has deep endometriosis, or a number of other considerations.⁶³ Surgical management was found to be effective at reducing pain related to endometriosis based in a 2014 Cochrane Systematic Review. The reviewers concluded that laparoscopic surgery with ablation or excision was associated with decreased pain when compared to diagnostic laparoscopy at 6 months (odds ratio 6.58, 5% confidence interval 3.31 to 13.10) and at 12 months (odds ratio 10.00, 95% confidence interval 3.21 to 31.17).⁶⁴ Additionally, surgical treatment was effective for infertility as well. Another Cochrane Systematic Review found that laparoscopic treatment of mild to moderate endometriosis was associated with higher live birth rate and ongoing pregnancy after 20 weeks when compared to diagnostic laparoscopy alone (odds ratio 1.64, 95% confidence interval 1.05 to 2.57).⁶⁵ Trials have shown no statistical difference between an ablative and excisional laparoscopic intervention.⁶⁶

Medical management is typically the first line of therapy. Many of the traditional first-line agents such as NSAIDs are often not effective, as referenced in a Cochrane Review from 2017, showing no evidence on pain relief when compared to placebo.⁶⁷ This leads to physicians often using opioids to help manage chronic pain in endometriosis. In one cross-sectional of obstetrician-gynecologists, 24% of them reported to prescribing opioids for endometriosis.⁶⁸ Other therapeutic options include contraceptive therapy with combined estrogen and progestin, which provides pain relief by inhibiting ovulation and leading to atrophy of the endometrial lesions as well as progestin therapy, which has a similar mechanism of pain relief.³⁶ Other drugs used include GnRH agonists such as leuprolide depot, aromatase inhibitors such as anastrozole, androgenic steroids such as danazol, GnRH antagonists such as Elagolix, and many more.³⁶ The choice of therapy depends on the patient’s clinical presentation, as well as the minimization of risks and side effects. One commonly used class of medication is the GnRH agonists, such as leuprolide depot, which inhibits gonadotropic secretion leading to pain relief.³⁶ They are effective treatments with a Cochrane Systematic Review finding that GnRH agonist treatment was more effective than placebo and just as effective as other modalities such as contraceptive therapy.⁶⁹ One of the more recently developed medications: elagolix, a GnRH antagonist, was FDA approved for the treatment of endometriosis-associated pain.⁷⁰ Elagolix phase 3 trials were effective in improving both dysmenorrhea and non-menstrual pain associated with endometriosis compared to placebo in 6 months.³⁷ With the further development of medications and treatment modalities, the management of endometriosis is rapidly evolving.

Elagolix

Elagolix (Orlissa) was recently approved by the FDA for the treatment of moderate to severe endometriosis pain. Manufactured by AbbVie Inc, Elagolix has been shown to reduce dysmenorrhea, non-menstrual pelvic pain, and dyspareunia symptoms.⁷¹ Currently, the medication is available in two doses, 150 mg taken once daily, and 200 mg taken twice daily, with differing indications for each dose.⁷¹

Background

Elagolix is a second-generation, non-peptide GnRH receptor antagonist that acts in the pituitary gland to reduce the production of estrogen and progesterone.⁷² Multiple trials have been conducted to evaluate the efficacy of the medication. They have demonstrated a dose-dependent reduction in various hormone levels, including LH, FSH, estradiol, and progesterone, in patients with endometriosis pain.⁷²

The medication is available in a 150 mg tablet, recommended to be used once daily, and a 200 mg tablet, recommended to be taken twice daily.⁷¹ Clinical trials have found a statistically significant reduction in dysmenorrhea symptoms and non-menstrual pelvic pain at both dosages.⁷⁰ However, only the higher dose of 200 mg taken twice daily was found to be statistically significant for improving dyspareunia symptoms.⁷⁰

Due to the reduction in estrogen and progesterone in the body, there are various adverse effects associated with elagolix, one of the most important being the possibility of bone mineral density loss.⁷³ As a result, elagolix is recommended to be used at the lowest effective dose and for the shortest duration of treatment.⁷¹ The maximum duration of treatment recommended by the manufacturer is 24 months for patients taking Orlissa 150 mg once daily, and 6 months for those patients taking 200 mg twice daily.⁷¹

Orlissa is metabolized by the liver, and as a result, dose adjustments need to be made for patients with moderate hepatic impairment.⁷¹ These patients should be treated with 150 mg once daily for a maximum of 6 months, and a higher dose of 200 mg twice daily is not recommended.⁷¹ In patients with severe hepatic impairment, the use of Orlissa is contraindicated.⁷¹

Elagolix is also contraindicated in patients with existing osteoporosis, pregnancy, and in those who are using strong organic anion transporting polypeptide (OATP) 1B1 inhibitors.⁷¹

Mechanism of Action

Elagolix treats endometriosis pain via the reduction of serum levels of estradiol and progesterone. Specifically, the medication is an oral, second-generation GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland.⁷⁴ It is highly potent, with a K_D of 54 pM.⁷⁵ As a result of the binding, the secretion of gonadotropins, follicle-stimulating hormone, and luteinizing hormone decreases, leading to an overall decreased concentration of estradiol and progesterone.⁷⁶ Regarding gonadotropin hormone suppression, elagolix suppresses luteinizing hormone faster and to a greater extent than follicle-stimulating hormone.⁷⁷ This suppression of hormones has been found to be dose-dependent, with the minimum dosing of 150 mg taken once daily, maintaining some estradiol in the body, and the maximum dosing of 200 mg taken twice daily, leading to almost complete suppression.⁷⁸ This property separates elagolix and other GnRH antagonists from GnRH agonists, which have been used for the treatment of multiple diseases, including endometriosis. GnRH agonists at high doses cause complete suppression of estradiol and, thus, have been associated with severe side effects due to the lack of estrogen, such as bone mineral density loss and hot flashes.^76,77 Maintaining low levels of estradiol with the low dose of elagolix is hoped to still inhibit endometrial implants while reducing the possible hypoestrogenic side effects.⁷⁷

In contrast with traditional GnRH agonists, the onset of action of elagolix is fast, with a maximum plasma concentration (T_max) reached in 1 hour.⁷¹ Elimination is also rapid, with a terminal phase elimination half-life of 4–6 hours, which allows for a fast reversal of gonadotropin suppression if the need arises.⁷¹ Studies have shown that there is a return to normal levels of estradiol after 48 hours.⁷⁷

Elagolix is metabolized hepatically, primarily through the cytochrome P450 3A mechanism.⁷¹ Minor metabolism pathways also include CYP 2D6, 2C8, and uridine glucuronyl transferase.⁷¹ In addition, elagolix is known to moderately induce CYP 3A and weakly inhibit CYP 2C19, and consequently, there are multiple drug interactions to be cautious about when prescribing.⁷¹ Specifically, due to the metabolism through CYP 3A, elagolix treatment should be limited to 200 mg twice daily for a maximum of 1 month or 150 mg once daily for a maximum of 6 months, in women being treated with strong CYP3A inhibitors.⁷¹

In addition, Wizenborg et al. found in their study on pharmacokinetics of elagolix that the organic anion transporting polypeptide (OATP) 1B1 genotype had a statistically significant impact on apparent clearance of the drug.⁷⁹ Furthermore, concomitant use with strong OATP1B1 inhibitors leads to increased elagolix concentrations, and as a result, is contraindicated.⁷¹ Specifically, rifampin is known to increase concentrations of elagolix, and consequently, concomitant use should be limited to a maximum of 6 months at the 150 mg once-daily dosing.⁷¹

An important consideration for women of reproductive age is the effect of hormonal contraception on the efficacy of elagolix. The efficacy is expected to decrease with the concomitant use of estrogen-containing contraceptives. Thus, patients are recommended to use non-hormonal methods of contraception while being treated with elagolix.⁷¹

Elimination is also primarily hepatic, with less than 3% of the medication eliminated renally.⁷¹ Consequently, studies have been done evaluating the safety and efficacy of the medication in patients with hepatic impairment. Ng et al. recently published a study evaluating safety and pharmacokinetics of elagolix in women with renal and hepatic impairment. They found that the mean maximum plasma concentration was similar between patients with normal renal function and ESRD, and renal impairment did not significantly affect exposure to medication.⁷⁸ Thus, dose or duration of treatment adjustments do not need to be made in patients with decreased renal function.⁷¹ In contrast, they found that decreased hepatic function did affect plasma concentrations of the drug.⁷⁸ In patients with normal hepatic function and mild hepatic impairment (Child-Pugh A), there was no significant difference in exposure, while patients with moderate hepatic impairment (Child-Pugh B) had a 3x increased exposure to the drug compared to normal.⁷⁸ The authors predicted that the 3x increased exposure to elagolix would cause patients on 150 mg once daily to have an elagolix concentration equivalent to that in women with normal hepatic function taking 200 mg twice daily. Thus, the duration of treatment should be limited to less than 6 months in those with moderate hepatic impairment.⁷⁸ In women with severe hepatic impairment, there was a 7x increased exposure, and thus, severe hepatic impairment is a contraindication for elagolix treatment.⁷⁸

Clinical Studies

One of the first human investigations of elagolix therapy in human subjects occurred in 2009, with the intention of establishing the safety profile, pharmacokinetics, and effects of various dosing regimens on gonadotropin and estradiol levels. The double-blind study included 55 premenopausal, regularly cycling women, who were given either placebo, a once-daily oral dose ranging from 25 mg to 400 mg, or a twice-daily oral dose of 100 mg. It was discovered that for women receiving at least 50 mg doses, estradiol levels were decreased within 24 hours, remaining at lower levels for all 7 days of treatment, and rapidly resuming normal levels upon the termination of treatment. Additionally, the estradiol suppression was dose-dependent, which, combined with the prompt response at initiation, and resolution at discontinuation, led the authors to conclude that elagolix showed therapeutic promise and warranted further long-term study.⁸⁰

In a 2013 phase 2 trial of 102 women, aged 18–49, with diagnosed endometriosis, one group received a placebo pill for 12 weeks, while the other group either received either 150 mg or 250 mg of elagolix once daily for the same period. At the conclusion of the first 12 weeks, the placebo group was re-randomized to either the 150 mg or 250 mg dose of elagolix, while the original treatment groups continued with their respective regimens for an additional 12 weeks. Estradiol was measured at regular intervals, and bone mineral density (BMD) was measured with DXA scans at 12 and 24 weeks. Patients recorded or self-reported subjective metrics such as non-menstrual pain, dysmenorrhea, dyspareunia, uterine bleeding, hot flashes, and quality of life. Treatment groups did experience mild to significant BMD loss during the course of the study, which was shown to either level out or recover in post-study follow-up. Women who received elagolix experienced longer menstrual cycles, reduced bleeding, with scores for both dysmenorrhea and dyspareunia seeing significant decreases. Pelvic pain was also reduced in the treatment group, however not significantly compared to the placebo group. While elagolix demonstrated an acceptable safety profile, multiple adverse events were reported in the treatment groups, such as nausea, anxiety, and headache. Overall, researchers concluded that elagolix showed potential to be a safe and effective new first-line therapy for women with endometriosis.⁸¹

In order to examine the possible effect of elagolix on endometriosis-associated fatigue, a 2019 phase 3 trial followed 860 women for 6 months. At the beginning of the trial, participants completed a Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 6a questionnaire with 54%–74% reporting “quite a bit” or “very much” fatigue. The women were then randomized into three groups; a placebo group, a group receiving 150 mg of elagolix QD, and a group receiving 200 mg of elagolix BID. At the conclusion of the study, both treatment groups saw a significant decrease in fatigue scores, with 29%–43% for the 150 mg QD group and 14%–29% for the 200 mg BID group. In the placebo group, 35%–50% of women reported fatigue in the PROMIS questionnaire, leading to the conclusion that reduced fatigue is another means by which elagolix therapy can be effective.⁸²

Seeking to clarify the results of different elagolix dosing strategies, two similar phase 3 trials of 6 months duration were conducted to specifically ascertain the impact on dysmenorrhea and non-menstrual pelvic pain women with laparoscopically confirmed endometriosis. Again, the treatment groups took either 150 mg QD or 200 mg BID. In the first trial, Elaris EM-1, 653 women completed the study. With regards to dysmenorrhea, 46.4% of the low-dose group and 75.8% of the high-dose group showed a clinical response, compared with 19.6% of the placebo group. In the second trial, Elaris EM-2, 632 women completed the study, and the low-dose, high-dose, and placebo groups demonstrated clinical response in 43.4%, 72.4%, and 22.7% of participants respectively. As for non-menstrual pelvic pain in Elaris EM-1, 50.4% of the low-dose participants and 54.5% of the high dose participants achieved a clinical response, while 36.6% of the placebo group did not. In the Elaris EM-2 cohort, 49.8% of the low-dose group and 57.8% of the high-dose group showed a clinical response regarding non-menstrual pain, compared with 36.6% of the placebo group. In sum, both dose regimens of elagolix elicited clinical improvement of both dysmenorrhea and non-menstrual pelvic pain compared to placebo.⁷⁰

Building upon the Elaris EM-1 and EM-2 trials phase 3 trials, Elaris EM-3 and Elaris EM-4 investigated the long-term effects of the same doses, by following 569 of the original participants for an additional 6 months, reaching a total of 12 months for those included. In the Elaris EM-3 arm of the study, 52.1% of the 150 mg QD group and 78.1% of the 200 mg BID group reported an effective clinical response for dysmenorrhea; in the Elaris EM-4 arm, response rates were 50.8% and 75.9% respectively. Non-menstrual pelvic pain response rates were 67.8% for the 150 QD group and 69.1% for the 200 mg BID group in Elaris EM-3, and 66.4%, and 67.2% for the respective groups in Elaris EM-4. There was a 45.2% dyspareunia response rate for the 150 mg QD and 60.0% for the 200 mg BID groups of Elaris EM-3, while in Elaris EM-4, the response rates were 45.9% and 58.1% for the respective doses. The authors concluded that long-term elagolix use should be considered an effective therapy for dysmenorrhea, non-menstrual pelvic pain, and dyspareunia.⁸³

Endometriosis-associated pain has been implicated in a significant amount of both missed workdays (absenteeism) and loss of productivity while still at work (presenteeism). A 2011 survey of 193 women with self-identified endometriosis found that when experiencing symptoms, 13% of their work hours were lost to absenteeism, 64% of their time at work was lost to presenteeism, and 60% of their daily activity time was impaired.⁸⁴ Taking advantage of the fact that questions pertaining to absenteeism and presenteeism had been collected in the EM-1 and EM-2 trials surveys, a post-hoc analysis of the data was undertaken to elucidate the impact elagolix had on these issues. It was determined that those who received the 150 mg QD dose experienced an average increase of > 2 total work time, and the 200 mg BID dose group experienced an average increase of > 4 hours total work time; in both groups, the greatest impact was on presenteeism. Over the course of 6 months, there was an estimated savings of $1,500 US savings per participant in the 150 QD group, and $3,300 US savings per participant in the 200 mg BID group. They concluded that elagolix treatment has the potential for remarkable economic benefits when considering productivity gains.⁸⁵

Recognizing that previous trials had relied upon either weekly or monthly recall scales, in which participants report the pain they remember experiencing of the past interval, researchers set out to utilize a new daily electronic diary (e-diary) with an updated Biberoglu-Behrman pain scale. Therefore, the primary aim of this study was to evaluate the efficacy of elagolix in treating non-menstrual pelvic pain, dysmenorrhea, and dyspareunia, while also assessing the validity of the novel pain scale. The phase 2 trial began with 8 weeks of establishing baseline levels, followed by 8 weeks of randomized, double-blinded treatment with either 150 mg QD elagolix or placebo, then 16 weeks of open-label extension, concluding with an 8-week follow-up. At the end of the 8 week treatment period, there was a significant improvement in the experimental group, with 60.3% reporting “much improved” or “very much improved” pain compared with 30.2% of those in the placebo group. Elagolix mitigated several dysmenorrhea symptoms by increasing the length of menstrual cycles, reducing the amount of bleeding on heavy flow days, and decreasing the number of breakthrough bleeding events. The authors acknowledged limitations such as the relatively short amount of time spent in the double-blinded portion and looked forward to long-term studies.⁸⁶

One of the more common first-line therapies for endometriosis has been subcutaneous depot medroxyprogesterone acetate (DMPA-SC), which is a high-dose progestin-only contraceptive. The resultant hypoestrogenic state of DMPA-SC often comes with several side effects, including decreased BMD. Given that elagolix also lowers estrogen levels, although, in dose-dependent increments, investigators sought to compare these two drugs based on their respective effects on BMD. Participants were followed for 24 weeks after being randomized to three double-blinded groups; 150 mg QD elagolix, 75 mg BID elagolix, and DMPA-SC, with 104mg/0.65mL subcutaneous injections at weeks 1 and 12. They were then studied for an additional 24 weeks once the respective treatments had been discontinued. The BMD of the spine and femur were measured with dual-energy x-ray absorptiometry (DXA), with all three groups demonstrating minimal losses of BMD. It was also determined that the effects on endometriosis symptoms were comparable, leaving desired fertility status to be the more notable consideration in the course of treatment since DMPA-SC additionally acts as a contraceptive.⁸⁷

Conclusion

Endometriosis is a common cause of chronic pelvic pain in women primarily of reproductive age and affects up to 10% of women of child bearing age. It is difficult to diagnose and treat and has a significant effect on the physical and psychological well-being of women who suffer from this disorder and has a grave impact on their quality of life. It has a hefty price tag and averages a cost of approximately 15,000 per patient annually. Risk factors include shorter cycles, heavy flow, early menarch, nulliparity, and other factors that increase the number and frequency of menstrual cycles, which is the scientific basis to the hormonal treatment of endometriosis.

Endometriosis often presents with dysmenorrhea, chronic pelvic pain, dyspareunia, infertility or pelvic masses. A definite diagnosis can only be achieved by direct surgical visualization of lesions. A presumptive diagnosis can be obtained through a combination of history, physical exam, and imaging. TVUS and MRI are equally predictive in making the diagnosis. The pathogenesis is unknown; the most accepted theory is that of reverse menstruation into the abdominal cavity, but transportation of endometrial cells via the venous or lymphatic system, cellular metaplasia, and stem cell differentiation have also been suggested. The development of endometrial lesions will, regardless, require implantation, immune evasion, and angiogenesis.

Traditional treatment includes medical and surgical management. Surgery is usually reserved for patients presenting with an emergent condition, such as torsion of an ovary. It is also offered to patients who failed medical management. Numerous studies found surgery to be effective in pain alleviation and improved fertility; however, it also carries bigger risks.

Medical treatment traditionally focuses on the suppression of ovulation, leading to atrophy of the endometrial lesions in the absence of supportive hormonal signals. This can be achieved with progestin and combination progestin-estrogen drugs, GnRH agonists, aromatase inhibitors, androgenic medication, and GnRH antagonists.

Elagolix (Orlissa) is a GnRH antagonist, suppressing the entire hormonal axis and thus reduces the production of progesterone and estrogen. It has been shown to be effective in pain alleviation and increased fertility. Elagolix was found to be relatively safe and well-tolerated and was shown to effectively reduce pelvis pain in endometriosis. Clinical studies showed 46.4%–75.8% (dose-dependent) improvement in dysmenorrhea and 42.4%–72.4% improvement and about 50% improvement in non-menstrual pelvic pain. Long term (12 months) follow-ups showed similar results for dysmenorrhea and improved even further (up to 67.2%) for non-menstrual pelvic pain. It was also shown to decrease missed work days and estimated to save $1500–$3300 a month per patient (on 150mg daily versus 200mg twice daily, respectively).

An important side effect is a reduction of mineral density and risk of osteopenia and osteoporosis as a result of hypoestrogenism; unlike GnRH agonists, elagolix does not shut down the axis completely, and a remaining basal level of estrogen is likely to retain its protective function.

Altogether, these results are encouraging and provide good evidence to support the use of Elagolix for treatment of pain secondary to endometriosis, both dysmenorrhea, and non-menstrual pain. It is well tolerated and has a good safety profile. Longer-term follow up will be required to describe the efficacy and safety of long term, chronic use.

References

Papers of particular interest, published recently have been highlighted as:

• Of Importance: 36, 64, 81

36. A review of endometriosis, pathogenesis, diagnosis and available treatment options.

64. A systematic review and meta-analysis of the efficacy and safety of laparoscopy for the treatment of endometriosis finding moderate quality evidence to support the improvement of fertility in endometriosis follow laparoscopy and only low quality evidence to support laparoscopy for pain alleviation.

81. Phase II study of Elagolix in endometriosis providing evidence to safety and efficacy of its use.

• Of Major Importance: 67, 83

67. A systematic review and meta-analysis of NSAID use in women with endometriosis finding now high quality evidence to support the use of NSAID in endometriosis and no preference to any specific NSAID over another.

83. Results of two extension studies for long-term (12 months) efficacy of elagolix in endometriosis providing evidence of continued efficacy of elagolix with varying degrees of success between 50% and 75% for dysmenorrhea and non-menstrual pelvic pain.