Digital Features for this Adis Drug Evaluation can be found at https://doi.org/10.6084/m9.figshare.25301113

FormalPara Relugolix/estradiol/norethisterone acetate: clinical considerations in endometriosis-associated pain

Combination of a GnRH receptor antagonist (relugolix) plus add-back hormone replacement therapy in one pill

Significantly improves dysmenorrhoea and non-menstrual pelvic pain

Benefits are sustained over the longer term

Generally well tolerated, with minimal impact on bone loss

1 Introduction

Endometriosis is a chronic inflammatory condition characterized by lesions of endometrium-like tissue outside the uterus [1, 2]. It affects ≈ 10% of women of reproductive age and is associated with chronic pelvic pain, dysmenorrhoea, dyspareunia, dysuria and dyschezia [1, 2]. These symptoms can have a profoundly negative impact on patients’ health-related quality of life (HRQoL) and social well-being [2]. Although the underlying pathogenesis of endometriosis is unclear, it involves a complex combination of hormonal, genetic, environmental and immunological factors [1, 2]. As such, the management of endometriosis-associated pain is multifaceted and may involve surgery, medications and non-drug interventions [1].

Endometriosis is a highly estrogen-dependent disease [3]. The estrogen steroid hormone estradiol is required for the proliferation of endometriotic tissue and increases the associated pain and inflammation. Therefore, lowering levels of circulating estrogens is considered an effective medical approach in the treatment of endometriosis [3]. Gonadotropin-releasing hormone (GnRH) receptor agonists (e.g. leuprorelin) suppress estradiol and have been used successfully to treat endometriosis-associated pain, but their efficacy is delayed by an initial disease flare-up and their long-term use is limited due to hypoestrogenic-induced bone mineral density (BMD) loss and hot flushes [1, 4, 5]. GnRH receptor antagonists (e.g. elagolix and relugolix) are not associated with a flare-up effect [4, 5]. The hypoestrogenic effects associated with GnRH receptor agonist or antagonist monotherapy may be offset by the addition of a low-dose estrogen/progestin combination (add-back therapy) containing an optimal concentration of estradiol [4, 5].

An oral fixed-dose combination (FDC) of relugolix/estradiol/norethisterone (also known as norethindrone) acetate 40/1/0.5 mg [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved for use in women with endometriosis [6, 7]. The pharmacological properties of relugolix combination therapy have been reviewed in detail previously and are summarized in Table 1. This review focuses on the clinical use of relugolix combination therapy for the management of endometriosis-associated pain. Relugolix combination therapy is also approved for the management of symptomatic uterine fibroids [8]; however, discussion of this indication is beyond the scope of this article.

Table 1 Overview of key pharmacological properties of relugolix/estradiol/norethisterone acetate [6, 7]
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2 Therapeutic Efficacy of Relugolix/Estradiol/Norethisterone Acetate

2.1 SPIRIT Trials

The efficacy of relugolix combination therapy in premenopausal women with endometriosis-associated pain was assessed in two replicate, randomized, double-blind, placebo-controlled, multicentre, phase III trials conducted in Africa, Australasia, Europe, North America and South America (SPIRIT 1 and SPIRIT 2; Fig. 1) [9]. Data from the SPIRIT trials are supported by a phase II dose-ranging study [10] and its extension [11], which are not discussed further.

Fig. 1
figure 1

Trial design of replicate phase III SPIRIT 1 and 2 studies (efficacy results are reported in the animated figure available online) [9]. The objective of the delayed relugolix CT treatment arm was to assess safety outcomes. Pts in this group initially received relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT for 12 weeks. CT combination therapy with estradiol/norethisterone acetate 1/0.5 mg/day, NRS numerical rating scale, pts patients, REL relugolix, wks weeks

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The SPIRIT trials enrolled premenopausal women aged 18–50 years with endometriosis that was surgically or directly visualized with or without histological confirmation, or histological diagnosis alone, within the previous 10 years [9]. Patients with self-reported moderate, severe or very severe dysmenorrhoea during their most recent menses and moderate, severe or very severe non-menstrual pelvic pain during the previous month (assessed by the Endometriosis Associated Pain Severity score) could enter the ≈ 35-day single-blind placebo run-in period. To be eligible for subsequent randomization, patients had to have a dysmenorrhoea Numerical Rating Scale (NRS) score of ≥ 4.0 [scores range from 0 (no pain) to 10 (pain as bad as you can imagine)] for ≥ 2 days during the run-in period along with a mean non-menstrual pelvic pain NRS score of ≥ 2.5, or a mean non-menstrual pelvic pain NRS score of 1.25 with a score of ≥ 5.0 on ≥ 4 days. Exclusion criteria included a bone mineral density (BMD) Z score of < 2.0 at the lumbar spine, total hip or femoral neck and a history of chronic pelvic pain not caused by endometriosis. At baseline, the mean age of patients was 34 years and 91% of patients were white. The proportion of patients taking opioids for pain relief was 29% in SPIRIT 1 and 48% in SPIRIT 2 [9].

Eligible patients were randomized 1:1:1 to receive relugolix combination therapy, delayed relugolix combination therapy (relugolix 40 mg monotherapy for 12 weeks followed by relugolix combination therapy for 12 weeks) or placebo once daily for 24 weeks [9]. Randomization was stratified by geographical region (North America vs all other regions) and time since surgical endometriosis diagnosis (< 5 years vs ≥ 5 years). The co-primary endpoints were the proportion of responders based on the dysmenorrhoea NRS score, and the proportion of responders based on the non-menstrual pelvic pain NRS score, both at week 24. The co-primary and key secondary endpoints were compared between the relugolix combination therapy and placebo groups in the modified intention-to-treat population. The delayed relugolix combination therapy group was included to compare safety between relugolix combination therapy and relugolix monotherapy at week 12 [9].

Relugolix combination therapy significantly improved endometriosis-associated pain in premenopausal women [9]. In both trials, the proportion of patients achieving a dysmenorrhoea response and the proportion of patients achieving a non-menstrual pelvic pain response was significantly higher with relugolix combination therapy than with placebo (Table 2). Sensitivity analyses of the co-primary endpoints were consistent with those of the primary analysis. The benefits of treatment with relugolix combination therapy were seen as early as week 8 for dysmenorrhea and week 12 for non-menstrual pelvic pain. The response rates with delayed relugolix combination therapy were similar to each other in both trials (Table 2); the trials were not designed to compare delayed relugolix combination therapy with relugolix combination therapy in terms of efficacy [9].

Table 2 Efficacy of relugolix 40 mg coadministered with estradiol/norethisterone acetate 1/0.5 mg in premenopausal women with moderate to severe endometriosis-associated pain in phase III clinical trials
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Relugolix combination therapy was significantly more effective than placebo for all sequential key secondary endpoints in SPIRIT 1 and for six of seven key secondary endpoints in SPIRIT 2 (Table 2) [9]. Compared with placebo, relugolix combination therapy significantly reduced NRS scores for dysmenorrhea, non-menstrual pelvic pain, overall pelvic pain and dyspareunia. The effects of pain on normal daily functioning and activities and HRQoL [assessed by the Endometriosis Health Profile 30-item (EHP-30) questionnaire pain domain] also improved significantly with relugolix combination therapy compared with placebo. Relugolix combination therapy was associated with reduced opioid use (Table 2) [9].

The majority of patients who received relugolix combination therapy or delayed relugolix combination therapy reported no bleeding (i.e. no bleeding during a bleeding profile period) or infrequent bleeding (i.e. 1–2 bleeding/spotting episodes during a bleeding profile period), while the majority of patients who received placebo reported normal bleeding, irregular bleeding (i.e. 3–5 bleeding/spotting episodes and < 3 bleeding-free intervals of ≥ 14 days during a bleeding profile period) or infrequent bleeding [9]. Among patients who did not enter the long-term extension study (Sect. 2.2), menses returned after cessation of relugolix combination therapy or delayed relugolix combination therapy (except in patients with a known reason for non-recovery, such as pregnancy, medications or surgery). The median time of menses return was 31 days in both relugolix groups, with menses returning within 2 months in the majority of patients (91–94%) [9].

2.1.1 Pooled Analyses

In pooled analyses of SPIRIT 1 and 2, the treatment effect of relugolix combination therapy in the European [12] and the North American [13] subpopulations was consistent with that in the overall SPIRIT populations. In both subpopulations, relugolix combination therapy significantly reduced dysmenorrhoea and non-menstrual pelvic pain [12, 13].

According to pooled data from SPIRIT 1 and 2, relugolix combination therapy significantly reduced endometriosis-associated pain and improved daily functioning regardless of the time since surgical diagnosis of endometriosis (< 5 years or ≥ 5 years) [14]. In the subgroup of patients diagnosed within 5 years of screening (n = 579), relugolix combination therapy was also associated with a significant reduction in non-menstrual pelvic pain relative to placebo [14].

In another pooled analysis of SPIRIT 1 and 2, relugolix combination therapy improved HRQoL in patients with endometriosis-associated pain [15]. At week 24, relugolix combination therapy was associated with significant improvements from baseline in multiple HRQoL domains of the EHP-30, including emotional wellbeing, control and powerlessness, self-image and social support (all p < 0.0001 vs placebo) [15].

2.2 SPIRIT Extension Study

The benefits of relugolix combination therapy in premenopausal women with endometriosis-associated pain were sustained over the longer term [16]. Patients who completed the 24-week SPIRIT trials were eligible to enrol in an open-label long-term extension study during which they received relugolix combination therapy for 80 weeks (Fig. 1). A total of 802 patients were enrolled; of these, 681 and 501 patients completed 52 and 104 total weeks of treatment with relugolix combination therapy [16].

At week 52, the dysmenorrhoea response rate was 85% and the non-menstrual pelvic pain response rate was 74% [16]. Dysmenorrhoea and non-menstrual pelvic pain NRS scores decreased from baseline by 84% and 64% [16]. The median time to NRS score ≤ 1 for dysmenorrhoea was ≈ 8 weeks, with 95% of patients reporting minimal/no pain at week 52 [17]. The median time to NRS score ≤ 1 for non-menstrual pelvic pain was ≈ 32 weeks, with 60% of patients reporting minimal/no pain at week 52. The median time to becoming analgesic-free was ≈ 16 weeks [17]. Most patients were analgesic-free (65%) or opioid-free (86%) at week 52 [16]. The average number of bleeding days per cycle decreased from 5.8 at baseline to 1.4 at week 52, and most patients (80%) achieved amenorrhoea [18].

At week 104, the dysmenorrhoea response rate was 85% and the non-menstrual pelvic pain response rate was 76% [16]. NRS scores for dysmenorrhoea, non-menstrual pelvic pain, overall pelvic pain and dyspareunia decreased from baseline by 84%, 69%, 69% and 59%, respectively. Most patients were analgesic-free (75%) or opioid-free (91%) and continued to report minimal/no dysmenorrhoea (95%) and minimal/no non-menstrual pelvic pain (71%) [16]. The average number of bleeding days per cycle was 1.2 [19]. The EHP-30 pain domain score decreased from baseline by 72% [20], with 89% of patients classified as responders based on the reduction in EHP-30 pain domain score [16] (i.e. clinically meaningful improvement in daily functioning [20]). Long-term treatment with relugolix combination therapy was also associated with improvements in all HRQoL domains of the EHP-30 [20].

3 Tolerability of Relugolix/Estradiol/Norethisterone Acetate

Relugolix combination therapy was generally well tolerated in premenopausal women with endometriosis-associated pain [9, 16]. In the pooled SPIRIT 1 and 2 trials, the most common (incidence ≥ 3%) adverse reactions with relugolix combination therapy were headache (33% vs 26% with placebo), vasomotor symptoms (13 vs 7%), mood disorders (9 vs 7%), abnormal uterine bleeding (7 vs 5%), nausea (6 vs 4%), toothache (6 vs 2%), back pain (5 vs 3%), decreased sexual desire and arousal (4 vs 1%), arthralgia (4 vs 2%), fatigue (3 vs 2%) and dizziness (3 vs 1%) [6]. Less common adverse reactions with relugolix combination therapy included diarrhoea, peripheral oedema and vulvovaginal dryness. Serious adverse reactions occurred in 3% of relugolix combination therapy recipients and 2% of placebo recipients. Serious adverse reactions with relugolix included uterine haemorrhage, suicidal ideation, cholelithiasis and cholecystitis. Five percent of relugolix combination therapy recipients and 3% of placebo recipients discontinued treatment due to adverse reactions, most commonly mood-related disorders [6]. In the SPIRIT extension study, the most common adverse reactions were similar to those reported in the SPIRIT 1 and 2, and no new safety signals were identified [16].

3.1 Bone Mineral Density

In the pooled SPIRIT 1 and 2 trials, the addition of estradiol/norethisterone acetate mitigated relugolix-induced BMD loss [21]. The least squares mean (LSM) changes from baseline in lumbar spine BMD with relugolix combination therapy versus placebo were − 0.49% versus + 0.09% at week 12 and − 0.72% versus + 0.12% at week 24. Among patients who received 12 weeks of relugolix monotherapy (i.e. those in the delayed relugolix combination therapy group), the LSM change from baseline in lumbar spine BMD was − 1.76% at week 12, which stabilized after the transition to relugolix combination therapy (LSM change from baseline − 1.94% at week 24 [21]. There was minimal bone loss with relugolix combination therapy over the longer term [16]. In the SPIRIT extension, the LSM change in lumbar spine BMD from pivotal studies baseline was –0.69% at week 52 and − 0.45% at week 104 [16].

A separate prospective observational study enrolled 452 untreated women with moderate to severe pain associated with endometriosis who were age-matched to SPIRIT trial participants [6]. In this cohort, the mean change from baseline in lumbar spine BMD was +0.35% at month 6 and +0.53% at month 12. At 12 months, a decline in lumbar spine BMD of > 3% was seen in 19.7% of women in the SPIRIT extension study and 9.1% of those in the observational study. A decline of > 7% to ≤ 8% was seen in 0.9% of women in the SPIRIT extension study and 0.6% of those in the observational study [6].

The benefits and risks of relugolix combination therapy should be considered in patients with a history of low-trauma fracture or other risk factors for osteoporosis or bone loss, including the use of medications known to affect BMD [6, 7]. Assessment of BMD by dual-energy X-ray absorptiometry is recommended before and annually during treatment with relugolix combination therapy [6, 7]. Calcium and vitamin D supplements may be beneficial for patients with inadequate dietary intake [6].

4 Dosage and Administration of Relugolix/Estradiol/Norethisterone Acetate

Relugolix/estradiol/norethisterone acetate 40/1/0.5 mg is indicated for the management of moderate to severe pain associated with endometriosis in premenopausal women in the USA [6] and for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis in the EU [7]. The recommended dosage is one FDC tablet once daily at approximately the same time, with or without food [6, 7]. Relugolix/estradiol/norethisterone acetate should be started as early as possible, within 5 days (EU [7]) and no later than 7 days (USA [6]) after the onset of menses. In the USA, the recommended total duration of treatment is 24 months [6].

Contraindications to relugolix/estradiol/norethisterone acetate include: venous thromboembolic disorder (for which there is a boxed warning in the USA [6]); arterial thromboembolic disorder; pregnancy; osteoporosis; hormone-sensitive [6] or sex-steroid influenced [7] malignancies; severe liver disease or impairment; undiagnosed abnormal uterine [6] or genital [7] bleeding; and hypersensitivity to the drug components or any of the excipients [6, 7]. Additional contraindications in the EU include: thrombophilic disorders; headaches with focal neurological symptoms or migraine headaches with aura; presence or history of liver tumours; concomitant use of hormonal contraceptives; and breastfeeding [7].

In the USA, patients are advised to use effective non-hormonal contraception during treatment with relugolix/estradiol/norethisterone acetate and for ≥ 1 week following discontinuation [6]. In the EU, relugolix/estradiol/norethisterone acetate is considered to provide adequate contraception; a non-hormonal contraceptive method is recommended for use for ≥ 1 month after initiation of treatment and for 7 days following two or more missed consecutive doses [7]. In the USA, patients are advised not to breastfeed while taking relugolix/estradiol/norethisterone acetate [6]. Consult local prescribing information for further details regarding contraindications, warnings and precautions, drug interactions and use in special patient populations.

5 Place of Relugolix/Estradiol/Norethisterone Acetate in the Management of Endometriosis-Associated Pain

The European Society of Human Reproduction and Embryology guidelines for the management of endometriosis recommend different options for the treatment of endometriosis-associated pain, including non-steroidal anti-inflammatory drugs or other analgesics, hormone therapies and surgery [22]. The guidelines recommend that the choice of hormone therapy should consider efficacy, tolerability, cost, availability and patient preference. Hormone therapy options include combined hormonal contraceptives (oral, vaginal ring or transdermal) and progestins (progesterone-only pill, levonorgestrel-releasing intrauterine system or etonogestrel-releasing subdermal implant), with GnRH receptor agonists and GnRH receptor antagonists recommended as second-line treatment [22].

The recent development of oral GnRH receptor antagonists (elagolix, relugolix) expanded the choice of hormone therapies available for endometriosis pain relief [5]. In the USA, elagolix is approved for the management of moderate to severe pain associated with endometriosis, either as a once-daily low dose or a twice-daily high dose [23]. However, due to hypoestrogenic-induced BMD loss and vasomotor symptoms, the maximum duration of treatment is 6 months for the high dose and 24 months for the low dose [9]. Likewise, relugolix monotherapy was found to reduce pelvic pain in women with endometriosis [11], but is also unsuitable for long-term use [4, 9], with treatment limited to 24 months in the USA (Sect. 4). There is a need for safe and effective treatments that can be used long term for chronic endometriosis-associated pain [4]. The availability of such treatments may also reduce the need for repeated surgical intervention, which carries a risk of complications and can have a negative effect on the ovarian reserve [24]. Relugolix/estradiol/norethisterone acetate is a once-daily FDC designed to achieve efficacy and minimize BMD loss and vasomotor symptoms [4].

In the pivotal SPIRIT trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women (Sect. 2.1). Of note, dysmenorrhoea response rates were higher than non-menstrual pelvic pain response rates (Table 2), which may be due to the mechanism of action of relugolix [9]. Relugolix decreases serum levels of estradiol and progesterone (Table 1), which drive the menstrual cycle. The causes of non-menstrual pelvic pain are not fully known but are likely to involve chronic inflammation, scar tissue (fibrosis, adhesions) and central sensitization, which may be less responsive to estradiol suppression [9]. Relugolix combination therapy was also associated with reductions in overall pelvic pain and dyspareunia, reduced analgesic and opioid use (Sect. 2.1), and improved HRQoL (Sect. 2.1.1).

Relugolix combination therapy was generally well tolerated in the SPIRIT trials, with the most common adverse reactions being headache, vasomotor symptoms and mood disorders (Sect. 3). Importantly, the addition of estradiol/norethisterone acetate mitigated relugolix-induced BMD loss. BMD loss was greater and hot flushes were more common in the delayed relugolix combination therapy group than in the relugolix combination therapy group, suggesting that the dose of estradiol in relugolix combination therapy is sufficient to maintain a therapeutically effective estradiol range [9].

The SPIRIT trials had several limitations [9, 25]. Many of the screened patients did not meet the required threshold for pelvic pain, most study participants were white, and subgroup analyses did not differentiate between deep (ovarian) and superficial (peritoneal) endometriosis. Both trials utilized a placebo comparator instead of an active comparator, preventing a direct comparison with surgery, hormone therapies or other cornerstones of treatment [9, 25]. However, use of an active control would have been difficult given that the agent would need to be approved in all participating countries and some potential comparators are only approved for short-term use [9]. Additional studies that directly (i.e. randomized controlled trials) or indirectly (i.e. systematic reviews and meta-analyses) compare relugolix combination therapy with other medical treatments for endometriosis would be beneficial. Pharmacoeconomic data on the cost effectiveness of relugolix combination therapy relative to other treatments would also be of interest.

Although the SPIRIT trials had a short treatment duration (6 months), the benefits of relugolix combination therapy were sustained over the longer term in an 80-week extension study (Sect. 2.2). There were no new safety signals observed with long-term treatment (Sect. 3) and BMD loss at week 52 was minimal (< 1%) (Sect. 3.1). Therefore, long-term (up to 24 months) use of relugolix combination therapy appears to be feasible [25]. A single-arm, open-label, phase IIIb study is currently underway to assess changes in BMD during continuous treatment with relugolix combination therapy for up to 4 years with 1 year of post-treatment follow-up in ≈ 1000 premenopausal women with either moderate to severe pain associated with endometriosis or heavy menstrual bleeding associated with uterine fibroids [26]. Results are awaited with interest.

In conclusion, relugolix/estradiol/norethisterone acetate is effective and generally well tolerated in premenopausal women with endometriosis, including over the longer term (up to 24 months). With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain.

Data Selection Relugolix/Estradiol/Norethisterone Acetate: 68 records identified

Duplicates removed

3

Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial)

12

Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials)

24

Cited efficacy/tolerability articles

15

Cited articles not efficacy/tolerability

14

Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were Myfembree, Ryeqo, relugolix combination, estradiol/norethisterone acetate/relugolix, estradiol/norethindrone acetate/relugolix, endometriosis. Records were limited to those in English language. Searches last updated 12 February 2024