An evaluation of relugolix/estradiol/norethindrone acetate for the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.

Uterine fibroids (AKA leiomyoma) is considered a substantial challenge to treat with an immense economic burden estimated to be in billions of dollars [ 50 ]. Clinically, hormonal treatments have been extensively explored for fibroid associated symptoms mainly HMB and also potential to shrink the tumor. Nevertheless, their efficacy is inadequate with a side effect profile that prohibit long-term use. Meanwhile, surgery has been traditionally the standard treatment for UFs and considered as the one solution that fits all sizes. Yet, young women who haven’t started their families wouldn’t prefer those options either complete removal of uterus “hysterectomy” or removal of tumor only “myomectomy” with negative impact on myometrium. Selective progesterone-receptor modulator (SPRM) ulipristal acetate was approved to treat UFs in some countries in cyclic fashion. Though, recently concerns of sporadic liver injury cases resulted in temporary suspension followed by precaution measures by the European medicines agency (EMA), where its use is limited only in premenopausal women with UFs who are not candidate for surgical procedures or ineffective [ 51 ]. Injectable GnRH agonists such as leuprolide acetate showed efficacy in reducing UF associated bleeding but resultant hypoestrogenic status restrict their long-term utility [ 2 ]. Lately, GnRH antagonists raised as a newer type of GnRH analogue and have been widely studied with advantages over agonists in being easily administrated as oral capsules, have rapid effect since they don’t trigger initial receptor activation, and can be used for longer duration in combination with ABT to decrease side effects associated with low levels of estrogen and to prevent any endometrial changes. Elagolix, has been in the lead of such category and showed efficacy in reducing HMB in women with UFs. In May 2020, FDA approved ORIAHNN™ as the first oral medication for the management of HMB related to UFs in premenopausal women as One capsule (elagolix 300 mg, E2 1 mg, NETA 0.5 mg) in the morning and one capsule (elagolix 300 mg) in the evening for up to 24 months [ 5 ]. Since elagolix involves twice-daily administration due its short half-life, relugolix posed an added advantage over elagolix in being dosed once daily with less serum estrogen level alteration over the day. Moreover, recent LIBERTY trials have shown efficacy in reducing UF-associated HMB and pain with tolerated side effect profile when combined with hormonal ABT. FDA has granted approval to Myfembree® (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) as the first once-daily pill that can reduce HMB associated with UFs in premenopausal women with a treatment duration of up to 24 months [ 5 , 19 ]. Notably, relugolix showed efficacy to alleviate endometriosis associated pain in women in a concentration–response fashion and was generally well tolerated with efficacy and safety comparable to those of leuprolide acetate with faster action. In addition, relugolix has been approved as androgen deprivation therapy for prostate cancer in males [ 52 , 53 ] Linzagolix (OBE2109), third oral GnRH antagonist is currently in advanced stage of clinical trials as treatment for HMB associated with UFs as well as pain associated with endometriosis, with encouraging findings [ 54 , 55 ] Although both uterine tissue and tumor will be unlikely to shrink due to the included ABT, with consequence of less alleviation of bulk symptoms, ABT is indispensable to avoid several side effects of using GnRH antagonist alone. Moreover, improved symptoms while treatment will probably resume shortly following relugolix treatment termination. relugolix may shape up as an attractive non-surgical alternative for patients who suffer from fibroids. As these trials show a safe and effective option to reduce HMB and pain, the treatment may be ideal for premenopausal patients who do not want to pursue surgery. Considering that similar BMD measures between the placebo and relugolix combination therapy groups, it may be considered for longer treatment duration beyond the two years limit. These effective oral GnRH antagonists can also be utilized as secondary prevention therapy to prevent tumor regrowth post myomectomy surgeries. However, more studies are need to compare clinical outcomes (i.e., decreased risk of fibroid recurrence, symptom recurrence, and need for reintervention) in patients with symptomatic UFs who are treated with relugolix combination therapy following surgery such as robotic, laparoscopic, or open abdominal myomectomy versus the standard of care treatment following myomectomy alone. Such studies might provide valuable insights into whether relugolix combination therapy is helpful in the postoperative management of women with symptomatic UFs. Interestingly, there are few randomized, double-blind, placebo-controlled studies on utilizing traditional Chinese medicine (TCM) for menopausal syndrome management [ 56 - 58 ]. Such compounds might offer added benefits in alleviating vasomotor symptoms in Women with UFs on oral GnRH antagonists. Yet, studies are needed to explore such prospect similar to studies showed that TCM improved perimenopausal symptoms induced by surgery, chemoradiotherapy, or endocrine treatment for breast cancer [ 59 ] Continuing research is needed for building enough awareness regarding potential benefits of using non-hormonal therapies. Remarkably, natural compounds are thrilling options to be considered for UFs management [ 60 , 61 ].

Traditionally, there has not been much progress in UFs treatment options, probably due to the fact they are benign with morbidity rather than mortality. invasive elimination of the fibroid with or without the uterus was the mainstay option. However, currently they are frequent therapeutic options are accessible starting from entirely non-invasive pharmacological treatments to minimally invasive procedures such as myomectomies and ending up with hysterectomy [ 2 ]. Historically, there was no universal consensus on a pharmacological drug as long-term treatment of UFs. Studies investigated various potential molecules that interrupt signaling pathways contributing to UF pathogenesis, with subsequent tumor shrinkage and symptoms relief [ 7 ]. Since UF growth relies on ovarian hormones so many hormonal treatment have been commonly explored for the managment of UF related symptoms. Novel nonpeptide orally active gonadotropin releasing hormone (GnRH)-receptor antagonists including elagolix, relugolix and linzagolix are currently the most explored anti-UF hormonal therapy on daily use [ 8 ]. Elagolix has been explored in several phase 2 and 3 trials for its efficacy in controlling bleeding in premenopausal women with UFs [ 9 , 10 ] [ 11 ] [ 12 ] besides increasing number of articles discussing the beneficial role of elagolix in UF bleeding and increasing afflicted women quality of life are being published in literature [ 13 - 16 ] [ 5 , 17 ]. Interestingly, recent study showed that even in 45% of patients, who were considered non responders in the pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2), have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria [ 18 ]. Therefore, elagolix was granted US Food and Drug Administration (FDA) approval in 2020 by the for the treatment UF related bleeding as two doses per day regimen in combination with Addback therapy (ABT) of estradiol /norethindrone acetate (E2/NETA) to overcome side effects resulting from low estrogen levels, importantly decreased bone mineral density (BMD), for maximum 2 years utility [ 5 ]. Notably, relugolix, in combination with same ABT, gained FDA approval in 2021 as the first drug administered once-daily for managing UFs related heavy menstrual bleeding (HMB) in premenopausal women, for up to years treatment length [ 5 , 19 ]. Yet, symptoms are expected to relapse following drug withdrawal. This drug evaluation emphasizes findings from prior and continuing clinical trials of relugolix for the management of HMB connected to UF in premenopausal women.

Relugolix (TAK-385) has molecular formula of C 29 H 27 F 2 N 7 O 5 S and molecular weight of 623.63 g/mol [ 20 ]. It was developed by Takeda pharmaceutical in 2011 for cure of hormonal dependent tumors like prostate cancer. [International Union of Pure and Applied Chemistry (IUPAC) name 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4 tetrahydro-thieno [2,3-d] pyrimidin-6-yl] phenyl}-3-methoxyurea] [ 21 ]. Chemical structure in the drug summary box below. Estradiol (E2) is an estrogenic steroid with molecular formula of C 18 H 24 O 2 and molecular weight of 272.3 g/mol, E2 is added to pass up the pseudo-menopause status and avoid postmenopausal osteoporosis and BMD loss. Norethindrone acetate (NETA) is a synthetic second-generation progestin with molecular formula of C 18 H 24 O 2 and molecular weight of 272.3 g/mol. NETA is added as contraceptive and to inhibit any endometrial hyperplasia due to unopposed estrogen. Relugolix is an orally active, highly selective, non-peptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors and prevent binding f endogenous GnRH [ 22 ], and consequently reduces the luteinizing hormone (LH) and follicle- stimulating hormone (FSH) production, which in turn decreases serum concentrations of the ovarian steroidal hormones estradiol (E 2 ) and progesterone (P4) and thus limits UFs induced HMB [ 8 , 23 , 24 ]. Studies of relugolix started with its ability to inhibit binding of GnRH agonist leuprorelin acetate (LA) to the human GnRH receptor in vitro. In addition, relugolix showed a dose dependent repression of the of GnRH-induced arachidonic acid secretion in Chinese hamster ovary cells that expressed monkey or human GnRH receptor [ 25 ]. Relugolix mode of action was confirmed in a pharmacokinetics and pharmacodynamics phase I trial conducted in 120 healthy adult premenopausal women utilizing single and multiple dosing. For single dosing, average E 2 levels following the 40- and 80 mg relugolix were comparable (30.2 pg/mL and 30.3 pg/mL, respectively) at 24 hours, indicating that maximal reductions in E 2 concentrations is 40 mg doses of relugolix. In the multiple dose part (10, 20, and 40 mg), mean LH, FSH, E 2 , and P4 concentrations were decreased as the dose increases. Regarding the group received 40 mg, absolute average E 2 pre-dose serum levels on days 4, 6, 8, 10, 12, and 14 were constantly low, with range 4.7-6.7 pg/mL compared to 59.5-109.1 pg/mL in placebo group [ 26 ]. As previously mentioned, relugolix monotherapy can result in hypoestrogenism and BMD loss. Therefore, utility of relugolix in combination with additional E 2 is recommended [ 27 ]. Notably, choice of E2 dosage is critical to mitigate other collateral problems. For example, E2 at high concentrations can induce epiphysial closure by directly acting on the growing chondrocytes, thus halt any additional expansion [ 28 ]. Therefore, it is necessary to use low-dose E2 to induce bone synthesis. Also, NETA is an oral progestin that protects the uterus from possible harmful endometrial effects of unopposed E2, and used to treat menopause and endometriosis [ 29 ], and is recommended as ABT to be supplemented with relugolix treatment After a single oral dose of relugolix (40 mg) treatment in premenopausal women (n=12), the AUC 0–∞ was 139.1 ng.h/mL and the C max was 29ng/mL after 90 min (t max 1.5 hr.). Relugolix’s half-life (t½) was 36-65 h approximately [ 23 ]. Interestingly in vitro study using radiolabeled relugolix showed that relugolix is 68-71% protein-bound in the plasma. After the administration of 80 mg relugolix, [ 14 C] relugolix was excreted in urine 4.4% and faces 82.7% [ 8 ]. More than 95-98% of E2 tent to bind tightly to the sex hormone binding globulin (SHBG). With oral tablet, the first digestion in gastrointestinal tract could rapidly break down the E2 pre-systematically and absorbed as E2, E1 and E1-sulphate to the systemic circulation [ 30 ] [ 31 ]. The metabolism started at liver and intestine [ 32 ]. Estradiol could be metabolized to estrone and estriol to be excreted in urine. The conjugation of E2 could activate biliary secretion and released back into intestine, which in turn induce it hydrolysis in gut and reabsorption [ 33 ]. The initial step of NETA metabolism is hepatic removal of acetate group along with transformation into 5α-reduced metabolites by hydroxysteroid dehydrogenase (HSD) enzymes within 34.8 hours [ 34 ]. Following oral administration of single dose, oral bioavailability was found to be 64 %, C max was ranged from 5.3 – 7.3 ng/ml after 60-120 minutes (T max ) and AUC 0-24 from 30-37 ng.hr. /ml. Finally,clearance of NETA in plasma was 0.4 L/hr./kg and in intrinsic was 73-81 L/hr. [ 35 ]. Phase I trial ( NCT04978688 ) aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics following multiple 40-mg dosing of relugolix either alone or in combination with 1 mg of E2 and 0.5 mg of NETA in healthy adult premenopausal women. The study is completed [ 36 ]. An open-label randomized study of 48 healthy adult premenopausal women in the US (MVT-601-1001) was conducted, the results showed that administration of a once daily relugolix 40 mg combined with E 2 /NETA (1 mg/0.5 mg) for 6 weeks induced suppression of the hypothalamic–pituitary–gonadal axis comparable to that following relugolix alone. Except for E2 where its level was 3.3-fold higher in the combination therapy compared to relugolix alone. which results inless frequency and severity of vasomotor symptoms and hot flashes reported by subjects due to the exogenous E2. In addition, relugolix treatment resulted in increased serum levels of N-telopeptide (NTx) and C-telopeptide (CTx), but no significant changes were observed with the co-administration of E2/NETA compared to baseline [ 37 ]. Table (1) Another five-period open-label, single-arm study was conducted on healthy menstruating women in Germany (MVT-601-046), the results showed that following intake of relugolix 40 mg combined with E 2 /NETA (1 mg/0.5 mg) once daily, ovarian inhibiting activity was markedly suppressed during the 84-day (3 x 28-day) treatment period. The average dominant follicle size (diameter), E2 and progesterone production, FSH and LH secretion were all significantly suppressed after relugolix combination therapy. The majority of people who do not bleed during menstruation may also be attributed to the decrease in the thickness of the endometrium after relugolix combination therapy. In addition, 66 out of 67 study participants resumed ovulation when treatment was discontinued [ 26 ]. Overall, concomitant administration of relugolix 40 mg and E2/NETA (1 mg/ 0.5 mg) once daily was generally safe and well tolerated in healthy premenopausal women. A randomized double-blinded phase II study was performed to evaluate once daily orally administrated relugolix alone, at doses 10, 20, and 40 mg, for 3 months in 216 Japanese women with UF and HMB (defined as a minimum score 120 of pictorial blood loss assessment chart (PBAC)). Results showed that from Week 6 to 12, the percentage of patients with PBAC score of less than 10 was 83.6% in relugolix 40 mg groups compared to 0% in placebo group. In addition, 74% of relugolix 40 mg group patients reached amenorrhea as well as reduction in both myoma and uterine volumes [ 38 ]. Phase III trials started first by investigating the noninferiority of relugolix (40 mg, oral, once daily) compared with LA (1.8 mg or 3.7 mg, monthly injection) for 6 months.in reducing HMB associated with UFs in Japanese women [ 39 ]. Results showed that not only relugolix was noninferior but also induced a faster effect on HMB cessation, besides being generally well tolerated. Same group investigated relugolix effect (40 mg) for 12 weeks in reducing pain associated with UF using Numerical Rating Scale in a multicenter phase 3 trial [ 40 ]. Results highlighted that relugolix improved UFs-associated pain and was well tolerated. Later in US, series of well-designed LIBERTY phase 3 trials assessed both efficacy and safety of relugolix combination therapy (40 mg of relugolix, 1 mg of E 2 , and 0.5 mg of NETA) in women with HMB associated with UFs as shown in Table (1) . In all of these studies, the primary endpoint is the percentage of women who reached a menstrual blood loss (MBL) volume of less than 80 mL and a ≥ 50% decrease from MBL volume baseline around the last 35 days of therapy. Secondary endpoints involved tumor and uterine sizes as well as hemoglobin levels. Recently results were published from two replicate double-blinded phase III trials in patients with UFs (MVT-601-3001, MVT-601-3002) [ 41 ], once-daily relugolix combination therapy resulted in 73% of the participants in LIBERTY 1 (L1) trial and 71% of those in LIBERTY 2 (L2) trial responded to the treatment as compared with 19% and 15% of women in the placebo groups after 24 weeks, respectively concluding that relugolix combination therapy was superior to placebo. The evidence included significant reduction in HMB (84.3% in both trial L1 and trial L2 vs. 23.2% in L1 trial and 15.1% in L2 trial) in women with UFs, resolution of anemia (more than 50%), a reduction in pain associated with uterine fibroids (43% in L1 trial and 47% in L2 trial vs. 10% in L1 trial and 17% in L2 trial), and reduced suffering from HMB and pelvic pain, while the overall uterine size was decreased significantly to a greater extent with relugolix combination therapy than with placebo [ 41 ]. In the two LIBERTY studies, relugolix combination therapy was able to reduce UF-associated pain as well [ 42 ]. In an open-label extension study, single-arm phase III trial of women with UFs, patients who have finished a 24-week treatment period in one of the original studies (MVT-601-3001, MVT-601-3002) were recruited. All participants will receive relugolix 40 mg orally once daily combined with E2 (1.0 mg) and NETA (0.5 mg) for an additional 28 weeks (MVT-601-3003). The once-daily oral relugolix combination therapy resulted in faster decline of HMB, and fibroid and uterine size, while improved hemoglobin levels and QOL. Specifically, the open-label extension study revealed that treatment with the combination therapy resulted in 87.7% response rate at 52 weeks, as well as an average reduction in menstrual blood loss of 89.9% from baseline [ 43 ]. However, symptoms would return after treatment cessation. Relugolix combination therapy has been evaluated in over 1,300 subjects in Phase III clinical trials to date, some of which are ongoing ( Table 1 ) [ 44 , 45 ]. In a double-blind, randomized withdrawal study (MVT-601-035) aim to assess the long-term efficacy and safety of the relugolix combination therapy (40 mg of relugolix, 1 mg of E 2 , and 0.5 mg of NETA) or placebo. Study was extended on patients who completed 52 weeks of treatment with more 52 weeks. Patients will need to submit their feminine products for alkaline hematin analysis at every visit till the return of HMB as confirmed by the test. Recently, LIBERTY withdrawal study preliminary data showed that after 2 years of treatment. relugolix combination efficacy and safety were durable. Also, HMB returned in most women after treatment cessation [ 46 ]. In a phase III, single-arm, open-label trials aim to assess the safety and contraceptive efficacy of relugolix combination therapy (40 mg of relugolix, 1 mg of E 2 , and 0.5 mg of NETA) in women with UFs or endometriosis. This study will enroll eligible patients with UFs or endometriosis diagnosis and receive only relugolix combination therapy as the sole contraceptive method for 13 consecutive 28-day treatment cycles. At present, the US FDA has approved Myfembree® (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) as the first once-daily pill that can reduce the HMB associated with UFs in premenopausal women [ 47 ]. There are still points that need attention. So far, serious AEs of Myfembree® included UFs discharge and menorrhagia in 1 woman; uterine fibroids prolapse [ 48 ], cholecystitis, and pelvic pain were reported in 1 woman each. Figure (1) summarizes the effect of relugolix/E2/NETA on decreasing uterine fibroid associated bleeding and shrinking tumor through blocking gonadotropin releasing hormone (GnRH) receptor. The adverse events caused by relugolix, in addition to hot flashes and headaches, according to the mode of action and animal experiments findings, relugolix may cause fetal harm and miscarriage to pregnant women [ 47 ]. It is recommended that barrier contraception methods should be used during the treatment period and within two weeks from the last dose of relugolix. But the adverse events may be improved by the relugolix combination therapy with E 2 and NETA. For example, in MVT-601-3001 and MVT-601-3002 study [ 41 ], the overall frequency of adverse events in the delayed relugolix combination treatment group was higher than that in the relugolix combination therapy group and the placebo group. The most frequent adverse event is hot flashes with similar results. It is worth mentioning that, in the delayed relugolix combination treatment group, at week 12 of receiving relugolix monotherapy, the BMD of the lumbar spine and total hip decreased from baseline, followed by a plateau after the start of the relugolix combination treatment. However, no difference between the relugolix combination treatment group and the placebo group as observed. No deaths and no cases of endometrial hyperplasia or endometrial cancer had occurred in both relugolix groups during the study. Recent published data from LIBERTY and SPIRIT trials assessed most frequent adverse events of relugolix combination therapy in premenopausal women treated for symptomatic estrogen caused condition and showed that relugolix combination was well tolerated with a common adverse event profile typical of UF and endometriosis patients [ 49 ]. Common side effects of relugolix are shown in table (2)

New GnRH antagonists are oral, non-peptide GnRH receptor antagonist such elagolix and relugolix are approved for the treatment of HMB associated with UFs. Use of low-dose hormonal ABT has shown efficacy in reducing hypoestrogenic side effects. Relugolix has added an advantage over elagolix of being administrated once daily. Drug characteristics are summarized in a drug summary box .

Uterine fibroids (UFs) are the highly frequent non-malignant tumors happening in women of reproductive age. The incidence of UFs is estimated to be about 25-70% pending various risk factors such as ethnicity, age, and vitamin D deficiency as the main contributing reasons [ 1 ]. Aberrant uterine bleeding, pelvic discomfort, and reproductive challenges are among the main common symptoms due to UF [ 2 ]. UFs comprise of smooth muscle cells positioned in a substantial quantity of incoherent extracellular matrix, moreover several signaling pathways were shown to be involved in UF pathogenesis. Genetics studies showed that these tumors are of monoclonal origin following normal myometrial stem cells transformation [ 3 ]. Uterine fibroid development is basically reliant on steroid sex hormones, considering that fibroid lesion doesn’t appear until reaching puberty. The transformation of normal myometrial stem cell into a tumor-initiating stem cell is the initial step in the complicated tumor development [ 4 ]. Sex hormones stimulate major paradigm in levels of genes, growth factors, and cytokines that in turn induce aberrant UF cell proliferation and fibers accumulation [ 5 ]. Among studied pathways involved in UFs pathogenesis, are wingless type/β-catenin, transforming growth factor beta (TGF-β), AKT, and inflammation [ 6 ]. Moreover, exposure at early stages to xenoestrogen was linked to higher chances of fibroid development later in life using in vivo models through increased DNA damage and chronic inflammatory response [ 4 ].