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Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

Overview of elagolix for the treatment ofendometriosis

Gian Benedetto Melis, Manuela Neri, Valentina Corda, Maria Elena Malune,Bruno Piras, Silvia Pirarba, Stefano Guerriero, Marisa Orrù, Maurizio NicolaD’Alterio, Stefano Angioni & Anna Maria Paoletti

To cite this article: Gian Benedetto Melis, Manuela Neri, Valentina Corda, Maria Elena Malune,Bruno Piras, Silvia Pirarba, Stefano Guerriero, Marisa Orrù, Maurizio Nicola D’Alterio, StefanoAngioni & Anna Maria Paoletti (2016): Overview of elagolix for the treatment of endometriosis,Expert Opinion on Drug Metabolism & Toxicology, DOI: 10.1517/17425255.2016.1171316

To link to this article: http://dx.doi.org/10.1517/17425255.2016.1171316

Accepted author version posted online: 29Mar 2016.

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Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Metabolism & Toxicology

DOI: 10.1517/17425255.2016.1171316

DRUG EVALUATION

Overview of elagolix for the treatment of endometriosis

Gian Benedetto Melis*, Manuela Neri, Valentina Corda, Maria Elena Malune, Bruno Piras, Silvia

Pirarba, Stefano Guerriero, Marisa Orrù, Maurizio Nicola D’Alterio, Stefano Angioni, Anna Maria

Paoletti

Clinica Ostetrica e Ginecologica, Dipartimento di Scienze Chirurgiche, Università di Cagliari, Italy

Azienda Ospedaliero Universitaria di Cagliari, Policlinico Duilio Casula, Cagliari, Italy

* Corresponding Author: Prof Gian Benedetto Melis, Clinica Ostetrica e Ginecologica, Dipartimento di

Scienze Chirurgiche, Università di Cagliari, Azienda Ospedaliero Universitaria di Cagliari, Policlinico

Duilio Casula, Blocco Q, Strada Statale 554, bivio Sestu, 09042 Monserrato (CA), Italy

Email: gineca.gbmelis@tiscali.it; gineca.annapaoletti@tiscali.it

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Abstract

Introduction: Suppression of sex-steroid secretion is required in a variety of gynecological conditions.

This can be achieved using gonadotropin releasing hormone (GnRH) agonists that bind pituitary

gonadotropin receptors and antagonize the link-receptor of endogenous GnRH, inhibiting the

mechanism of GnRH pulsatility. On the other hand, GnRH antagonists immediately reduce gonadal

steroid levels, avoiding the initial stimulatory phase of the agonists. Potential benefits of GnRH

antagonists over GnRH agonists include a rapid onset and reversibility of action. Older GnRH

antagonists are synthetic peptides, obtained by modifications of certain amino acids in the native

GnRH sequence. They require subcutaneous injections, implantation of long-acting depots. The peptide

structure is responsible for histamine-related adverse events and the tendency to elicit hypersensitivity

reactions.

Areas Covered: Research has worked towards the development of non-peptidic molecules exerting

antagonist action on GnRH. They are available for oral administration and may have a more beneficial

safety profile in comparison with peptide GnRH antagonists. This article focuses on the data of the

literature about elagolix, a novel non-peptidic GnRHantagonist, in the treatment of endometriosis.

Expert Opinion: Elagolix demonstrated efficacy in the management of endometriosis-associated pain

and had an acceptable safety and tolerability profile. However, further studies are necessary to evaluate

its non-inferiority in comparison with other endometriosis’s treatments.

Keywords: Elagolix, endometriosis, GnRH agonists, GnRH antagonists

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1. Introduction

1.1 Native GnRH, GnRH agonists and antagonists

Gonadotropin-Releasing Hormone (GnRH) is a decapeptide expressed by hypotalamus, known for its

role in regulating reproduction: it binds specific receptors on pituitary gonadotroph cells leading to the

synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [1]. The

correct function of hypothalamic-pituitary-gonadal axis depends on pulsatile release of GnRH [2].

Continuous administration of native GnRH causes the suppression of gonadotropin secretion and

ovarian steroidogenesis [3].

Native GnRH and GnRH agonists (GnRHag) exert a suppression of gonadotropin release through a

down-regulation of GnRH receptors, after a stimulatory phase of about 1-2 weeks [4], when they are

administered in a continuous (non-pulsatile) manner. The down-regulation of GnRH receptors may

occur through the reduction of number of receptors on cell surface or reduction of GnRH receptor

mRNA [3]. Receptors bound by GnRH or GnRHag are internalized and partially degraded. Native

GnRH has a very brief half-life and is rapidly degraded by peptidase; for this reason different agonists

with more potency and longer duration have been synthetized in the past 30 years. Agonists, such as

leuprolide, triptorelin, goserelin, are about 50-100 times more potent than GnRH [5]. To date, GnRHag

are a well-established therapeutic option for treatment of infertility, sex-hormone sensitive cancers and

benign gynecological conditions (as endometriosis or uterine fibroid) [6]. GnRH agonists are synthetic

peptides obtained by one or more substitutions in the amino acid chain of the natural decapeptide

confering high biologic stability and high receptor affinity [7].

Currently, marketed GnRHag are formulated as subcutaneuous, intramuscular depot, nasal spray and

subcutaneuous implant; on the contrary of daily administration of nasal spray, the depot formulations

are commonly used with an administration either every month or every three months [7].

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Antagonistic analogs of GnRH (GnRHant) have a synthetic peptide structure obtained by multiple

substitution on the first three positions and 6, 8 and 10 positions of the decapeptide [8]. GnRH

antagonists are capable of binding the pituitary GnRH receptors, competing with the endogenous

molecule, but they do not induce receptor activation. The immediate suppression of the gonadotropins

release and the reduction on gonadal steroid levels avoid the initial stimulatory phase of the agonists

[9]. Thus, potential benefits of GnRHant over GnRHag include a rapid onset of action, without the

initial flare-up associated with GnRHag [8-10]. Furthermore, thanks to the competitive blockade of

receptors, the discontinuation of GnRHant treatment leads to a rapid restarting of the pituitary gonadal

function. The degree of gonadal function suppression is directly related to the GnRHant doses [11-12].

Older GnRHant, synthetized more than 20 years ago, were characterized by a low tolerability in

relationship to hypersensitivity and anaphylactoid reactions, caused by histamine release [13]. Another

limit of these compounds is the low solubility and the propensity to form gel in aqueous solution. Thus,

efforts have been made to obtain a new generation of GnRHant without severe side effects and with a

good solubility.

In the past 10 years three peptidergic compounds have been largely evaluated on clinical trials and are

now available on the market: cetrorelix, ganirelix and degarelix actually indicated to prevent premature

ovulation in controlled ovarian stimulation in the field of assisted reproductive technologies [14-15].

Degarelix is a GnRHant approved for the treatment of patients with advanced hormone-dependent

prostate cancer [16]. All these antagonists do not induce significant histamine-related events [17-18].

Although they are approved only for protocols of reproductive medicine, they have been largely tested

and might be used for other medical conditions like sex-hormones dependent cancer, endometriosis and

uterine fibroids [6].

1.2 Clinical use of GnRH agonists in the woman

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GnRH agonists are extensively used with the aim to obtain a suppression of sex hormone levels: sex-

hormone dependent cancer (mainly breast cancer), benign gynecological diseases, such as fibroids and

endometriosis, precocious puberty; they have been tested in contraception and polycystic ovary

syndrome. However, GnRHag have earned the biggest role in the context of reproduction and ovarian

stimulation protocols.

1.2.1 Reproductive medicine

In assisted-reproduction technologies, the reversible suppression of pituitary and ovarian function

induced by GnRHag abolishes the interference of endogenous gonadotropins and permits ovarian

stimulation with exogenous gonadotropins followed by ovulation induction either with human

chorionic gonadotropin or with recombinant LH [19]. Different treatment schemes can be employed.

The “short protocols” are based on the simultaneous administration of GnRHag and gonadotropins, in

order to take advantage on initial flare-up effect of GnRHag. Instead, the “long protocols” are based on

a complete pituitary suppression obtained by the administration of GnRHag, before starting ovarian

stimulation [20]. In spite of more protract and expensive treatment this last protocol seems to exert the

most favourable effects on pregnancy rates. The use of GnRHant permits to short the protocols of

stimulation in comparison with GnRHag: antagonists can be administered after ovarian stimulation has

already started with gonadotropins, so lower amounts of gonadotropins are needed. Both cetrorelix and

ganirelix effectively block LH surge [21]. Nevertheless, the number of oocytes and embryos obtained

with GnRHag are higher than those with GnRHant [22].

1.2.2 Gynecological Sex-hormone related cancer

GnRH agonists have been evaluated in the treatment of breast and endometrial cancer. Several studies

show positive results with the use of GnRHag in breast cancer, either alone for treatment of advanced

or metastatic breast cancer [23], either in combination with tamoxifen [24] and aromatase inhibitors

[25], or also as adjuvant treatment [26-27]. It has been proposed that GnRHag inhibit proliferation in

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endometrial cancer cell lines [28] and provide a prolonged relapse-free survival and better quality of

life in some cases of recurrent endometrial cancer [29]. There are still few data about the clinical use of

GnRHant in these gynecological cancers. Several studies demonstrated the expression of GnRH and

GnRH receptors on tumor cells: in particular, a second structural variant of GnRH has been found in

mammals, with antiproliferative effects on human endometrial, ovarian, and breast cancer cells [30].

GnRH antagonists can induce apoptosis in these cancer cells [31], thus they could be suitable drugs for

an efficacious and less toxic cancer therapy not only for the suppression of sex hormone production,

but also for a direct effect on cancer cells. However, the role of peripheral GnRH receptors is still

controversial and this mechanism may not represent the primary mechanism of action of GnRHag in

endometrial cancer [32].

GnRH agonists have also been used to protect gonad and oocytes from toxic effect before and during

chemotherapy [33].

1.2.3 Uterine fibroids

Uterine fibroids are hormone-dependent benign tumors. The rational for GnRHag in this condition is

the hypoestrogenism due to the inhibition of gonadal axis; in fact, a lot of evidences show that uterine

fibroids are primarily progesterone-dependent with estrogen having a permissive role [34, 35]. GnRH

agonists are capable of significantly and progressively reducing fibroid size, but the most common

adverse events (hot flashes, insomnia, mood disorders, vaginal dryness) and the risk of bone mineral

density loss hinder long term therapy. Surgical treatment of severe symptomatic fibroids is the

preferred approach, and GnRHag are frequently administered before surgery to reduce fibroids size, to

facilitate surgical procedure and to reduce abnormal uterine bleeding with a significant improvement of

preoperative levels of hemoglobin and haematocrit [36].

GnRH antagonists could be advantageous in relationship to their rapid effect. Cetrorelix demonstrated

to be an efficacious and well tolerated as preoperative treatment of fibroids [37]. Ganirelix treatment

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induces a significant reduction of fibroid size in a median of 19 days [38]. Trials assessing a novel

GnRHant, elagolix, as long-term medical treatments for heavy menstrual bleeding associated with

uterine fibroids are under evaluation [39].

1.2.4 Endometriosis

Endometriosis is a gynecological disease characterized by endometrial implants outside the uterus,

which are hormone-sensitive as normal endometrium. Medical therapy for patients with endometriosis

mainly is the management of endometriosis-associated pain. The GnRHag is a useful therapeutic

choice to counteract this disorder: it allows to obtain relief of pelvic pain and dysmenorrhea, a

reduction in size of endometrial implants [40]. Moreover, GnRHag demonstrated to reduce the activity

of paracrine factors with angiogenic and growth promoting function, likely involved in the

pathogenesis of endometriosis [41]. GnRH agonists are used for 3-6 months period, to avoid the long-

term side effect on bone health. To permit a prolonged use of GnRHag without relevant side effects, a

co-administration of low estrogen and progestogen doses (add-back therapy) has been proposed and

has been proven to be as effective as agonists alone [42].

In relationship to the complexity of this estrogen-dependent disease in which many factors contribute to

the maintenance of chronic inflammation, there are emerging therapies for the treatment of

endometriosis-related pain [43, 44, 45].

To date, there are very few clinical data on the efficacy of available injectable, peptide GnRHant for the

treatment of endometriosis related pain [46]; in a small feasibility study in 15 women with

endometriosis, cetrorelix, administered for 8 week period, showed a rapid decrease of disease-related

symptoms and a persistent efficacy thoughout 8 weeks after the administration [47]. There are no data

on ganirelix for the treatment of endometriosis-associated pain. Currently, the injective GnRHant

(cetrorelix, ganirelix) are used in the assisted reproductive technology to prevent a premature LH surge

[44].

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2. Non peptidic antagonists of GnRH

Currently marketed GnRHant are all peptide molecules which cannot be taken orally because the

protein structure undergoes proteolysis in the gastrointestinal tract before absorption [8]. Over the last

15 years, scientific research has worked towards developing of new molecules which were available for

oral administration, with the aim to improve dose flexibility and patient acceptance; the oral

administration also allows to avoid injection site reactions.

Since 1998, Cho et al [48] described the first orally active non-peptide GnRHant. Other studies

evaluated different molecules as potential candidates [49]. Although many clinical studies are still in

progress testing several non-peptide antagonists, to date, there are published clinical data about three

non-peptidic molecules: two uracil derivatives (NBI-42902 and elagolix), and a thienopyrimidine

derivative known as TAK-013 [50-55]. None of these drugs received approval for the market and

elagolix is the only one who currently undergoes Phase III trials. In in-vitro experiments, elagolix

(NBI-42902) showed a potent functional, competitive antagonism on GnRH receptors, suggesting that

it could be useful as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis [54]. The

non-peptide antagonist TAK-013 has been evaluated in healthy post-menopausal women, to study

safety, tolerability, pharmacodynamics, pharmacokinetics, and metabolic effects, and it has

demonstrated to be a well-tolerated, orally active, and effective GnRHant [55] .

The main advantages of these non-peptidic GnRHant are the loss of histamine-releasing effect and their

oral activity.

2.1 Elagolix

2.1.1 Chemistry

Elagolix is an orally active, non-peptidic, GnRHant initially developed by Neuroendocrine Biosciences,

in-licensed by Abbott Laboratories, and it is currently being developed by AbbVie Inc. The compound

is the sodium salt of 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-

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(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-

phenylethyl}amino)butanoate. The structural and molecular formula of this uracil phenylethylamines

bearing a butyric acid is shown in Figure 1.

2.1.2 Pharmacodynamics

Elagolix is a highly potent antagonist of the human GnRH receptors [54]. The pharmacodynamic data

from Phase I study, in premenopausal healthy female subjects, showed that LH and FSH concentrations

almost immediately decrease after a single 25 mg dose of elagolix; higher doses lead to a more

enduring reduction of gonadotropin levels. Mean estradiol concentration declines after at least 50 mg

dose treatment and estradiol levels remain partially suppressed after 24 h; 100 mg twice daily (bid)

showed a consistent significant suppression of estradiol levels compared with placebo. After the

discontinuation of 7 day elagolix treatment, estradiol levels return to normal values independently of

daily doses administered [54].

2.1.3 Pharmacokinetics and metabolism

Clinical pharmacokinetic (PK) studies show that elagolix is rapidly absorbed through the

gastrointestinal tract following oral administration. Its peak of plasma concentrations is approximately

30-60 minutes [54]. The area under the plasma concentration versus time curve (AUC) of the

immediate-release tablet formulation decreases approximately 25% by food. Clinical PK studies

indicate that elagolix exposure is more or less dose-proportional across the daily dose range studied (25

to 400 mg) [54]. Plasma half-life of elagolix across a range of dosage regimens is changed from 2.4 to

6.3 hours. Repeated daily administrations do not result in significant accumulation of this drug.

Elagolix has little effect on inhibition of CYP3A4 [56]. After rapid metabolism, less than 3% of the

orally administered dose is excreted unchanged in the urine. Liver exerts the main metabolism of

elagolix, with a 90% of excretion in the feces. Plasma exposure of each metabolite of elagolix is less

than 3% [54, 56].

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Despite the suppression on gonadotropin levels, elagolix is not a contraceptive.

In the pre-clinical study of Chen et al [56] the oral administration of elagolix in castrated macaques

suppresses LH levels. At the doses of 30 mg/kg the oral administration of elagolix exerts a more potent

and rapid inhibitory effect on LH secretion in comparison to other GnRH non peptide antagonists.

However, the study shows the reversibility of the LH inhibition with an increase of LH plasma levels

36 hours after a single oral compound administration [56].

2.1.4 Clinical Efficacy

2.1.4.1 Phase I studies

In the phase I study of Struthers et al [54] performed in healthy premenopausal women elagolix was

compared with placebo in a double-blind study with the administration of single and multiple daily

doses. In comparison to placebo elagolix shows a suppression of gonadotropin and estradiol levels with

a rapid reversibility after discontinuation [54]. Elagolix is able to suppress estradiol levels for 24 hours

when it is administered at least at 50 mg in a single dose. Daily doses (50, 100, 200 mg) or twice-daily

dose (100 mg) of elagolix administered throughout 7 days suppress estradiol levels in comparison to

placebo in which there is an increment in 24 hours. However, a consistent statistically significant

suppression of serum estradiol levels was observed with 100 mg bid treatment compared with placebo

[51]. These results are similar to those observed with cetrorelix and ganirelix [18, 57], but with a lower

suppression of serum LH and FSH obtained with elagolix. The most important outcome of this study

was the observation that the inhibitory effects of elagolix on pituitary-gonadal axis were dose

dependent (from partial suppression at lower doses to near full suppression at higher doses) [54].

2.1.4.2 Phase II studies

A phase II study with elagolix was performed in women with endometriosis-associated pain. Elagolix

oral treatment at the daily doses of 150 mg qd and 75 mg bid was compared with subcutaneous depot

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medroxyprogesterone acetate (DMPA-SC). Elagolix at 150 mg qd shows a statistically non-inferiority

effect to DMPA-SC in reducing dysmenorrhea and non-menstrual pelvic pain [58].

The phase II study by Carr et al [59] conducted at 37 US centers, is a randomized, placebo-controlled

study. In the study, the double-blind treatments were performed in 8 week period followed by a 16-

week open label period in which all participants were treated with elagolix. In the elagolix group, in

which the drug was administered at the daily doses of 150 mg, a significant reduction of endometriosis-

associated pain (dysmenorrhea, dyspareunia and non-menstrual pelvic pain) was calculated in

comparison to placebo, with a parallel improvement in women-quality of life [59].

The phase II study of Diamond et al [51] demonstrates that 150 and 250 mg daily doses of elagolix

meaningfully reduces dysmenorrhea, dyspareunia and non-menstrual pelvic pain with a significant

difference in comparison with placebo at weeks 8 [51]. After elagolix discontinuation, the return of

symptoms generally coincides with the resumption of menstruation [51].

2.1.4.3 Phase III studies

Phase III trials are assessing two separate doses of elagolix (150 mg qd and 200 mg bid) over a 24-

week treatment period. The first randomized, double-blind, placebo-controlled trial (M12-665) (Violet-

PETAL) enrolled about 800 women with endometriosis in 160 clinical centers of the United States,

Canada and Puerto Rico [60]. The primary endpoint was to compare the daily non-menstrual pelvic

pain and the daily dysmenorrhea scores through the third and the sixth month of treatment versus daily

baseline scores. On January 2015, AbbVie Pharmaceutical, Inc released preliminary results, showing

that, after six months of treatment, both doses of elagolix are able to reduce scores of endometriosis

associated pain [61]. A second Phase III study of elagolix (M12-671) (Solstice) [62], similar in

structure to the first, started by AbbVie Pharmaceutical Inc. in 2013 with the aim to evaluate the safety

and efficacy of elagolix in the management of moderate to severe endometriosis-associated pain in

adult premenopausal women. This study, performed in 200 centers, is still ongoing.

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However, the completion of the study is estimated on November 2016, and final results will be

published after November 2016 [62].

2.1.4.3 Postmarketing Surveillance

There is not postmarketing surveillance.

2.1.5 Safety and tolerability

In the phase I and phase II studies above reported [51, 54, 56-59], the safety profile of elagolix was

evaluated mainly considering the incidence of adverse events, with special interest on hypoestrogenic

adverse events and cutaneous and hypersensitivity events.

In the phase I study of Struthers et al [54], the most commonly adverse events were headache, nausea,

abdominal pain and hot flush. In most cases these events were reported as mild in intensity. The

occurrence of hot flushes in this study was dose-dependent. There was one case of serious adverse

event (pelvic abscess) that was judged by investigators not associated to elagolix. All symptoms

disappeared after study drug discontinuation in few days, without intervention [54].

Diamond et al in phase II study [51] reported that the most frequent adverse events in elagolix

treatment groups were headache, nausea and anxiety. Hot flushes occurred both in placebo and elagolix

treatment-groups, but with a stricter relation with elagolix. There was only one drug discontinuation

due to hot flushes, and this symptom was in general reported as mild to moderate in intensity. Overall

elagolix demonstrated an acceptable safety profile during this study [51].

In the phase II study, which compared efficacy and safety of elagolix with DMPA-SC for treatment of

endometriosis [58], the pattern and the incidence of adverse events were similar in all treatment groups.

There were 3 serious adverse events in patients randomized to elagolix treatment groups and 6 serious

adverse events in patients randomized to DMPA-SC treatment group; the serious adverse events

occurred in elagolix treatment groups were judged by investigators probably not associated to elagolix

[58]. To evaluate general safety, vital signs and clinical laboratory parameters, such as renal and liver

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function, hematological, electrolytes and metabolic parameters, were assessed on phase II

endometriosis studies, throughut 24 week treatment: no clinically significant differences were observed

[58,59]. No clinically significant ECG abnormalities have been observed in subjects who assumed

elagolix [58,59].

In examined elagolix studies [51, 58], some pregnancies have been reported. Of the cases conceived

during elagolix treatment, one resulted in spontaneous abortion [51]; two pregnancy-related serious

adverse events occurred: one case of cleft palate [58]; and one case of tracheoesophageal fistula [51].

It is however unlikely that both cases have to be related to elagolix, even considering that literature data

did not reveal any evidence for teratogenic effect of GnRHant.

Considering the hypoestrogenic effect related to elagolix treatment, the main interest has been focused

on bone health. A minimal reduction from baseline on mean bone mineral density (BMD) were seen at

the lumbar spine [51]. These effects seem depend on the dose of elagolix and duration of treatment

[51]. The phase II study evaluating efficacy of elagolix for endometriosis-associated pain, shows

significant changes in spine BMD at the 12th week of 250 mg daily treatment, and in spine and femur at

week 24 after both 150 and 250 mg daily treatments [51]. Serum levels of N-telopeptide (a bone

reabsorption biomarker) remained largely unchanged throughout the study [51]. In the phase II study of

Carr et al [58] the percentage of change from baseline in BMD at spine and femur levels was calculated

at 24 weeks of treatment in women affected by endometriosis divided in three groups of treatment:

elagolix 150 mg/day, single dose (150 mg q.d.), elagolix (75 mg twice a day) (75 mg b.i.d.),

subcutaneous depot medroxyprogesterone acetate 104 mg/0.65 mL at week 1 and 12) (DMPA-SC). The

same evaluation was performed at the interrumption of treatments (24 weeks posttreatment, 48 weeks)

to evaluated the reversibility of treatments. A minimal reductions from baseline on mean of BMD were

found with the treatments with reversibility of values at 48 weeks. However, in women treated with

150 mg qd the percentage change of spine and femur BMD was lower than that observed in women

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treated with elagolix 75 mg bid and in those treated with DMPA-SC. These differences in the BMD

changes, even minimal and not significant, seem to be related to E2 levels changes during the courses

of treatments, with higher levels in the group 150 mg q.d. than in the other groups [58]. At 24 weeks of

treatment, percentage change in spine BMD was lower than 3 and 4.6 with the 150 mg and 250 mg of

elagolix daily doses, respectively. At the same time period of treatment, the percentage change at femur

BMD was lower than 3 with both doses of elagolix daily treatment.

More data by ongoing phase III studies could better explain the interference of elagolix treatment on

bone metabolism.

2.1.6 Regulatory Affairs

The study M12-665 and the study M12-671, above reported, are sponsored by Abbvie Pharmaceutical,

Inc. Only preliminary results of the study M12-665 are reported by the sponsored pharmaceutical

company [61]. The study M12-671 started in 2013 and is similar in design to the study M12-665. Study

M12-671, and the extension studies for Study M12-665 and M12-671, are currently ongoing.

3. Conclusions

Thanks to its mechanism of action, which allows to obtain a partial dose-related estrogen suppression,

elagolix could be an effective treatment strategy in the management of endometriosis-related

symptoms. This non peptide GnRHant can reduce endometriosis-associated pain, with the advantage of

an oral administration.

The studies on elagolix showed an acceptable safety and tolerability profile; adverse events related with

its use were consistent with the drug's mechanism of action and their intensity was usually mild or

moderate. Furthermore, the pharmacokinetic and pharmacodynamic characteristics of elagolix permit a

rapid reversibility of its action after treatment discontinuation. This property is desirable for women of

reproductive age who may plan pregnancy, but also has the drawback of the symptoms recurrence with

resumption of menses.

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Clearly, the ongoing studies of Phase III will confirm the benefits of elagolix for endometriosis, and

will better evaluate its safety also in longer treatment period. Thus, the use of an oral agent such as

elagolix may be an alternative to current therapies if it provides overall improvements in the safety and

tolerability profile.

4. Expert Opinion

Endometriosis related symptoms require a chronic treatment with the aim to reduce the cyclic hormonal

stimulation of endometriotic implants. Phase I [54] and phase II [51, 58-59] studies show that the non-

peptidic GnRHant, elagolix, is capable of inhibiting hypophyseal-gonadal axis in a short time period,

with a dose-related inhibition of estradiol secretion. The maintenance of an inhibition without a

complete inhibition of estradiol levels is sufficient to counteract the endometriosis symptoms without

the indesiderable adverse events related to hypoestrogenism, such as neurovegetative symptoms and

loss of bone mineral density. The studies published so far are limited to a short period of time, lower

than 12 months of treatment. The results of phase III studies designed to evaluate the efficacy and

safety of elagolix treatment in comparison to placebo in a longer period of treatment (12 months) could

give further evidences on the efficacy and safety of this medical treatment of endometriosis-related

symptoms. In addition, the drug formulation permits an oral administration with a good compliance and

tolerability of the treatment. However, the oral daily administration could be not preferred by some

women, in relationship to the necessity to remember the daily assumption of the drug. Moreover, in the

opinion of the authors, more phase III studies are necessary to demonstrate the non-inferiority of

elagolix treatment in comparison with other medical treatment of endometriosis. First of all, inhibition

of pituitary-gonadal axis can be obtained with a progestin or estroprogestin chronic treatment. Many

studies agree with the efficacy and safety of these latest treatments [63-65]. Furthermore, no studies

have been published so far to compare the efficacy and safety of elagolix treatment with those of

GnRHag, while this last is considered a very effective medical treatment of endometriosis, so that

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several studies of other innovative medical treatments for endometriosis are compared to GnRHag [66,

67]. Finally, further studies have to be designed with the aim to evaluate whether elagolix treatment

could reduce the size and the activity of endometriotic implants that can represent the main results of a

medical endometriosis treatment.

Declaration of interest

GB Melis, AM Paoletti, S Angioni, S Guerriero, M Neri, ME Malune, V Corda, S Pirarba and MN

D’Alterio are all employees of the University of Cagliari, while B Piras and M Orrù are employees of

the Cagliari University Hospital (Azienda Ospedaliero Universitaria di Cagliari). AbbVie was asked to

review for accuracy the safety and efficacy data disclosed in this manuscript, all of which is in the

public domain. The content and opinion expressed in the manuscript is solely that of the authors.

The authors have no other 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 apart from those disclosed.

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Box 1. Drug Summary Box

Drug name (generic) Elagolix

Phase (for indication under discussion) III, pivotal

Indication (specific to discussion) Endometriosis

Pharmacology description/ mechanism of action GnRH no peptide antagonist/inhibition of pituitary-

gonadal axis

Route of administation Oral

Chemical Structure uracil phenylethylamines bearing a butyric acid

Pivotal trials M12-665 [60] and M12-671 Phase III trials

[62], the last ongoing

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Elagolix sodium structure

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