Treatment of endometriosis-

associated pain with linzagolix,

an oral gonadotropin-releasing
hormone–antagonist: a randomized
clinical trial
Jacques Donnez, M.D., Ph.D.,a Hugh S. Taylor, M.D., Ph.D.,b Robert N. Taylor, M.D., Ph.D.,c
Mark D. Akin, M.D.,d Tatyana F. Tatarchuk, M.D., Dr. Sc.,e Krzysztof Wilk, M.D.,f Jean-Pierre Gotteland, Ph.D.,g
Veronique Lecomte, Pharm.D.,g and Elke Bestel, M.D.g
a

te
Socie
de recherche pour l'infertilite

, Catholic University of Louvain, Leuven, Belgium; b Department of Obstetrics,
Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut; c Department of Obstetrics
and Gynecology, University of Utah, Salt Lake City, Utah; d Austin Area Obstetrics Gynecology and Fertility, Austin,
Texas; e Department of Endocrine Gynecology, Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of
Ukraine, Kiev, Ukraine; f Vita Longa Sp. z o.o, Katowice, Poland; and g ObsEva S.A, Geneva, Switzerland

Objective: To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-
associated pain (EAP).
Design: A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial.
Setting: Clinical centers.
Patient(s): Women aged 18–45 years with surgically confirmed endometriosis and moderate-to-severe EAP.
Intervention(s): The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24
weeks.
Main Outcome Measure(s): The primary endpoint was the number of responders (R30% reduction in overall pelvic pain) after 12
weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL)
measures, and bone mineral density (BMD).
Result(s): Compared with placebo, doses R 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at
12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea
and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved,
and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75
mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern.
Conclusion(s): Linzagolix significantly reduced EAP and improved QoL at doses of 75–200 mg and decreased BMD dose-
dependently.
Clinical Trial Registration Number: NCT02778399 (Fertil SterilÒ 2020;114:44-55. Ó2020 by American Society for Reproductive Med-
icine.)
El resumen está disponible en Español al final del artículo.
Key Words: Endometriosis-associated pain, linzagolix, GnRH antagonist, BMD
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/61162-29165

Received October 16, 2019; revised February 21, 2020; accepted February 28, 2020; published online June 4, 2020.
J.D. reports consulting fees and other payments from ObsEva and Preglem, Scientific Advisory Board membership of ObsEva S.A., Board membership of
PregLem, and travel/meeting expenses from Gedeon Richter and Zuellig. H.S.T. reports consulting fees from Obseva, Abbvie, DOT lab and Bayer.
R.N.T. reports consulting fees from ObsEva and Abbvie and a grant from Ferring. M.D.A. reports a research grant from ObsEva. T.F.T. reports a research
grant from ObsEva and payments for lectures from Abbott, Bayer, and Gedeon Richter. K.W. reports a research grant from ObsEva. J.P.G. is an
employee and stockholder of ObsEva S.A. V.L. is an employee and stockholder of ObsEva S.A. E.B. is an employee and stockholder of ObsEva S.A.
Reprint requests: Elke Bestel, M.D., ObsEva S.A., Chemin des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland (E-mail: elke.bestel@obseva.ch).

Fertility and Sterility® Vol. 114, No. 1, July 2020 0015-0282/$36.00

Copyright ©2020 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2020.02.114

44 VOL. 114 NO. 1 / JULY 2020


E
ndometriosis, defined as the presence of endometrial-
like tissue outside the uterus, is a very common
estrogen-dependent gynecological disease occurring
in 6%–10% of women of reproductive age (1, 2). The patho-
physiology of endometriosis is complex with various pro-
posed etiologies, including retrograde menstruation, genetic
factors, alterations to the immune system, differentiation of
mesenchymal stem cells, and metaplasia of mesothelial cells
(1, 3–5). By promoting proliferation of endometrial tissue
outside the uterus, endogenous estrogen production plays a
crucial role in the development of endometriosis (1, 2, 6).
Additionally, oxidative stress and environmental factors
likely interfere with or promote the growth of the lesions (3).
As an inflammatory condition, endometriosis is respon-
sible for a range of pain symptoms, such as dysmenorrhea
(DYS), non-menstrual pelvic pain, dyspareunia, dyschezia,
and, less commonly, constipation, dysuria, and painful urina-
tion (1, 7). These pain symptoms often have a profound impact
on the quality of life of affected women and often lead to work
absenteeism and productivity loss (7, 8). Indeed, endometriosis-
associated pain results in a substantial economic burden and a
number of published studies have stressed the huge financial
costs for society and health insurance systems (9–12).
A variety of medical and surgical therapies are available
for treatment of endometriosis and guidelines have been is-
sued by the European Society of Human Reproduction and
Embryology (13) and the American Society for Reproductive
Medicine within the past years to aid in the clinical manage-
ment of this complex syndrome (14).
Combined oral contraceptives have been historically
first-line approach (15), although for some patients, progesto-
gens as a single agent are preferred (16). Combined oral con-
traceptive administration causes inhibition of ovulation,
reduction of menstrual blood flow, and decreased cell prolif-
eration in eutopic and ectopic endometrial tissue (15). Proges-
togens induce anovulation and a hypoestrogenic state by
down-regulation of pituitary gonadotropins and decidualiza-
tion and atrophy of endometriotic implants, but have bother-
some side effects that include unscheduled uterine bleeding,
weight gain, mood changes, reduced libido, and breast
tenderness (17). Moreover, progesterone resistance is
observed commonly in endometriotic lesions and limits the
efficacy of this treatment approach (18).
Second-line therapies include injectable depot formula-
tions of gonadotropin-releasing hormone (GnRH) agonists,
such as leuprolide acetate, goserelin, and buserelin (19–21).
Down-regulation of the pituitary GnRH receptor leads to a
very significant reduction in estrogens to postmenopausal
levels. These drugs are effective for treatment of
endometriosis-related pain, but are associated with a flareup
effect with initial use, and hypoestrogenic side effects (bone
mineral density [BMD] loss, severe vasomotor symptoms,
vaginal dryness, and loss of libido). In the absence of add-
back therapy, their use is limited to 6 months (19, 21, 22).
Surgical ablation or excision of endometriosis lesions also
can be effective for relief of pain (20, 21). Nevertheless, recur-
rence is common and symptoms often progressively increase
with time, requiring repeated courses of pain management
and multiple repeated surgeries for many patients (23, 24).
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Fertility and Sterility®
Clearly, there is a large unmet medical need for improved
therapies for endometriosis (25). According to the estrogen
threshold hypothesis suggested by Barbieri (26), complete
estrogen suppression may not be necessary. Managing estro-
gen levels to minimize estrogen withdrawal symptoms and
sequelae, while maintaining efficacy in terms of reduction
of endometriosis-related pain, may constitute a viable
treatment option.
Oral GnRH antagonists have emerged as a potential alter-
native to allow dose-dependent control of estradiol (E2) levels
(25). Taylor et al. (27) recently demonstrated in two similar
double-blind, randomized, phase 3 trials that elagolix, an
oral, non-peptide, GnRH antagonist, given at doses of 150
mg once daily and 200 mg twice daily, was effective for treat-
ing EAP. Elagolix has a short half-life of about 4–6 hours (28)
and twice daily dosing for the higher dose is required to
achieve near full suppression of E2 (29).
Linzagolix is a new investigational oral, non-peptide,
GnRH antagonist currently in clinical development. The phar-
macokinetics, pharmacodynamic impact on E2, and safety of
linzagolix were investigated previously in a phase 1 study in
healthy female volunteers (30). Linzagolix has a half-life of
15–18 hours, high oral bioavailability, low volume of distri-
bution, lack of food effect, and lack of interactions with trans-
porters and CYP3A4 enzymes (data on file). These
characteristics suggest that the compound may be optimal
for achieving stable, partial, or near full suppression of E2
with once-daily dosing.
The aims of the present phase 2b, double-blind, placebo-
controlled, dose-ranging study were to evaluate the efficacy
and safety of linzagolix in women with moderate to severe
EAP and to establish doses for evaluation in phase 3 trials.
MATERIALS AND METHODS
Trial Design and Overview
The EDELWEISS trial was a phase 2b, multinational,
multicenter, double-blind, randomized, parallel-group, pla-
cebo-controlled, dose-ranging trial conducted in 62 clinical
centers in the United States and Europe in 2016–2017.
The trial comprised a screening period, during which EAP
was evaluated during two menstrual cycles, and a 24-week
treatment period. Subjects completing the 24-week treatment
period were invited to continue active treatment up to 52
weeks in an extension phase. Here we report the results of
the first 24-week treatment period only.
The trial was approved by an ethics committee or
institutional review board for each participating center and
performed in accordance with International Conference on
Harmonization guidelines, applicable regulations, and ethical
principles of the Declaration of Helsinki. The trial was regis-
tered on ClinicalTrials.gov: NCT02778399. All potential study
subjects provided written informed consent prior to any
screening activities. The sponsor, ObsEva S.A, designed the
trial and analyzed the data. A contract research organization,
Chiltern International Inc., managed the trial. The investiga-
tors, contract research organization, and sponsor conducted
the trial and gathered the data jointly. All the authors had
full access to the data. The first draft of the manuscript was
45
SEMINAL CONTRIBUTIONS
written by a medical doctor (J.D.) and all the authors provided
feedback on all versions of the manuscript. All the authors
can attest to the completeness and accuracy of the data and
analyses, and adherence to the trial protocol.
Patients
Eligible subjects were premenopausal women aged between
18 and 45 years, with a confirmed surgical diagnosis of endo-
metriosis in the previous 10 years and currently experiencing
moderate to severe EAP. Women were excluded if their
chronic pelvic pain was not caused by endometriosis (in the
opinion of the investigator), or they had liver enzyme anom-
alies, osteoporosis, or other metabolic bone disease. There was
no BMD cut-off for participation. Women also were excluded
if they had taken specific medications such as oral contracep-
tives, GnRH analogues, or systemic glucocorticoids, with a
specified wash-out period for each based on the time period
these medications might be expected to have a continued
effect. All subjects were instructed to use non-hormonal,
double-barrier contraception such as condom or diaphragm,
each combined with a spermicide. A full list of inclusion
and exclusion criteria is provided in Supplemental Table 1
(available online).
Interventions
Eligible subjects were randomized on trial Day 1 (between
menstrual days 1 and 7) in a 1:1:1:1:1:1 ratio to one of six
treatment groups: placebo, fixed-dose (FD) linzagolix at 50
mg, 75 mg, 100 mg, and 200 mg, and a titrated-dose (TD)
group starting at 75 mg (Supplemental Figure 1, available on-
line). Subjects in the placebo arm received placebo for 12
weeks, after which they were crossed over to 100 mg linzago-
lix for 12 weeks.
In the TD arm, all subjects started on 75 mg daily for
12 weeks, after which the dose was titrated to 50, 75, or
100 mg for the following 12 weeks. Titration was based
on mean serum E2 concentrations at weeks 4 and 8 ac-
cording to the following algorithm: the dose for subjects
with mean serum E2 levels of <20 pg/mL was titrated
down to 50 mg daily, whereas the dose for those with
mean serum E2 levels of >50 pg/mL was titrated up to
100 mg daily. Subjects with mean serum E2 levels in
the 20–50 pg/mL range remained on 75 mg daily. To
maintain study blinding, serum E2 values were not
communicated to the subjects, investigators, nor the study
operations team. No clinical responses were taken into ac-
count for the titration. The rationale for this titration was
the hypothesis suggested by Barbieri (26) described in the
introduction.
Randomization and Blinding
Randomization was done according to a computer-generated
randomization list prepared using Statistical Analysis System
software Version 9.2 (SAS Institute Inc., Cary, NC, USA) and
was performed in blocks of a pre-determined length and com-
plete blocks were allocated to each site. Placebo treatments
were identical in appearance to the active treatments. Treat-
46
ment allocation was blinded to subjects, investigators, and
trial operations team (including the sponsor).
Trial Procedures and Assessments
Patients were required to complete an electronic daily diary at
the same time each evening starting during the screening
period and continuing throughout the 24 weeks of treatment.
Patients reported pelvic pain, uterine bleeding, dyspareunia,
dyschezia (weekly), analgesic use, and difficulty of doing
daily activities. Mean 28-day scores were calculated for
pain and activity assessments over the 28-day period prior
to the endpoint except for the baseline mean score, which
was calculated during two complete menstrual periods. Qual-
ity of life questionnaires were collected electronically at trial
visits. Serum estradiol levels were measured at each visit
using a validated sensitive assay (tandem mass spectrometry
high performance liquid chromatography, Esoterix Endocri-
nology, Calabasas Hills, CA, USA).
BMD of the spine, hip, and femoral neck was measured
using dual-energy x-ray absorptiometry at baseline and
week 24. Differences to placebo control were not calculated
because the placebo control was only given for 12 weeks,
which is too short an interval to detect reliably measurable
change in BMD. Dual-energy x-ray absorptiometry equip-
ment was centrally calibrated using identical phantom scans
at each study site, and readings and blinded scans were read
centrally.
Subjects were supplied ibuprofen and paracetamol/acet-
aminophen tablets and requested to use these for rescue
analgesia, if required, for endometriosis pain.
Outcomes
The primary efficacy endpoint was a reduction of 30% or
more in the mean overall pelvic pain (OPP) score from base-
line to week 12, assessed daily on a 0–3 verbal rating scale
(VRS) for EAP (27). Secondary efficacy endpoints included
reduction of 30% or more in the mean pelvic pain score on
days with uterine bleeding (DYS) and on days with no
uterine bleeding (non-menstrual pelvic pain [NMPP]). OPP
also is reported as a mean change from baseline at weeks 4,
8, 12, and 24.
Other secondary efficacy endpoints at weeks 12 and 24
included mean change from baseline OPP scores assessed
on a 0–10 numerical rating scale (NRS), dyspareunia (0–3
VRS) and dyschezia (0–10 NRS), use of analgesics for pelvic
pain, incidence of amenorrhea (defined as no uterine bleeding
during the 4-week period prior to each time point), Patient
Global Impression of Change (PGIC), and the 30-item
Endometriosis Health Profile (EHP-30). The dyspareunia
questionnaire included an option ‘‘Not applicable: I was not
sexually active for reasons other than my endometriosis or
did not have sexual intercourse’’ and the scoring accounted
for patients who avoided sexual intercourse for reasons other
than EAP.
Safety evaluations included adverse event reporting
during clinic visits (including incidence of hot flushes),
VOL. 114 NO. 1 / JULY 2020

changes in BMD, endometrial assessments, and laboratory
measurements.
Statistical Analysis
The planned sample size of 330 (55 per treatment group) was
based on pairwise comparisons for each active dose versus
placebo with a two-sided type I error of 0.05, not adjusted
for multiple comparisons against placebo. Fifty-five subjects
per treatment arm provided a power of 90% assuming a pla-
cebo responder rate of 45.5% and an active treatment
responder rate of 76.9% (based on data from an unpublished
Japanese trial).
Results from the 75 mg FD group and 75 mg TD were
combined for analysis at week 12. All statistical hypothesis
tests and confidence intervals (CIs) were two-sided, using a
type I error rate of 0.05. No adjustment was made for multiple
comparisons. Efficacy was analyzed according to randomized
treatment using the Full Analysis Set (all randomized subjects
who received at least one dose of study drug and had at least
one assessment after first dose). Safety was analyzed
according to actual treatment received using the Safety Set
(all randomized subjects who received at least one dose of
the study drug).
Analysis of the primary endpoint was conducted via a
generalized linear model for binary data with repeated
(correlated) measures, using generalized estimating equations
(marginal model), with the model including terms for the
treatment group, 4-week period, baseline, and the
interactions: treatment group
4-week period, and baseline

4-week period.
Between-group comparisons for continuous endpoints
were investigated via linear mixed models for repeated mea-
sures. Between-group comparisons for binary endpoints were
analyzed via generalized linear models with repeated
measures and chi-square tests. Between-group comparisons
for count data (e.g., number of days) also were analyzed via
generalized linear models with repeated measures. Missing
values were not imputed and were handled within the
repeated measures models.
All measures as well as derived efficacy and safety
endpoints were summarized using descriptive statistics for
each treatment group and overall, and for each time point,
if applicable, using observed data. Safety and tolerability
profiles were assessed versus baseline conditions and
differences between treatment groups and summarized using
descriptive statistics, where applicable.
RESULTS
Disposition and Baseline Characteristics
A total of 328 patients were randomized and 327 were treated
(Safety Set). These included 177 subjects from 48 sites in the
USA and 151 subjects from 14 sites in Europe. Four subjects
were excluded from the Full Analysis Set prior to unblinding,
due to non-compliance to the protocol at one site. Of the ran-
domized patients, 289 (88.1%) completed 12 weeks of treat-
ment, and 253 (77.1%) completed 24 weeks of treatment. By
week 24, 68.5%, 83.7%, 84.2%, 79.3%, 73.6%, and 73.7% of
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Fertility and Sterility®
patients had completed treatment in the placebo/100 mg, 50
mg, 75 mg FD, 75 mg TD, 100 mg, and 200 mg groups, respec-
tively. Details regarding enrollment, follow-up rates, and
reasons for trial discontinuation are shown in Supplemental
Figure 2 (available online).
Baseline demographic and clinical characteristics were
similar in the different treatment groups (Table 1). Overall,
92% of the patients were white, with a mean age of approxi-
mately 32 years and mean body mass index of 26 kg/m2.
Patients reported a mean of 3.4 years since the first surgi-
cal diagnosis of endometriosis. In addition to DYS and NMPP,
approximately 88% of patients reported dyspareunia and
55% reported dyschezia during screening (Supplemental
Table 2, available online).
Primary Efficacy Endpoint
Estimated percentages of women with a R30% reduction in
OPP at week 12 were 34.5%, 49.4%, 61.5%, 56.4%, and
56.3% in the placebo, 50 mg, 75 mg, 100 mg, and 200 mg
groups, respectively (Figure 1). Compared with placebo, sig-
nificant differences were observed in the 75 mg (P¼ .003),
100 mg (P¼ .039), and 200 mg (P¼ .034) dose groups but
not in the 50 mg dose group (P¼ .155).
Secondary Efficacy Endpoints
Estimated percentages of women experiencing a reduction of
R30% in DYS and a reduction of R30% in NMPP at week 12
were 43.3% (P¼ .141) and 46.2% (P¼ .380) in the 50 mg
group, 68.2% (P< .001) and 58.5% (P¼ .017) in the 75 mg
group, 68.6% (P< .001) and 61.5% (P¼ .022) in the 100 mg
group, and 78.9% (P< .001) and 47.7% (P¼ .297) in the 200
mg group, compared with the placebo percentages of 28.5%
and 37.1% (Figure 1).
The percentages of women with a R30% reduction in
OPP at week 24 were 52.5%, 70.8%, 66.7%, 66.7%, and
77.3% in the 50 mg, 75 mg FD, 75 mg TD, 100 mg, and 200
mg groups, respectively (Figure 1). The percentage of re-
sponders for OPP as well as DYS and NMPP at week 12 was
either maintained or increased at week 24.
The mean change from baseline in OPP at weeks 4, 8, and
12 is shown in Supplemental Figure 3 (available online). There
was a significant decrease in the 75 mg (P%.001), 100 mg
(P¼ .018), and 200 mg (P¼ .001) dose groups compared with
placebo at week 12, which was already evident at week 4 in
the 75 mg (P¼ .034) and 100 mg (P¼ .015) dose groups and
week 8 in the 75 mg (P¼ .001), 100 mg (P¼ .009), and 200
mg (P< .001) dose groups.
Results at week 12 for OPP assessed using a 0–10 NRS,
dyspareunia and dyschezia, use of analgesics, and difficulty
of doing daily activities questionnaire are shown in Table 2.
There was a significant decrease in OPP assessed using a
0–10 NRS in the 75 mg (P¼ .003), 100 mg (P¼ .022), and 200
mg (P¼ .010) dose groups at 12 weeks.
Similarly, there was a significant decrease in dyschezia in
the 75 mg (P¼ .002), 100 mg (P¼ .004), and 200 mg (P¼ .022)
dose groups at 12 weeks.
Dyspareunia scores at week 12 decreased significantly
compared with placebo in the 200 mg dose group (P¼ .023).
47
SEMINAL CONTRIBUTIONS

TABLE 1

Demographic and clinical characteristics of the patients at baseline.

Placebo 50 mg 75 mg, FD 75 mg, TD 100 mg 200 mg
Characteristic (N [ 53) (N [ 49) (N [ 56) (N [ 58) (N [ 51) (N [ 56)
Age (y), mean 32.4 (5.8) 30.9 (6.0) 32.0 (6.8) 31.2 (5.9) 33.0 (5.8) 30.9 (6.0)
(SD)
BMI (kg/m2), 27 (7.6) 26 (7.7) 26 (6.0) 27 (7.1) 26 (6.0) 25 (5.5)
mean (SD)
Race, n (%)b
White 49 (92.5) 47 (95.9) 51 (91.1) 50 (86.2) 48 (94.1) 53 (94.6)
Black 4 (7.5) 2 (4.1) 6 (10.7) 8 (13.8) 4 (7.8) 4 (7.1)
Other 0 1 (2.0) 0 0 2 (3.9) 1 (1.8)
Pain scores, mean (SD)c
OPP (0–3 VRS) 1.8 (0.46) 1.7 (0.49) 1.7 (0.47) 1.7 (0.49) 1.8 (0.46) 1.7 (0.51)
DYS (0–3 VRS) 2.1 (0.44) 2.1 (0.39) 2.1 (0.43) 2.1 (0.45) 2.1 (0.40) 2.1 (0.42)
NMPP (0–3 1.7 (0.50) 1.5 (0.56) 1.6 (0.53) 1.5 (0.56) 1.7 (0.50) 1.6 (0.58)
VRS)
OPP (0–10 NRS) 5.9 (1.84) 5.2 (1.97) 5.5 (1.79) 5.5 (1.77) 5.7 (1.75) 5.3 (1.70)
Dyspareunia 1.7 (0.80) 1.4 (0.82) 1.7 (0.86) 1.4 (0.85) 1.7 (0.89) 1.6 (0.84)
(0–3 VRS)
Dyschezia (0– 5.9 (2.40) 4.6 (2.84) 5.8 (2.51) 5.8 (2.26) 5.9 (2.65) 5.4 (2.56)
10 NRS)

Lipid values, mean (SD)

HDL cholesterol 59 (15) 67 (19) 67 (19) 66 (15) 64 (15) 65 (15)
(mg/dL)
LDL cholesterol 109 (31) 103 (24) 107 (30) 106 (29) 104 (25) 102 (22)
(mg/dL)
Triglycerides 105 (64) 101 (97) 96 (47) 105 (67) 107 (72) 96 (60)
(mg/dL)
LDL-C to HDL- 2.0 (0.82) 1.7 (0.68) 1.8 (0.74) 1.7 (0.76) 1.7 (0.59) 1.6 (0.51)
C ratio
BMD - z-score, mean (SD)
Femoral neck -0.1 (0.88) 0.2 (0.89) 0.3 (0.87) 0.1 (0.90) -0.1 (1.15) -0.1 (1.10)
Total hip 0.2 (0.90) 0.3 (0.97) 0.4 (0.90) 0.5 (0.95) 0.2 (1.17) 0.1 (1.12)
Lumbar spine 0.3 (0.79) 0.2 (1.31) 0.1 (0.92) 0.2 (1.03) -0.0 (1.05) -0.1 (1.13)
Note: Demographics and baseline characteristics are presented for the Full Analysis Set (FAS). BMD ¼ bone mineral density; BMI ¼ body mass index; DYS ¼ dysmenorrhea; FD ¼ fixed dose; HDL ¼
high-density lipoprotein; LDL ¼ low-density lipoprotein; NMPP ¼ non-menstrual pelvic pain; NRS ¼ numerical rating scale; OPP ¼ overall pelvic pain; SD ¼ standard deviation; TD ¼ titrated dose;
VRS ¼ verbal rating scale.
a
Race was reported by the patients. If more than one race was reported, the patient is presented in each race, therefore, percentages do not necessarily add up to 100%. ‘‘Other’’ included Asian,
American Indian or Alaskan Native, and Native Hawaiian or other Pacific Islander.
b
Pain scores were reported daily in an electronic diary and averaged across the baseline period (during two full menstrual cycles). The VRS scores ranged from 0 (none) to 3 (severe) and the NRS
scores ranged from 0 (none) to 10 (most severe pain imaginable).
Donnez. Linzagolix for endometriosis-associated pain. Fertil Steril 2020.

Lower dyspareunia scores also were observed at week 12 in
the other linzagolix dose groups although there was no statis-
tical difference compared with placebo.
More than 95% of patients were using analgesics for EAP
at baseline. This percentage was significantly decreased at
week 12, ranging from 68.9%–76.1% in the 75 mg (P¼ .03),
100 mg (P¼ .012), and 200 mg (P¼ .024) dose groups
compared with the placebo group (91.7%).
The difficulty in doing daily activities as measured on a
0–10 NRS was significantly reduced in the 75 mg (P¼ .005)
and 200 mg (P¼ .025) dose groups compared with placebo
at week 12.
The mean change from baseline in 4-week scores for OPP
(using both VRS and NRS scales), DYS, NMPP, dyspareunia,
and dyschezia from weeks 4 to 24 are shown in
Supplemental Figure 4 (available online). Reductions in pelvic
pain scores were maintained or increased at week 24
compared with week 12.
There was a dose-dependent increase in the rate of
amenorrhea from weeks 4 to 24. At week 12 the estimated
amenorrhea rates were 4.3% in the placebo group and
11.1% (P¼ .247), 36.3% (P< .001), 55.8% (P< .001), and
80.9% (P< .001) in the 50, 75, 100, and 200 mg dose groups,
respectively. The observed rates were similar at all time
points from week 8 to 24 (Supplemental Figure 5, available
online).
Significantly more women reported ‘much’ or ‘very much’
improvement on the PGIC scale by week 12 in the 75
(P¼ .010), 100 (P¼ .026), and 200 mg (P¼ .003) dose groups
compared with the placebo group (Supplemental Figure 6,
available online).
Based on the EHP-30 questionnaire results, treatment
with linzagolix resulted in improvements in quality of life.
Improvements were most apparent and significant in the
pain and in the control and powerlessness domains from 50
mg to 200 mg (P< .05) (Supplemental Figure 7, available on-
line). In the other domains of emotional well-being, social
support, and self-image changes were smaller and only
consistently significantly different to placebo in the 200 mg
dose group.

48 VOL. 114 NO. 1 / JULY 2020

 Fertility and Sterility®

Serum Estradiol Levels

FIGURE 1
Median levels of serum E2 are presented in Figure 2. There
was rapid and full suppression to 11 pg/mL in the 200 mg
OPP dose group by week 4, which was maintained (range, 11–
100
16 pg/mL) up to week 24. With the other doses of linza-
% responders (≥ 30% reduction in pain)

Week 12 Week 24
80
golix, there was dose-dependent partial suppression of
** * * 70.8
77.3 serum estradiol to between 20 and 60 pg/mL. With pla-
66.7 66.7
60 61.5 cebo, there was an increase in median serum E2 levels
56.4 56.3
49.4
52.5 from 59 pg/mL at baseline up to a maximum of 102
40
pg/mL by week 12, which is probably due to increasing
34.5

20
asynchronicity of some of the subjects’ menstrual cycles
(i.e., those with cycles shorter or longer than 28 days)
0 with the regular 4-week testing intervals over time.
g

g
o

FD

TD

g
)
TD
m

m
eb

m
g

g
&
50
ac

50

0
m

m
10

20

10

20
D
Pl

(F

Bone Mineral Density

75

75
g
m
75

DYS Mean percent changes from baseline in BMD at the lumbar

100
spine, total hip, and femoral neck at week 24 are shown in
% responders (≥ 30% reduction in pain)

Week 12 Week 24
***
80 *** 84.1
Figure 3. Mean percent (95% CI) BMD changes for lumbar
*** 78.9
82.1

71.1
spine from baseline to week 24 in the 50, 75 (FD), 75 (TD),
68.2 68.6
60 100, and 200 mg dose groups were 0.14% (-0.83, 1.11),
58.3

47.5
-0.80% (-1.57, -0.03), -1.0% (-1.71, -0.29), -1.37% (-2.14,
40 43.3
-0.59), and -2.60% (-3.56, -1.65), respectively. BMD change
20
28.5 in femoral neck and total hip showed a similar pattern but
with generally smaller changes from baseline. The percentage
0 decreases in the 75 mg TD group were similar or numerically
larger than in the FD group.
g

g
o

FD

TD

g
)
TD
m

m
eb

m
g

g
&
ac

50

50

0
m

m
10

20

10

20
D
Pl

Categorical changes in BMD of the lumbar spine are

(F

75

75
g
m
75

shown in Supplemental Figure 8 (available online). The per-

NMPP
100 centages of subjects with a reduction of >3% BMD at week
% responders (≥ 30% reduction in pain)

Week 12 Week 24 24 were 7.9%, 13.3%, 19.0%, 21.6%, and 52.6% in the 50,
80
*
75 FD, 75 TD, 100, and 200 mg dose groups, respectively. A
* 72.9 72.7 decrease of more than 8% was recorded in 0%, 0%, 0%, 0%,
60 64.4 64.1
61.5
58.5 and 2.6% in the respective dose groups.
47.7 50.0
40 46.2
37.1
Treatment-Emergent Adverse Events
20

From screening to week 12, percentages of subjects report-

0
ing at least one treatment-emergent adverse event (TEAE)
g

g
o

FD

TD

g
)
TD
m

m
eb

m
g

g
&
50

50

0
ac

were 54.5%, 57.1%, 64.9%, 65.4%, and 71.9% in the

m

m
10

20

10

20
D
Pl

(F

75

75
g
m

placebo, 50, 75, 100, and 200 mg dose groups, respectively.

75

The most frequently reported TEAEs related to the trial treat-

Responder rates for overall pelvic pain (OPP), dysmenorrhea (DYS), ments were hot flushes and headaches; hot flushes were
and non-menstrual pelvic pain (NMPP) at 12 and 24 weeks. The 75
mg fixed dose (FD) and titrated-dose (TD) groups were pooled for more frequent at higher doses of linzagolix (10.9%, 14.3%,
analysis at 12 weeks. The 75 mg TD group received 75 mg 19.3%, 26.9%, and 42.1% at week 12 for placebo, 50, 75,
linzagolix daily until week 12 and then were titrated to 50, 75, or 100, and 200 mg, respectively, with similar dose-related
100 mg depending on the mean serum E2 measured at weeks 4
and 8. Percentage responders at week 12 and comparisons with
differences at week 24). All TEAEs reported in R5% of sub-
placebo are from a generalized linear model for binary data with jects in any dose group are shown in Supplemental Table 3
repeated (correlated) measures. Error bars are 95% confidence (available online). Up to week 24, 23 subjects withdrew from
intervals. Percentage responders at week 24 are based on observed treatment due to TEAEs, with the following TEAEs leading to
data only. No statistical testing was performed at week 24 because
there was no placebo control. A responder was defined as having discontinuation in more than one subject: headache (four
R30% decrease in the mean 28-day pain score compared with subjects), abdominal pain (three subjects), nausea, bone den-
baseline. *P<.05, **P<.005, ***P<.001. sity decreased, mood swings, and hot flush (two subjects
Donnez. Linzagolix for endometriosis-associated pain. Fertil Steril 2020. each). A total of six serious TEAEs were recorded up to
week 24; none were considered related to linzagolix. Four
There was no evidence that efficacy was enhanced in the pregnancies occurred up to week 24. One (in the 100 mg
75 mg TD group compared with the 75 mg FD group. Changes dose group) was an ectopic pregnancy treated using right
in OPP, NMPP, DYS, dyschezia, and analgesic use were very salpingectomy. The other three (one in the placebo/100 mg
similar between these groups. group and two in the 75 mg FD dose group) resulted in

VOL. 114 NO. 1 / JULY 2020 49

50

SEMINAL CONTRIBUTIONS
TABLE 2

Secondary endpoints after 12 weeks of treatment.

Variable Placebo 50 mg 75 mga 100 mg 200 mg
Overall pelvic pain (0–10 NRS)
No. of women 52 48 114 51 55
Mean CFB -1.17 -1.75 -2.15 -2.06 -2.14
95% CI -1.70, -0.65 -2.29, -1.20 -2.50, -1.80 -2.60, -1.52 -2.65, -1.63
Difference from placebo -0.57 -0.98 -0.88 -0.97
95% CI -1.34, 0.19 -1.61, -0.34 -1.64, -0.13 -1.71, -0.23
P value vs. placebo .139 .003 .022 .010
Dyspareunia (0–3 VRS)
No. of women 47 40 90 44 44
Mean CFB -0.39 -0.62 -0.59 -0.66 -0.79
95% CI -0.63, -0.16 -0.87, -0.37 -0.76, -0.43 -0.91, -0.41 -1.03, -0.54
Difference from placebo -0.23 -0.20 -0.26 -0.39
95% CI -0.57, 0.12 -0.48, 0.09 -0.60, 0.08 -0.73, -0.06
P value vs. placebo .197 .173 .133 .023
Dyschezia (0–10 NRS)
No. of women 52 48 113 50 55
Mean CFB -0.78 -1.55 -1.87 -1.97 -1.7
95% CI -1.34, -0.22 -2.14, -0.96 -2.25, -1.49 -2.55, -1.39 -2.25, -1.15
Difference from placebo -0.77 -1.09 -1.19 -0.92
95% CI -1.59, 0.05 -1.77, -0.41 -2.00, -0.38 -1.71, -0.13
P value vs. placebo .064 .002 .004 .022
Difficulty in doing daily activities (0–10 NRS)
No. of women 52 48 114 51 55
Mean CFB -1.17 -1.65 -2.06 -1.88 -1.99
95% CI -1.68, -0.65 -2.18, -1.12 -2.41, -1.72 -2.41, -1.36 -2.49, -1.49
Difference from placebo -0.48 -0.89 -0.72 -0.82
95% CI -1.22, 0.26 -1.51, -0.28 -1.45, 0.02 -1.54, -0.10
P value vs. placebo .199 .005 .055 .025
Percentage of subjects with any analgesic use
No. of women 52 48 114 51 55
Percentage 90.6 77.1 74.8 68.8 72.1
95% CI 78.6, 96.2 62.7, 87.1 65.7, 82.1 54.1, 80.5 58.4, 82.7
Odds ratio 0.35 0.31 0.23 0.27
95% CI 0.11, 1.15 0.11, 0.89 0.07, 0.72 0.09, 0.84
P value vs. placebo .084 .030 .012 .024
Percentage of women with amenorrhea
No. of women 46 45 102 43 47
Percentage 4.3 11.1 36.3 55.8 80.9
95% CI 1.1, 16.0 4.7, 24.3 27.4,46.2 40.7,69.9 66.9, 89.8
VOL. 114 NO. 1 / JULY 2020

Odds ratio 2.75 12.52 27.79 92.89

95% CI 0.49, 15.32 2.81,55.74 5.84,132.26 18.50, 466.45
P value vs. placebo .247 < .001 < .001 < .001
Note: Means, percentages, and differences from means were estimated from the logistic model. Mean scores were calculated over the number of days the diary was completed; during the baseline period (during two full menstrual cycles) or 28 days before the week 12
visit. CFB ¼ change from baseline; CI ¼ confidence interval; NRS ¼ numerical rating scale (NRS scores ranged from 0 [none] to 10 [most severe pain imaginable]); VRS ¼ verbal rating scale (VRS scores ranged from 0 [none] to 3 [severe]). All data were collected using a daily
electronic diary.
a
Groups 75 mg FD and 75 mg titrated dose were pooled for analysis at week 12.
Donnez. Linzagolix for endometriosis-associated pain. Fertil Steril 2020.

FIGURE 2
placebo 50 mg 75 mg FD 75 mg TD
120
Median serum E2 pg/mL
100
80
60
40
20
0 weeks. The error bars represent 95% confidence intervals. The 75 mg
e
12
16
4
8
in
k
k
ee
ee
el
ee
ee
ee
as
B
Median serum estradiol levels. Serum estradiol levels were measured
at each visit using a validated sensitive assay (tandem mass
spectrometry high performance liquid chromatography; Esoterix
Endocrinology). FD ¼ fixed dose; TD ¼ titrated dose.
Donnez. Linzagolix for endometriosis-associated pain. Fertil Steril 2020.
the birth of healthy newborns and there were no fetal anom-
alies or obstetric complications. No deaths were reported in
the trial.
Clinical Laboratory Tests
Two subjects had increases >3
the upper limit of normal
(ULN) but <5
ULN, for both alanine aminotransferase
and aspartate aminotransferase, without a concomitant in-
crease in total bilirubin. Both were in the 100 mg linzagolix
group. No increase of >3
ULN was noted for gamma-glu-
tamyl transpeptidase. The liver enzyme increase led to drug
withdrawal in one subject with pre-existing nonalcoholic
steatohepatitis; in the second subject, liver function values
spontaneously returned to normal while she was still on the
study drug. The increase was attributed to use of a concomi-
tant medication with a known effect on liver function tests.
Mean serum low-density lipoprotein (LDL) cholesterol,
high-density lipoprotein (HDL) cholesterol, ratio of LDL
cholesterol to HDL cholesterol, and triglyceride levels were
similar in all groups at baseline (Table 1). There were increases
in LDL cholesterol, HDL cholesterol, LDL cholesterol to HDL
cholesterol ratio, and triglycerides at 12 weeks, which were
maintained at 24 weeks (Supplemental Table 4, available
online). It should be noted that the post-baseline samples
were not always fasted and, therefore, the triglycerides values
were variable. Except for the LDL cholesterol to HDL
cholesterol ratio, the highest increases were observed in the
linzagolix 200 mg dose group; at week 24 there was an
approximately 8% increase in HDL cholesterol, 10% increase
in LDL cholesterol, and 24% increase in triglycerides. The
corresponding increases in the 75 mg FD group at 24 weeks
were 4% for HDL cholesterol, 7% for LDL cholesterol, and
5% for triglycerides. In all treatment groups, the percentage
VOL. 114 NO. 1 / JULY 2020
Fertility and Sterility®
FIGURE 3
100 mg 200 mg 2
change from baseline
1
Mean percentage
50 mg
0
75 mg FD
-1 75 mg TD
100 mg
-2
200 mg
-3
-4
Femoral Neck Total Hip Lumbar Spine
Mean percentage change from baseline in bone mineral density at 24
titrated-dose (TD) group received 75 mg linzagolix daily until week 12
20
24
and then were titrated to 50, 75, or 100 mg depending on the mean
k
ee
serum E2 measured at weeks 4 and 8. FD ¼ fixed dose.
W
Donnez. Linzagolix for endometriosis-associated pain. Fertil Steril 2020.
of women with LDL cholesterol >160 mg/dL or triglycerides
>200 mg/dL at 24 weeks was <10% and overall the percent-
ages were similar at 24 weeks compared with baseline. One
subject (in the 100 mg dose group) had an increase in LDL
cholesterol from <160 mg/dL to >190 mg/dL and one subject
(in the 75 mg TD group) had an increase in triglycerides from
<300 mg/dL to >500 mg/dL.
Uterine Assessments
At weeks 12 and 24, reductions from baseline in endometrial
thickness and uterine volume were more noticeable at doses
of 100 mg and 200 mg linzagolix (Supplemental Table 5,
available online). Endometrial biopsy was performed during
treatment if endometrial thickness assessed with ultrasound
was >5 mm. An isolated case of hyperplasia (without atypia)
was observed at week 12 in the 200 mg group in a subject
whose screening biopsy results were normal. A follow-up bi-
opsy at week 24 revealed no abnormalities.
DISCUSSION
Endometriosis is a chronic and progressive inflammatory dis-
ease that is highly estrogen-dependent (6). Indeed, estrogen is
believed to play an important role in the pathophysiology of
endometriosis due to its proliferative effect in ectopic endo-
metrial cells (1, 2). First-line therapies include combined
oral contraceptives or progestin-only treatment (15, 16).
However, some forms of endometriosis-related pain are resis-
tant to estrogen/progestin combinations and to progestin-
only therapy. The use of GnRH agonists is limited to 6 months
because they are associated with bone loss and severe vaso-
motor symptoms due to complete suppression of estrogen
production (19–21).
Ideally, according to the estrogen threshold hypothesis,
partial estrogen suppression to levels adequate for EAP con-
trol while avoiding menopausal signs or symptoms should
be feasible (26). Partial suppression of E2 may thus be consid-
ered a new and important approach to endometriosis
management (25).
51
SEMINAL CONTRIBUTIONS
Vercellini et al. (31) have suggested that the reduction of
estrogen to treat the symptoms of endometriosis does not
address the underlying disease process. However, until the
relationship between endocrine and inflammatory pathways
in this condition are further clarified (32), the development
of targeted therapies will remain a challenge.
There are conflicting data in the literature concerning the
efficacy of combined oral contraceptives in this setting. In a
review, Casper considers that progestin-only pills theoreti-
cally constitute a better first-line approach than estroproges-
tins (16) because the dose of ethinyl estradiol in combined oral
contraceptives is equivalent to four to six times the physio-
logical dose of estradiol, which could favor implantation
and proliferation of ectopic endometrial cells.
There are also other concerns about estrogen/progestin
and progestin use (25): two thirds of symptomatic women
experience an improvement in their general condition and
pain relief, but at least one third are non-responders due to
progesterone resistance (18); there is an increased risk of
venous or arterial embolism (15); and the side effects of estro-
gen/progestins are common and related to the dose and type
of progestin used (16).
Concerns about GnRH agonist use are linked essentially
to the need for add-back therapy if long-term treatment is
required (19). In addition to the increased risks and side effects
mentioned, administration of estrogen and/or progestin add-
back complicates therapy and is not approved for long-term
use. Novel safe and effective options are needed, and, with
well-studied GnRH antagonist doses, there is a possibility
that add-back therapy may not be necessary in a majority
of patients (25).
In this phase 2b prospective, dose-finding, randomized,
parallel group, double-blind, placebo-controlled trial, for
the primary endpoint, defined as a response of R30% in
OPP, there were significantly different response rates
compared with placebo (34.5%) at doses of 75 mg (61.5%),
100 mg (56.4%), and 200 mg (56.3%). The response rate in
the 50 mg group (49.4%) was not significantly different to
placebo. A similar pattern was observed for responder rates
of DYS and NMPP, with significant differences compared
with placebo at 12 weeks for doses of 75 mg and greater
but not at 50 mg. The response rates for OPP, DYS, and
NMPP were maintained or increased after 24 weeks of treat-
ment. Furthermore, a significant reduction in OPP was
already evident at 4 to 8 weeks after starting treatment.
Again, a similar pattern was observed for the secondary
endpoints including the following, OPP measured using an
NRS scale, dyschezia, difficulty of doing daily activities, per-
centage of subjects using analgesics, percentage of subjects
with amenorrhea, and the PGIC, with significant changes
compared with placebo at 12 weeks for doses of 75 mg and
greater but not with 50 mg.
There was also a significant reduction compared with pla-
cebo in dyspareunia pain at 12 weeks with 200 mg dose and
not with 50, 75, or 100 mg. It also was observed with another
GnRH antagonist, elagolix, that dyspareunia pain was only
significantly reduced at the highest daily dose (200 mg twice
daily) but not at a lower dose (150 mg once daily), whereas the
other type of EAP had been significantly reduced with both
52
the lower and higher dose (27). It is not clear why dyspareunia
pain may respond differently to treatment with a GnRH
antagonist compared with other types of EAP. However, not
all subjects in these studies had dyspareunia at baseline and
dyspareunia pain can only be reported with sexual activity,
which may be infrequent and vary in frequency due to other
circumstances in the subject’s life. These factors may make
assessment of a change in dyspareunia pain more difficult.
All of these observed significant changes in the primary
and secondary endpoints were consistent with the rapid and
differential suppression of serum estradiol levels across the
dose range of 50 to 200 mg linzagolix, with full suppression
to post-menopausal levels with the highest dose and partial
suppression in the 20 to 60 pg/mL range with the lower doses.
A differential effect of linzagolix also was observed in the
different domains of the EHP-30 questionnaire (Supplemental
Figure 7, available online). For the pain and powerlessness
domains there were significant changes in the domain scores
for all active dose groups (including 50 mg) compared with
placebo, whereas for the other domains of emotional well-
being, social support, and self-image there was consistent sig-
nificant difference to placebo only in the 200 mg dose group.
These results suggest that, although partial suppression of
estradiol has a significant effect on important aspects of
well-being, full suppression with 200 mg had a consistent
effect across more aspects of quality of life affected by
endometriosis.
Changes in the incidence of hypoestrogenic effect such as
BMD decreases and the incidence of vasomotor symptoms
also were consistent with the partial or full suppression of
estradiol at the different linzagolix doses.
Interestingly, with the 75 mg dose, which was the lowest
dose to reduce significantly most symptoms of EAP, mean
BMD loss in the lumbar spine at 24 weeks was -0.80%,
with the lower 95% CI of BMD decrease from baseline to
week 24 at -1.57%. Some minimal changes also were
observed for the femoral neck (-0.33%) and total hip
(-0.46%) in the 75 mg group. These data strongly suggest
that a daily dose of 75 mg could be administered without
the need for hormonal add-back therapy. In contrast, most
subjects on the 200 mg dose showed a BMD decrease of
>3% at 24 weeks, which would necessitate hormonal add-
back therapy for longer-term use. It should be noted that
calcium and vitamin D supplementation were not provided
as part of the trial protocol and, therefore, if these were rec-
ommended consistently in future studies and/or clinical use
then some of the BMD loss observed in this study could be
possibly ameliorated.
The incidence of hot flushes up to week 12 was dose-
dependent, with rates of 10.9% in the placebo group, 19.3%
in the 75 mg group, and 42.1% in the 200 mg group. Similar
dose-related differences were observed up to week 24 between
the 75 mg and 200 mg groups. The incidence of headaches,
the most frequently reported TEAE, was 20%–30% in all
groups, including the placebo group.
There were small percentage increases in LDL cholesterol,
HDL cholesterol, LDL to HDL ratio, and triglycerides after 12
weeks, which did not increase further at 24 weeks. The highest
increases were observed generally in the highest dose group
VOL. 114 NO. 1 / JULY 2020

(except LDL to HDL ratio). Similar increases in lipids were
reported after 6 months of treatment with another GnRH
antagonist (27). These small percentage increases did not
result in an increased number of patients reaching levels of
concern for LDL cholesterol (>160 mg/dL) or triglycerides
(>200 mg/dL); after 24 weeks, <0.5% of subjects receiving
linzagolix had shifts in LDL cholesterol from <160 mg/dL
to >190 mg/dL or in triglycerides from <300 mg/dL to
>500 mg/dL.
After 12 and 24 weeks of linzagolix treatment, reductions
in endometrial thickness and uterine volume from baseline
were more significant at the higher doses of 100 and 200
mg; endometrial biopsy results did not raise any safety con-
cerns. Two subjects receiving 100 mg linzagolix had asymp-
tomatic increases equivalent to R3 x ULN for both ALT and
AST, not accompanied by increases in bilirubin.
Four pregnancies occurred in this trial despite subjects
being instructed to use non-hormonal double-barrier
contraception. Although GnRH antagonism suppresses
ovulation, it has not been demonstrated to be contraceptive
even at full suppression. Further studies would be required
to evaluate whether hormonal contraception such as
progestogen-only contraceptives could be used at the same
time as linzagolix.
The strengths of this trial were that it was a multinational,
multi-center, randomized, placebo-controlled trial in patients
with surgically confirmed endometriosis and confirmed
moderate-to-severe endometriosis pain at baseline, in which
four different doses of linzagolix were compared with
placebo. Assessments of pain were based primarily on
patient-reported outcomes recorded daily into electronic
diaries using validated scales for EAP. Other comprehensive
assessments included quality of life, uterine bleeding, and
serum estradiol (using a highly sensitive assay). Safety assess-
ments included a controlled assessment of BMD loss at 24
weeks.
The limitations of this trial were that the placebo control
was only for 12 weeks, pairwise comparisons were made only
between each active group and placebo, and the presented re-
sults are only for up to 24 weeks of treatment. Longer-term
treatment in the trial extension will provide further informa-
tion and larger confirmatory trials, ideally with longer-term
placebo control, are required.
In conclusion, in the present clinical trial, once-daily
doses of 75 mg, 100 mg, and 200 mg linzagolix significantly
reduced EAP and improved quality of life. Moreover, a dose of
75 mg linzagolix daily was identified that provided signifi-
cant decrease in EAP but minimal BMD loss, with partial sup-
pression of serum estradiol, consistent with the estrogen
threshold hypothesis of Barbieri (26). These characteristics
suggest that the 75 mg dose could be suitable for chronic
treatment of EAP without the need for concomitant hormonal
add-back therapy.
Nevertheless, consistent with full suppression of serum
estradiol to post-menopausal levels, once-daily 200 mg linza-
golix provided additional significant efficacy on dyspareunia
and some aspects of quality of life. However, a higher rate of
hypoestrogenic symptoms were observed, importantly a BMD
loss of R3% after 24 weeks, indicating that a once-daily 200
VOL. 114 NO. 1 / JULY 2020
Fertility and Sterility®
mg dose will require hormonal add-back therapy for treat-
ment with linzagolix for longer than 6 months.
The 75 mg alone and 200 mg (with hormonal add-back)
doses have been selected for further testing for the treatment
of EAP in two large confirmatory phase 3 trials, which will
allow a more comprehensive assessment of the efficacy and
safety of linzagolix, and to test more clearly the estrogen
threshold hypothesis.
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 Fertility and Sterility®

Tratamiento del dolor asociado a la endometriosis con linzagolix, un antagonista de la hormona liberadora de gonadotropina (GnRH)
oral: un ensayo clínico aleatorizado
Objetivo: estudiar el efecto de un nuevo antagonista oral de la hormona liberadora de gonadotropina en investigaci

on, linzagolix, en el
dolor asociado a la endometriosis (EAP).
~o: un ensayo multinacional, de grupos paralelos, aleatorizado, controlado con placebo, doble ciego y de rango de dosis.
Disen
Lugar: centros clínicos.
Paciente (s): Mujeres de 18 a 45 a~
nos con endometriosis confirmada quir

urgicamente y EAP moderado a severa.
Intervenci
on (es): las intervenciones fueron 50, 75, 100 o 200 mg de linzagolix (o placebo equivalente) administrado una vez al día
durante 24 semanas.
Medida (s) principal (es) de resultado: El objetivo primario final fue el n
umero de respondedores (reducci
on de >30% en el dolor
p
elvico general) despu
es de 12 semanas. Otros objetivos incluyeron dismenorrea, dolor p
elvico no menstrual, estradiol s
erico, amenor-
rea, calidad de vida (QoL) medidas y densidad mineral o
sea (DMO).
Resultado (s): en comparaci
on con placebo, las dosis de R75 mg dieron como resultado una proporci
on significativamente mayor de
respondedores para el dolor p
elvico general en 12 semanas (34.5%, 61.5%, 56.4% y 56.3% para placebo, 75, 100 y 200 mg, respecti-
vamente). Se observ
o un patr

on similar para la dismenorrea y el dolor p
elvico no menstrual. Los efectos se mantuvieron o aumentaron
a las 24 semanas. El estradiol s
erico se suprimi

o, la calidad de vida mejor

o, y la tasa de amenorrea aument
o de forma dependiente de la
dosis. La p
erdida media de DMO (columna vertebral) a las 24 semanas fue <1% a dosis de 50 y 75 mg y aument
o de forma dependiente de
la dosis hasta 2.6% por 200 mg. La DMO del cuello femoral y la cadera total mostr
o un patr

on similar.
Conclusi
on (es): Linzagolix redujo significativamente la EAP y mejor

o la calidad de vida a dosis de 75–200 mg y disminuy

o la DMO de
forma dosis-dependiente.

VOL. 114 NO. 1 / JULY 2020 55