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Reprint requests: Kristof Chwalisz, M.D., Ph.D., Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, Michigan.
Elagolix is the first oral gonadotropin-releasing hormone antagonist that entered clinical development and received regulatory approval for the management of women with endometriosis and heavy menstrual bleeding associated with uterine fibroids in combination with a hormonal add-back therapy. This mini review aims to summarize the key clinical studies that led to its regulatory approval.
Oral gonadotropin-releasing hormone (GnRH) antagonists represent a new treatment option for the treatment of ovarian hormone–dependent diseases in women, including endometriosis and uterine fibroids. Both injectable and oral GnRH antagonists competitively inhibit GnRH receptors in the pituitary gland and lead to a rapid and dose-dependent reduction in circulating gonadotropins and ovarian sex hormones, including estradiol (E2) (
). Therefore, oral GnRH antagonists provide a potential for adjusting the dose to balance efficacy and safety, which cannot be achieved with depot GnRH agonists and has not been clinically implemented with injectable GnRH antagonists (
). Elagolix is the first oral nonpeptide GnRH antagonist that have been approved by the US Food and Drug Administration for the management of endometriosis (trade name Orilissa, AbbVie Inc., North Chicago, IL) and heavy menstrual bleeding (HMB) associated with uterine fibroids in combination with hormonal add-back therapy (trade name Oriannh, AbbVie Inc., North Chicago, IL).
The cloning of the human GnRH receptor and its characterization was a starting point for drug discovery of small molecules that bind to this receptor using high-throughput screening (
). A focused drug discovery program of oral GnRH antagonists at Neurocrine Biosciences (San Diego, CA) led to the discovery of several lead compounds, including elagolix (Fig. 1), which was selected for clinical development (
3-[(2R)-amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization.
Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor.
This review was based on a PubMed search for human studies with elagolix conducted to date with focus on advanced phase II and III studies.
Phase I Studies
Elagolix was evaluated in a large phase I study in healthy premenopausal women during 21 days of continuous administration of increasing elagolix doses up to 400 mg 2 times per day (
). The results of this study demonstrated a dose-dependent suppression of luteinizing hormone, follicle-stimulating hormone, and E2 within hours of elagolix administration on day 1 of treatment and a rapid reversibility of these effects after stopping therapy. The E2 suppression reached a maximum using elagolix at a dose of 200 mg 2 times per day and inhibition of ovulation at elagolix doses of ≥100 mg 2 times per day (Fig. 2). Elagolix demonstrated an acceptable safety profile, with hot flushes being the most frequent adverse event (AE). The results of this study defined the elagolix doses that produce either partial or near-full E2 suppression and provided the rationale for dose selection for consecutive phase II and III studies in women with endometriosis and uterine fibroids.
Figure 2Dose-dependent suppression of gonadotropins (luteinizing hormone [LH], follicle-stimulating hormone [FSH]), estradiol (E2), and progesterone (P) in healthy premenopausal women. Concentrations (means ± SD) of (A) FSH, (B) LH, (C) E2, and (D) P during 21 days of dosing with placebo or elagolix. For the placebo group, the error bars for some time points have been truncated. (From Ng et al. [
). These studies showed that elagolix is a weak-to-moderate inducer of CYP3A and may decrease plasma concentrations of drugs that are substrates for this enzyme, for example, midazolam. Because CYP3A has been implicated in the metabolism of continuous oral contraceptives (COCs), drug interaction studies of elagolix 150 mg once daily were conducted with the progestin norethindrone and a triphasic COC containing ethinyl E2 and norgestimate (
). No clinically relevant changes in plasma progestin concentrations were observed, suggesting that elagolix is unlikely to reduce the contraceptive efficacy of progestin-only contraceptives and COCs.
Phase II and III studies in women with endometriosis
Phase II Studies
Endometriosis is an estrogen-dependent disease, and lowering of estrogen levels is associated with both improvement in symptoms and reduction in disease progression (
). Neurocrine Biosciences conducted 6 phase II studies with elagolix in women with laparoscopically diagnosed endometriosis with moderate to severe pain (
). The overall objective of these studies was to evaluate the safety and efficacy of elagolix at low doses (ranging from 50 to 250 mg once daily and 75 mg 2 times per day) that produce partial E2 suppression. These studies differed in design, comparator group (placebo, depot medroxyprogesterone acetate, and leuprolide acetate), pain assessment methods, and quality of life instruments (5). The last of these studies (8-week placebo-controlled study of elagolix 150 mg once daily vs. placebo) that used a novel electronic, highly sensitive, daily, 4-point pain-impact diary showed statistically significant reductions in both dysmenorrhea and nonmenstrual pelvic pain (NMPP) vs. placebo at week 8. This diary was used in subsequent phase III studies that were conducted by Abbott Laboratories and AbbVie Inc. (North Chicago, IL). The treatment with elagolix was generally well tolerated in phase II studies, with headache, hot flush, and nausea being the most frequent AEs (
) with 2 elagolix doses (150 mg once daily and 200 mg 2 times per day) and 2 double-blind, randomized, 6-month extension studies (Elaris EM-III and Elaris EM-IV) (
) in women with surgically diagnosed endometriosis with moderate to severe endometriosis-associated pain.
Placebo-controlled phase III trials (Elaris EM-I and Elaris EM-II)
The Elaris EM-I (n = 872) and Elaris EM-II (n = 817) studies had a similar design but included a different population; Elaris EM-I was conducted in the United States, whereas Elaris EM-II was a global study. Most women (74.9% and 77.4% in Elaris EM-I and EM-II, respectively) completed these studies. There were 2 primary efficacy end points in these trials: the proportion of women who showed clinically meaningful responses (pain reduction and stable/decreased rescue analgesic use) with respect to dysmenorrhea and NMPP at month 3 of treatment assessed using the validated, electronic, daily 4-point pain-impact diary (
). Key secondary efficacy end points included the following: mean changes from baseline to month 3 in endometriosis-associated pain, as assessed with the 11-point numeric rating scale; reductions from baseline in dysmenorrhea and NMPP at month 6; use of rescue analgesics at months 3 and 6; significant change from baseline in dyspareunia at month 3; and use of rescue opioids at month 3. Additional efficacy end points included improvements in Patient Global Impression of Change and the 30-item Endometriosis Health Profile quality of life questionnaire. Safety evaluations included endometrial assessment, laboratory measures, and changes in bone mineral density (BMD).
Both elagolix doses (150 mg once daily or 200 mg 2 times per day) resulted in a significantly greater proportion of women with a clinically meaningful response with respect to dysmenorrhea and NMPP than that using the placebo at month 3 (primary efficacy end points) and month 6 (Fig. 3). These effects were dose-dependent. Both elagolix doses resulted in a significant reduction from baseline to month 3 in the numeric rating scale score and significant reductions from baseline to month 6 in dysmenorrhea and NMPP compared with placebo (secondary efficacy end points). However, only elagolix 200 mg 2 times per day significantly reduced dyspareunia and the use of rescue analgesic agents at 3 and 6 months compared with placebo. Consistent with the improvement in pain, significantly more women taking either the dose of elagolix reported “much” or “very much” improvement on the Patient Global Impression of Change scale at 6 months than women who received placebo. Both elagolix doses resulted in a better quality of life on the basis of the mean change from baseline to 3 and 6 months on the dimensions of the 30-item Endometriosis Health Profile compared with the placebo group.
Figure 3Reduction in dysmenorrhea and nonmenstrual pelvic pain during treatment with elagolix in women with endometriosis-associated pain (Elaris EM-I and EM-II studies). The percentages of women in whom the 2 primary end points (clinically meaningful reduction in dysmenorrhea or in nonmenstrual pelvic pain, as measured by the decreased or stable use of rescue analgesic agents) were reported at 3 and 6 months in (A) Elaris EM-I and (B) Elaris EM-II. In Elaris EM-I, 3-month data were provided for 373 women who received placebo, 248 who received the lower elagolix dose (150 mg once daily), and 244 who received the higher elagolix dose (200 mg twice daily); the corresponding 6-month data were provided for 372, 247, and 243 women. In Elaris EM-II, 3-month data were provided for 353 women who received placebo, 221 who received the lower elagolix dose, and 225 who received the higher elagolix dose; the corresponding 6-month data were provided for 355, 221, and 225 women. EM = endometriosis; CI = confidence interval. (From Taylor et al. [
The most frequently reported AEs in each trial were hot flushes, headache, and nausea. The rate of hot flushes was significantly higher with each dose of elagolix compared with that with placebo. The severity of hot flushes in elagolix groups was mild or moderate in most women, and the discontinuation rate because of hot flushes was low (<1% with elagolix 150 mg once daily and 3% with elagolix 200 mg 2 times per day). There was a significant dose-dependent decrease in the spine, total hip, and femoral neck BMDs at month 6 of treatment in both elagolix groups compared with that with placebo (with the exception of the femoral neck BMD at elagolix 150 mg once daily). The changes in the lumbar spine BMD at month 6 ranged between −0.32% and −0.72% at elagolix 150 mg once daily and −2.61% and −2.49% at 200 mg 2 times per day. Asymptomatic elevations in the alanine aminotransferase (up to 3 times the upper reference range) were observed in a small percentage of women in both elagolix groups compared with that in placebo (150 mg once daily, 1/450, 0.2%; 200 mg 2 times per day, 5/443, 1.1%; placebo, 1/696, 0.1%), and no cases of liver injury were attributed to elagolix treatment.
Phase III extension studies (Elaris EM-III and Elaris EM-IV)
The objective of Elaris EM-III and Elaris EM-IV studies was to evaluate the long-term outcomes after an additional 6 months of treatment (total of 12 months of continuous treatment) (
). These studies consisted of a 6-month treatment period and a posttreatment follow-up period of up to 12 months. Women who were on active treatment in Elaris EM-I and Elaris EM-II trials received the same elagolix dose in the extension studies, whereas women who received placebo in the preceding studies were rerandomized to each elagolix dose group. Both studies used similar efficacy and safety end points as the preceding placebo-controlled phase III trials.
The results of the phase III extension studies showed that long-term elagolix treatment (up to 12 months) provided sustained reductions in dysmenorrhea, NMPP, and dyspareunia, as demonstrated by clinically meaningful response to treatment and changes from baseline in pain scores (Fig. 4), which were comparable with those observed in placebo-controlled preceding phase III studies.
Figure 4Mean percentage change from baseline in the dysmenorrhea, nonmenstrual pelvic, and dyspareunia pain scores during the long-term treatment with elagolix in women with endometriosis-associated pain (Elaris EM-III and EM-IV studies). Mean percentage change from baseline in the (A and D) dysmenorrhea, (B and E) nonmenstrual pelvic pain, and (C and F) dyspareunia scores. Error bars represent 95% confidence intervals. Between-group comparisons were not predefined and not performed. Months 1–6 in Elaris EM-I and Elaris EM-II were from women who enrolled in the extension studies Elaris EM-II and Elaris EM-IV. EM = endometriosis. (From Surrey et al. [
No new safety concerns were identified in the extension studies. The most common AEs were hot flushes, headache, and nausea. The incidence of hot flushes was dose-dependent, with the maximum severity of mild to moderate in most women. The mean percentage changes from baseline in the lumbar spine BMD in Elaris EM-III and Elaris EM-IV were −0.63% and −1.1% with elagolix 150 mg once daily and −3.60% and −3.91% with elagolix 200 mg 2 times per day, respectively. There was a continuous recovery from BMD decreases during the posttreatment follow-up period.
Phase II and III studies in women with heavy menstrual bleeding and uterine fibroids
Because uterine fibroids growth and bleeding symptoms are mostly progesterone-dependent, all clinical phase II and III studies were focused on higher elagolix doses that inhibit ovulation. These doses require hormonal add-back therapy for chronic treatment. All phase II and III studies were conducted by AbbVie Inc. (North Chicago, IL).
Phase II Studies
The safety and efficacy of elagolix vs. placebo and elagolix with low-dose add-back therapy was evaluated in a proof-of-concept (phase IIa), dose-ranging, multiple-cohort study in premenopausal women with fibroids and HMB,(menstrual blood loss [MBL], >80 mL per cycle) (
Women (n = 271) were treated for 3 months with elagolix alone (100 mg 2 times per day, 200 mg 2 times per day, 300 mg 2 times per day, 400 mg once daily, or 600 mg once daily [all but the 600 mg once daily arm were placebo-controlled]) or elagolix plus add-back therapy (200 mg 2 times per day plus continuous low-dose E2 0.5 mg/norethindrone acetate [NETA] 0.1 mg or elagolix 300 mg 2 times per day plus E2 1 mg continuously and cyclic progesterone 200 mg). The main outcome efficacy and safety measures were the mean percentage change in MBL and AEs, respectively. The mean age was 41.8 years; 73.8% were black; the mean baseline MBL was 267 mL. The MBL percentage change from baseline to the last month was significantly greater with elagolix alone and was dose-dependent (range, −72% to −98% vs. placebo [range, −8% to −41%]); the mean percentage changes with add-back regimens were −80% to −85%. Hot flush was the most common AE. The study concluded that elagolix significantly reduced HMB in women with fibroids and low-dose add-back regimens substantially reduced flushing with marginal effects on efficacy.
The selected treatment regimens were further evaluated in a large (n = 571) phase IIb study of a 6-month treatment duration (
). This placebo-controlled study evaluated the efficacy and safety of elagolix in cohorts 1 (300 mg 2 times per day) and 2 (600 mg once daily) with 4 arms per cohort: placebo; elagolix alone; elagolix with 0.5 mg E2/0.1 mg NETA; and elagolix with 1.0 mg E2/0.5 mg NETA. The composite primary end point was the percentage of women who had <80 mL of MBL and ≥50% reduction in MBL from baseline to the last 28 days of treatment. Safety assessments included changes in the BMD. The results of this study showed that elagolix with and without add-back therapy significantly reduced MBL (responder rates, elagolix groups, >73%, and placebo, 27%) in women with uterine fibroids. Add-back therapy reduced the hypoestrogenic effects, including a decrease in the BMD.
Phase III Studies
The phase III program consisted of 2 identical, double-blind, randomized, placebo-controlled, 6-month phase III trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) (
The UF-1 (n = 412) and UF-2 (n = 378) trials evaluated the efficacy and safety of elagolix 300 mg 2 times per day with hormonal add-back therapy (E2 1 mg and NETA 0.5 mg once daily) in women with fibroid-associated bleeding during treatment for 6 months (
). The primary end point was MBL of <80 mL during the final month of treatment and at least a 50% reduction in MBL from baseline to the final month. The key secondary efficacy end points included changes in additional bleeding parameters, increases in the hemoglobin levels, and impact on symptoms using the Uterine Fibroid Symptom and Quality of Life questionnaire.
Approximately 68% of the women who were enrolled in these studies were black, which is consistent with the uterine fibroid epidemiology. In the elagolix alone groups, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2 (Fig. 5). In addition, in the elagolix plus add-back groups a greater percentage of women showed an increase in hemoglobin levels more than 2 g/100 mL (from a baseline level of 10.5 g/100 mL or less) compared to placebo. These treatments were associated with significant improvements in scores on the Uterine Fibroid Symptom and Quality of Life questionnaire. Hot flushes (the most common AE) were significantly more common with elagolix plus add-back therapy (20.4% and 19.6%, respectively, in UF-1 and UF-2) and elagolix alone (64.4% and 43%) than with placebo (8.8% and 4%). The hypoestrogenic effects of elagolix, especially decreases in the BMD, were attenuated with add-back therapy.
Figure 5Reduction in heavy menstrual bleeding in women with uterine fibroids. The percentages of women who met the criteria for the primary end point (a menstrual blood loss volume of <80 mL in the final month and a >50% reduction in the menstrual blood loss volume from baseline to the final month) in the 2 trials. A significantly greater percentage of women who received elagolix with add-back therapy met the criteria for the primary end point than women who received placebo. The final month was defined as the last 28 days before and including the last treatment period visit date. CI = confidence interval. (From Schlaff et al. [
). The safety and efficacy end points were similar to the placebo-controlled phase III studies. The percentage of women who met the primary end point in this elagolix with add-back group was 87.9% (95% confidence interval, 83.4–92.3) (Fig. 6). The most frequently reported AEs with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). The mean percentage decreases in the BMD from baseline to extension month 6 were significantly lower with elagolix plus add-back therapy than with elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with add-back therapy.
Figure 6Reduction in heavy menstrual bleeding in women with uterine fibroids during long-term treatment. Percentage of women who met (A) the primary end point and (B) mean change from baseline in menstrual blood loss in women treated with up to 12 months of elagolix with add-back therapy. Data are % or mean with error bars indicating 95% confidence interval. Baseline was before first dosing in the Elaris Uterine Fibroids 1 (UF-1) and 2 (UF-2) studies. ∗The mean changes from baseline in menstrual blood loss for UF-1 and UF-2 are presented as least squares means. (From Simon et al. [
Elagolix is the first novel, nonpeptide, orally active GnRH antagonist that has been approved by the Food and Drug Administration in the United States for the management of moderate to severe endometriosis-associated pain and HMB associated with uterine fibroids. Elagolix competitively inhibits GnRH receptors in the pituitary gland and leads to a rapid and dose-dependent reduction in circulating gonadotropins and ovarian sex hormones, including E2.
In women with endometriosis-associated pelvic pain, both higher (200 mg 2 times per day) and lower (150 mg once daily) doses of elagolix were effective in improving dysmenorrhea and NMPP during a 6-month period in the placebo-controlled phase III trials and sustained pain reduction during long-term extension studies. The regulatory approval of elagolix (Orilissa) offers a new medical treatment option for the management of moderate and severe pain associated with endometriosis. The recommended treatment duration with Orilissa in women with normal liver function or mild hepatic impairment is up to 24 months for 150 mg once daily and up to 6 months for 200 mg 2 times per day (
Elagolix (300 mg 2 times per day) with add-back therapy (E2 1 mg and NETA 0.5 mg once daily; Oriannh) was also effective in reducing HMB in women with uterine fibroids. The phase III studies showed that up to 12 months of elagolix plus add-back therapy provides sustained reductions in MBL in women with uterine fibroids. Add-back therapy attenuated the hypoestrogenic effects of elagolix alone with marginal effects on efficacy. This treatment offers an alternative to surgical approaches. The use of Oriannh should be limited to 24 months because of to the risk of continued bone loss, which may not be reversible.
References
Ng J.
Chwalisz K.
Carter D.C.
Klein C.E.
Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women.
3-[(2R)-amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization.
Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor.
K.C., as a former employee of TAP Pharmaceuticals, Abbott Laboratories, and AbbVie Inc., was involved in the clinical development of elagolix and owns AbbVie stock.
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