Development of relugolix combination therapy as a medical treatment option for women with uterine fibroids or endometriosis

After oral administration, relugolix is rapidly absorbed, reaching an initial peak concentration by 15 minutes postdose, followed by multiple subsequent peaks up to 12 hours postdose; the majority of relugolix is absorbed within 6 hours postdose. The multiple postdose peaks are hypothesized to reflect the variable expression of permeability-glycoprotein (P-gp), an intestinal efflux transporter along the gastrointestinal tract, including other factors such as gastric emptying time. Thereafter, plasma concentrations decline in a multi-phasic manner with a terminal phase elimination half-life of 61.5 hours. The absorption of relugolix after oral administration is primarily mediated by P-gp, for which relugolix is a substrate. The intestinal P-gp-mediated efflux of relugolix is thought to limit its oral bioavailability (absolute bioavailability of 11.6%) and governs absorption-mediated drug interactions; therefore, intestinal P-gp is the primary driver of systemic exposure to relugolix. The primary route of elimination of relugolix is metabolism through multiple biotransformation pathways, including CYP3A and CYP2C8, with contributions from renal and biliary excretion of unchanged drug. Co-administration of a 40 mg dose of relugolix with erythromycin, an oral P-gp and moderate CYP3A inhibitor, resulted in a 3.5-fold higher total exposure to relugolix, which is clinically meaningful and considered to be primarily based on the inhibition of intestinal P-gp efflux by erythromycin. Given that the mechanism for P-gp inhibition is a competitive and reversible process and most of the absorption of relugolix is complete by 6 hours postdose, it is recommended to administer relugolix first followed by administration of the oral P-gp inhibitor at least 6 hours afterward, when concomitant use of relugolix and an oral P-gp inhibitor cannot be avoided. Co-administration of relugolix with voriconazole, a strong CYP3A inhibitor devoid of P-gp inhibition, did not increase the exposure to relugolix in a clinically meaningful manner. However, for relugolix-CT, because both E2 and norethindrone (NET; the active form of NETA) undergo oxidative metabolism by CYP enzymes, including CYP3A4, inhibitors of CYP3A may increase the plasma concentrations of E2 or NET. Combined P-gp and strong CYP3A inducers, such as rifampin, decrease the exposure to relugolix, E2, and/or NET. Therefore, co-administration of relugolix-CT with strong CYP3A4 and P-gp inducers may result in a decrease in the therapeutic effects of relugolix-CT. Based on a population pharmacokinetic (PopPK) model developed using relugolix concentration data from across the clinical development program, age did not have a statistically significant effect on the pharmacokinetic parameter estimates for relugolix. Multivariate covariate simulations using the final PopPK model indicated that the effect of the race (Black vs. nonBlack, Asian vs. nonAsian) and body weight on the exposure to relugolix is minimal. In dedicated clinical pharmacology studies, moderate or severe renal impairment and mild or moderate hepatic impairment did not have a clinically meaningful effect on the exposure to relugolix. The effect of end-stage renal disease with or without hemodialysis or severe hepatic impairment has not been evaluated for relugolix. The use of E2 in patients with hepatic disease is contraindicated, and as a result, the administration of relugolix-CT to patients with known hepatic impairment or disease is also contraindicated. The physicochemical and pharmacokinetic characteristics of relugolix are provided in Table 1 . Table 1 Pharmacological characteristics of relugolix. Generic name Relugolix Other codes TAK-385 and T-1331285 (Takeda codes), RVT-601 (Roivant Sciences code), MVT-601 (Myovant code) Chemical name (IUPAC) N -(4-{1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3- (6-methoxypyridazin-3-yl)- 2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d ]pyrimidin-6-yl}phenyl)- N '-methoxyurea Molecular formula C 29 H 27 F 2 N 7 O 5 S Molecular weight 623.63 Route Oral Physical properties White to off-white to light yellow, slightly hygroscopic solid, and practically insoluble in water. In aqueous solutions, it is soluble in 0.1N HCl, sparingly soluble at pH 3.0, slightly soluble at pH 5.0, and practically insoluble at pH 7.0–12.9. In organic solvents, it is freely soluble in dimethyl sulfoxide, soluble in benzyl alcohol, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, acetonitrile, and ethanol. Structure Mechanism of action Gonadotropin-releasing hormone (GnRH) receptor antagonist Absolute bioavailability mean (%CV) 11.6 (62%) AUC 0-inf (ng·hr/mL), mean (SD) † 198.1 (111.6) C max (ng/mL), mean (SD) † 26.0 (18.2) T max (hr), median (min, max) † 2.00 (0.25, 5.00) Distribution Plasma protein binding is 68% to 71% Metabolism CYP3A and, to a lesser extent by CYP2C8 in vitro Excretion Approximately 81% was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged) Terminal phase elimination half-life (t 1/2 ), mean (SD) 61.5 (13.2) hr AUC = area under the concentration-time curve; AUC 0-inf = AUC from time 0 extrapolated to infinity; C max = maximum observed concentration; T max = time to maximum observed concentration. † After single dose administration of relugolix combination therapy. Pharmacological characteristics of relugolix. AUC = area under the concentration-time curve; AUC 0-inf = AUC from time 0 extrapolated to infinity; C max = maximum observed concentration; T max = time to maximum observed concentration. After single dose administration of relugolix combination therapy.

In parallel with the phase 3 program of relugolix monotherapy in Japan, the development of relugolix-CT was envisioned to demonstrate significant symptom relief in women with UF or EM while maintaining E2 concentrations within a range that minimizes the effects of hypoestrogenism associated with relugolix monotherapy, leading to BMD loss and vasomotor symptoms. On administration of relugolix 40 mg alone or relugolix-CT once daily for 6 weeks in healthy premenopausal women, median 24-hour average E2 concentrations were 26 pg/mL higher for relugolix-CT compared with relugolix alone (31.5 pg/mL and 6.2 pg/mL, respectively). The E2 concentrations with relugolix-CT reflect the combined effect of suppression of endogenous E2 production by relugolix and exogenous administration of 1 mg of E2 as a component of relugolix-CT. They are consistent with those observed in the early follicular phase of a natural menstrual cycle and fall within the hypothesized range (ie, 20 to 50 pg/mL) required to minimize BMD loss, enabling the potential for long-term treatment of symptoms of UF ( 17 ) or EM ( 18 ). An open-label, single-cohort study in healthy premenopausal women was conducted to assess the effects of relugolix-CT on ovarian function over an 84-day treatment period and the return of ovulation after discontinuation of treatment. Relugolix-CT inhibited ovulation in 100% of the 67 women who completed the study treatment, with a Hoogland-Skouby Score < 5 during the entire 84-day treatment period. The systemic LH and FSH concentrations were consistently maintained low without preovulatory LH surges during treatment. The addition of a 1 mg dose of E2 as a component of relugolix-CT resulted in median E2 concentrations across all women consistently maintained between 36.8 to 39.1 pg/mL during treatment. All women ovulated or returned to menses after discontinuation of treatment, with a mean time to return to ovulation of 23.5 days ( 23 ). In summary, relugolix-CT was associated with a rapid onset of action, effectively suppressed ovarian function in women of reproductive age, with a rapid return of ovulation within the first cycle after discontinuation of treatment in most women. Relugolix-CT provided systemic E2 concentrations within a therapeutic range that is expected to effectively manage symptoms associated with UF and EM while minimizing the risk for BMD loss and vasomotor symptoms. To demonstrate the safety and efficacy of once daily oral relugolix-CT for the management of UF- or EM-associated symptoms, 2 comprehensive phase 3 clinical programs were designed. The LIBERTY and SPIRIT programs included each 2 replicate, randomized, double-blind, placebo-controlled, multinational, phase 3 studies, with similar designs in premenopausal women 18 to 50 years of age with HMB (defined as MBL volume of > 80 ml) associated with UF or moderate to severe pain associated with EM, respectively ( Fig. 4 ). These patients were randomly allocated (1:1:1) to placebo or relugolix-CT for 24 weeks or to delayed combination therapy (12 weeks relugolix 40 mg monotherapy followed by 12 weeks relugolix-CT therapy). Figure 4 Replicate, double-blind, randomized, placebo-controlled, multinational, phase 3 studies to evaluate relugolix-CT in women with HMB associated with uterine fibroids (LIBERTY) or endometriosis-associated pain (SPIRIT). Relugolix-CT = relugolix combination therapy; HMB = heavy menstrual bleeding. Replicate, double-blind, randomized, placebo-controlled, multinational, phase 3 studies to evaluate relugolix-CT in women with HMB associated with uterine fibroids (LIBERTY) or endometriosis-associated pain (SPIRIT). Relugolix-CT = relugolix combination therapy; HMB = heavy menstrual bleeding. In LIBERTY 1 (L1) and 2 (L2) studies, respectively, 388 and 382 premenopausal women with UF-associated HMB were randomized ( 24 ). The proportion of patients with MBL volume of < 80 mL and at least a 50% reduction from baseline in MBL volume over the last 35 days of treatment, the primary endpoint in these studies, was significantly higher ( P <.001) in the relugolix-CT group (73% in L1 and 71% in L2) relative to the placebo group (19% in L1 and 15% in L2) ( Fig. 5 ). Seven key secondary endpoints were evaluated in both trials ( Table 2 ), of which 6 endpoints (MBL measures, including amenorrhea, pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume but not fibroid volume) were significantly improved with relugolix-CT compared with placebo in both studies. The mean percent decrease in MBL volume from baseline, a key secondary endpoint, was 84.3% in the relugolix-CT group in both trials compared with 23.2% and 15.1% in the placebo group ( P <.001 each) in L1 and L2, respectively. In a secondary analysis of L1 and L2 pooled data, relugolix-CT significantly reduced moderate to severe UF-associated pain in 45.2% of the women compared with 13.9% of women treated with placebo (nominal P <.001) with a significant effect on both menstrual (65.0% relugolix-CT vs. 19.3% placebo; nominal P <.001) and nonmenstrual pain (44.6% relugolix-CT vs. 21.6% placebo; nominal P =.004) ( 25 ). Overall, relugolix-CT was well tolerated, with an incidence of adverse events similar to those observed with a placebo. Vasomotor symptoms, including hot flashes, were the most frequently reported adverse events in the relugolix-CT group (10.6%) and at a higher incidence than in the placebo group (6.6%) in pooled data from both trials ( Table 3 ). Figure 5 Primary endpoint for LIBERTY 1 and 2 studies. The proportion of women responding with MBL volume < 80 mL and ≥ 50% reduction from baseline to week 24 (last 35 days of treatment) in MBL volume. MBL volume measured by alkaline hematin method. Error bars show an upper limit of 95% confidence interval; analysis was conducted using Cochran–Mantel–Haenszel test statistic for proportions stratified by mean MBL at baseline mean and geographic region. MBL = menstrual blood loss; Relugolix-CT = Relugolix Combination Therapy. (From Al-Hendy et al. ( 24 ). Reprinted by permission of the publisher.). Table 2 LIBERTY 1 and 2 key secondary efficacy endpoints. Key secondary efficacy endpoints Placebo Relugolix-CT Difference (95% CI) P value LS mean (SE) % LS mean (SE) % Amenorrhea over last 35 d of treatment period L1 6 52 47 (37 to 56) <.001 L2 3 50 47 (38 to 57) <.001 Menstrual blood loss volume (% change from baseline at wk24) L1 –23.2 (4.6) –84.3 (4.7) −61.1 (−73.5 to −48.6) <.001 L2 –15.1 (5.5) –84.3 (5.5) −69.2 (−84.1 to −54.3) <.001 Bleeding and Pelvic Discomfort scale score (change from baseline at wk24) L1 −16.1 (2.8) −45.0 (2.9) −28.9 (−36.3 to −21.5) <.001 L2 −18.3 (2.9) −51.7 (2.9) 33.4 (−41.2 to −25.5) 2 g/dl at wk 24 † L1 22 50 28 (4 to 53) .038 L2 5 61 56 (37 to 75) <.001 Maximum NRS score ≤1 over last 35 days of treatment period among participants in pain-evaluation subgroup ‡ L1 10 43 33 (18 to 48) <.001 L2 17 47 30 (16 to 44) <.001 Volume of primary uterine fibroid (% change from baseline at wk24) § L1 −0.3 (5.4) −12.4 (5.6) −12.1 (−26.3 to 2.0) .092 L2 −7.4 (5.9) −17.4 (5.9) −10.0 (−25.8 to 5.8) .215 Uterine volume (% change from baseline at wk24) L1 2.2 (3.0) −12.9 (3.1) −15.1 (−23.0 to −7.3) <.001 L2 −1.5 (3.4) −13.8 (3.4) −12.2 (−21.3 to −3.2) .008 Data are n (%) or least squares mean (SE) unless otherwise stated. Changes from baseline at week 24 with adjustment for multiplicity. L1 = LIBERTY 1; L2 = LIBERTY 2; LS = least squares; SE = standard error; CI = confidence interval; NRS = Numerical Rating Scale. The first 4 (L1) and the first 3 and fifth (L2) end points were tested sequentially in the order listed, and the remaining ones were tested using the Hochberg step-up procedure. Adapted from N Engl J Med , Al-Hendy A, Lukes AS, Poindexter AN, Venturella R, Villarroel C, Critchley HOD, et al., Treatment of uterine fibroid symptoms with relugolix combination therapy, 384:630–42. Copyright © (2021) Massachusetts Medical Society. Reprinted with permission. ( 24 ) † Calculated in the subgroup of participants with anemia (hemoglobin level ≤10.5 g per deciliter) at baseline with hemoglobin data reported at week 24, it was tested as the fourth in trial L1 and fifth in trial L2. ‡ Calculated in the subgroup of participants with pain ratings that could be evaluated (maximum NRS score of ≥4 at baseline, with ≥28 days [80% of the last 35 days of the treatment period] of pain scores recorded in an electronic diary); it was tested as the fifth in trial L1 and fourth in trial L2. § P -value did not meet the cutoff for statistical significance according to the Hochberg procedure. Table 3 Adverse reactions occurring in 3% or more of women treated with relugolix-CT and at a greater incidence than placebo in studies LIBERTY 1 and 2. Adverse Reaction Relugolix-CT (N = 254) % Placebo (N = 256) % Vasomotor symptoms ∗ 10.6 6.6 Abnormal uterine bleeding † 6.3 1.2 Alopecia 3.5 0.8 Libido decreased ‡ 3.1 0.4 From: MYFEMBREE Prescribing Information ( 19 ). ∗ Includes hot flashes, hyperhidrosis, or night sweats † Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and irregular menstruation ‡ Includes decreased libido and loss of libido. Relugolix-CT = relugolix combination therapy. Primary endpoint for LIBERTY 1 and 2 studies. The proportion of women responding with MBL volume < 80 mL and ≥ 50% reduction from baseline to week 24 (last 35 days of treatment) in MBL volume. MBL volume measured by alkaline hematin method. Error bars show an upper limit of 95% confidence interval; analysis was conducted using Cochran–Mantel–Haenszel test statistic for proportions stratified by mean MBL at baseline mean and geographic region. MBL = menstrual blood loss; Relugolix-CT = Relugolix Combination Therapy. (From Al-Hendy et al. ( 24 ). Reprinted by permission of the publisher.). LIBERTY 1 and 2 key secondary efficacy endpoints. Data are n (%) or least squares mean (SE) unless otherwise stated. Changes from baseline at week 24 with adjustment for multiplicity. L1 = LIBERTY 1; L2 = LIBERTY 2; LS = least squares; SE = standard error; CI = confidence interval; NRS = Numerical Rating Scale. The first 4 (L1) and the first 3 and fifth (L2) end points were tested sequentially in the order listed, and the remaining ones were tested using the Hochberg step-up procedure. Adapted from N Engl J Med , Al-Hendy A, Lukes AS, Poindexter AN, Venturella R, Villarroel C, Critchley HOD, et al., Treatment of uterine fibroid symptoms with relugolix combination therapy, 384:630–42. Copyright © (2021) Massachusetts Medical Society. Reprinted with permission. ( 24 ) Calculated in the subgroup of participants with anemia (hemoglobin level ≤10.5 g per deciliter) at baseline with hemoglobin data reported at week 24, it was tested as the fourth in trial L1 and fifth in trial L2. Calculated in the subgroup of participants with pain ratings that could be evaluated (maximum NRS score of ≥4 at baseline, with ≥28 days [80% of the last 35 days of the treatment period] of pain scores recorded in an electronic diary); it was tested as the fifth in trial L1 and fourth in trial L2. P -value did not meet the cutoff for statistical significance according to the Hochberg procedure. Adverse reactions occurring in 3% or more of women treated with relugolix-CT and at a greater incidence than placebo in studies LIBERTY 1 and 2. From: MYFEMBREE Prescribing Information ( 19 ). Includes hot flashes, hyperhidrosis, or night sweats Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and irregular menstruation Includes decreased libido and loss of libido. Relugolix-CT = relugolix combination therapy. In the phase 3 SPIRIT 1 (S1) and 2 (S2) studies, respectively, 638 and 623 women with moderate to severe EM-associated pain were randomized. Patients were considered responders if they achieved a mean reduction in Numerical Rating Scale scores of ≥ 2.8 points for dysmenorrhea or ≥ 2.1 points for NMPP with no increase in the use of analgesic medications recorded in a daily eDiary at week 24 or at the end of the treatment pain-assessment period. Significantly higher ( P <.0001) proportion of patients (75%) in the relugolix-CT group in both studies met the dysmenorrhea responder criteria compared with the placebo group (27% in S1 and 30% in S2) ( Fig. 6 ) ( 26 ). Similarly, a significantly greater proportion of patients ( P <.0001) met the NMPP responder criteria in the relugolix-CT groups (59% in S1 and 66% in S2) compared with the placebo groups (40% in S1 and 43% in S2). All secondary endpoints were met in S1, and 6 of 7 key secondary endpoints were met in S2 ( Table 4 ). Relugolix-CT significantly reduced the effect of pain on daily function, assessed by the Endometriosis Health Profile questionnaire (EHP-30) pain domain at week 24 relative to placebo. The mean dysmenorrhea Numerical Rating Scale score rapidly decreased from severe pain at baseline to mild pain by week 8, and this improvement was sustained through week 24, with a decrease from baseline of 73% and 75%, in S1 and S2, respectively. The NMPP also decreased with relugolix-CT, approximately 50%, from moderate pain at baseline to mild pain over 24 weeks in both trials. Relugolix-CT achieved significant improvement in dyspareunia with a mean reduction of 40% and 46% from baseline in S1 and S2, respectively. Significantly higher proportions of women in the relugolix-CT groups were analgesic-free and/or opioid-free at week 24 compared with those in the placebo group. The most common adverse events were headache, nasopharyngitis, and vasomotor symptoms, including hot flashes, as most frequent in both trials ( Table 5 ). Figure 6 Co-Primary Endpoints for SPIRIT 1 and 2 Studies: Dysmenorrhea and Nonmenstrual Pelvic Pain. Error bars show an upper limit of 95% confidence intervals. ∗No increase in analgesic use. Relugolix-CT = relugolix combination therapy; NRS = Numerical Rating Scale. (From Giudice et al. ( 26 ). Reprinted by permission of the Lancet .) Table 4 SPIRIT 1 and 2 co-primary and key secondary efficacy endpoints. Placebo Relugolix-CT Difference (95% CI) P value LS mean (SE) % LS mean (SE) % Dysmenorrhea responders S1 27 75 48 (39 to 56) <.0001 S2 30 75 44.9 (36.2 to 53.5) <.0001 Nonmenstrual pelvic pain responders S1 40 59 18.9 (9.5 to 28.2) <.0001 S2 43 66 23.4 (14.0 to 32.8) <.0001 Change in EHP-30 pain domain∗ S1 –18.7 (1.8) –33.8 (1.8) –15·1 (–19.7 to –10.5) <.0001 S2 –19.9 (1.7) –32.2 (1.7) –12.3 (–16.7 to –7.9) <.0001 Change in dysmenorrhea NRS S1 –1.8 (0.2) –5.1 (0.2) –3.3 (–3.8 to –2.8) <.0001 S2 –2.0 (0.2) –5.1 (0.2) –3.2 (–3.7, too –2.7) <.0001 Change in nonmenstrual pelvic pain NRS S1 –2.0 (0.2) –2.9 (0.2) –0·9 (–1.4 to –0.4) .0002 S2 –2.0 (0.2) –2.7 (0.2) –0·7 (–1.2 to –0.3) .0012 Change in overall pelvic pain NRS S1 –1.9 (0.2) –3.1 (0.2) –1·1 (–1.6 to –0.7) <.0001 S2 –2.0 (0.2) –2.9 (0.2) –0.9 (–1.4 to –0.5) <.0001 Patients not using opioids during treatment S1 76 86 9.4 (2.0 to 16.8) .0005 S2 66 82 15.9 (7.5 to 24.2) <.0001 Change in dyspareunia NRS S1 –1.7 (0.2) –2.4 (0.2) –0.7 (–1.3 to –0.1) .0149 S2 1.9 (0.2) –2.4 (0.2) –0.5 (–1.0 to 0.0) .0371 Patients not using analgesics for endometriosis-associated pain during treatment † S1 31 56 25.5 (16.4 to 34.6) <.0001 S2 24 54 30.8 (21.9 to 39.8) <.0001 Change in daily analgesic use ‡ S1 –0.4 (0.1) –0.5 (0.1) –0.1 (–0.3 to 0.1) .4094 S2 –0.4 (0.1) –0.5 (0.1) –0·1 (–0.3 to 0.0) .1141 Data are n (%) or least squares mean (SE) unless otherwise stated. Changes from baseline at week 24. Relugolix-CT = relugolix combination therapy; S1 = SPIRIT 1; S2 = SPIRIT 2; LS = least squares; SE = standard error; CI = confidence interval; NRS = Numerical Rating Scale. EHP-30 = Endometriosis Health Profile∗ 30-item questionnaire to evaluate the effect of pain on normal daily activity, including the ability to stand, sit, walk, exercise, sleep, participate in social events and jobs, and the effect on appetite. † SPIRIT2 and ‡ SPIRIT 1, data from a post-hoc exploratory analysis. Adapted from The Lancet , Giudice LC, As-Sanie S, Arjona Ferreira JC, Becker CM, Abrao MS, Lessey BA, et al, Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: 2 replicate phase 3, randomized, double-blind, studies (SPIRIT 1 and 2), 2022;399:2267–79. Creative Commons License (CC BY 4.0). ( 26 ) Table 5 Adverse reactions occurring in 3% or more of women treated with relugolix-CT and at a greater incidence than placebo in studies SPIRIT 1 and 2. Adverse Reaction Relugolix-CT (N = 418) % Placebo (N = 416) %  Headache 33.0 26.4 Vasomotor symptoms ∗ 13.2 7.2  Nasopharyngitis 10.0 7.0  Mood disorders † 9.1 7.2 Abnormal uterine bleeding ‡ 6.7 4.6  Nausea 6.0 4.1  Toothache 5.5 2.4  Back pain 4.8 2.9 Decreased sexual desire and arousal § 4.3 1.2  Bone density decreased 3.8 2.2  Urinary tract infection 3.6 2.6  Arthralgia 3.6 2.2  Influenza 3.3 2.4  Fatigue 3.1 2.4  Dizziness 3.1 1.2 From: MYFEMBREE Prescribing Information ( 19 ). ∗ Includes hot flashes, hyperhidrosis, night sweats, and flushing. † Includes affect lability, affective disorder, anxiety, depressed mood, depression, emotional distress, generalized anxiety disorder, irritability, mixed anxiety and depressive disorder, mood altered, mood swings, and suicidal ideation ‡ Includes menorrhagia, metrorrhagia, vaginal hemorrhage, uterine hemorrhage, polymenorrhea, and menstruation irregular § Includes libido decreased, libido disorder, and female sexual arousal disorder. Relugolix-CT = relugolix combination therapy. Co-Primary Endpoints for SPIRIT 1 and 2 Studies: Dysmenorrhea and Nonmenstrual Pelvic Pain. Error bars show an upper limit of 95% confidence intervals. ∗No increase in analgesic use. Relugolix-CT = relugolix combination therapy; NRS = Numerical Rating Scale. (From Giudice et al. ( 26 ). Reprinted by permission of the Lancet .) SPIRIT 1 and 2 co-primary and key secondary efficacy endpoints. Data are n (%) or least squares mean (SE) unless otherwise stated. Changes from baseline at week 24. Relugolix-CT = relugolix combination therapy; S1 = SPIRIT 1; S2 = SPIRIT 2; LS = least squares; SE = standard error; CI = confidence interval; NRS = Numerical Rating Scale. EHP-30 = Endometriosis Health Profile∗ 30-item questionnaire to evaluate the effect of pain on normal daily activity, including the ability to stand, sit, walk, exercise, sleep, participate in social events and jobs, and the effect on appetite. † SPIRIT2 and ‡ SPIRIT 1, data from a post-hoc exploratory analysis. Adapted from The Lancet , Giudice LC, As-Sanie S, Arjona Ferreira JC, Becker CM, Abrao MS, Lessey BA, et al, Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: 2 replicate phase 3, randomized, double-blind, studies (SPIRIT 1 and 2), 2022;399:2267–79. Creative Commons License (CC BY 4.0). ( 26 ) Adverse reactions occurring in 3% or more of women treated with relugolix-CT and at a greater incidence than placebo in studies SPIRIT 1 and 2. From: MYFEMBREE Prescribing Information ( 19 ). Includes hot flashes, hyperhidrosis, night sweats, and flushing. Includes affect lability, affective disorder, anxiety, depressed mood, depression, emotional distress, generalized anxiety disorder, irritability, mixed anxiety and depressive disorder, mood altered, mood swings, and suicidal ideation Includes menorrhagia, metrorrhagia, vaginal hemorrhage, uterine hemorrhage, polymenorrhea, and menstruation irregular Includes libido decreased, libido disorder, and female sexual arousal disorder. Relugolix-CT = relugolix combination therapy. In general, relugolix-CT minimized the incidence of hot flashes associated with relugolix monotherapy. In studies L1 and L2, and S1 and S2, hot flashes were reported in 3% to 10% of the participants in the placebo groups, 6% to 14% of those in the relugolix-CT groups, and 34% to 36 % of those in the delayed relugolix-CT groups ( 24 , 26 ). To evaluate the benefit/risk profile and demonstrate the long-term safety of relugolix-CT, changes in BMD were assessed. Overall, least squares mean percentage change in lumbar spine BMD from baseline in the relugolix-CT groups was < 1% in all 4 studies, and in the delayed relugolix-CT group was -1.82% in L1, -2.12% in L2, –2.0% in S1, and –1.9% in S2 at week 24. As expected, lumbar spine and total hip BMD decreased from baseline with relugolix monotherapy at week 12 but stabilized after relugolix-CT initiation ( Fig. 7 ) ( 24 , 26 ). Figure 7 LS Mean Percent Change in Lumbar Spine BMD from LIBERTY 1 and 2 ( A ) and SPIRIT 1 and 2 ( B ) studies. Error bars show the upper and lower limit of 95% confidence intervals. Delayed relugolix-CT = 12 weeks relugolix monotherapy, then 12 weeks relugolix-CT. BMD = bone mineral density; relugolix-CT = relugolix combination therapy. A (From Al-Hendy et al. ( 24 ). Reprinted by permission of the publisher.) ( 24 ). B – (From Giudice et al. ( 26 ). Reprinted by permission of the Lancet .). LS Mean Percent Change in Lumbar Spine BMD from LIBERTY 1 and 2 ( A ) and SPIRIT 1 and 2 ( B ) studies. Error bars show the upper and lower limit of 95% confidence intervals. Delayed relugolix-CT = 12 weeks relugolix monotherapy, then 12 weeks relugolix-CT. BMD = bone mineral density; relugolix-CT = relugolix combination therapy. A (From Al-Hendy et al. ( 24 ). Reprinted by permission of the publisher.) ( 24 ). B – (From Giudice et al. ( 26 ). Reprinted by permission of the Lancet .). These 4 phase 3 pivotal trials showed that relugolix-CT reduced the UF-associated HMB and EM-associated pain when compared with placebo, without substantive hypoestrogenic effects, over a 24-week period. Both programs had extension periods comprising women treated with relugolix-CT for up to 104 weeks ( Fig. 4 ). Eligibility criteria excluded women who had a Z-score < –2.0 or had a ≥ 7% BMD decrease from the pivotal study baseline at lumbar spine, total hip, or femoral neck based on the pivotal study week 24 dual-energy X-ray absorptiometry assessment of BMD. These long-term extension studies demonstrated sustained efficacy with symptom control without new safety signals identified over a longer treatment period. In the LIBERTY program, women who participated and met the responder criteria at one year in the long-term extension study were eligible to enroll in a randomized withdrawal study. The study evaluated efficacy and safety in patients re-randomized 1:1 to continue with blinded treatment with relugolix-CT or switch to placebo for up to additional 52 weeks, totaling 104 weeks. There was evidence of the durability of the effect in maintaining low MBL volume in women who continued with relugolix-CT. The HMB returned in most women who received a placebo. Re-treatment with relugolix-CT in women with HMB relapse was associated with a reduction in MBL volume to < 80 mL. No meaningful changes in BMD or new safety signals were observed with relugolix-CT over the 52-week treatment period. In phase 3 pivotal and long-term extension LIBERTY and SPIRIT studies, relugolix-CT provided sustained symptom relief to women with UF and EM, respectively, while maintaining BMD. The Food and Drug Administration approved relugolix-CT, as MYFEMBREE, for the management of HMB associated with UF on 26 May 2021 and the management of moderate to severe pain associated with EM on 5 August 2022 in premenopausal women, with a treatment duration up to 24 months ( 19 ). Relugolix-CT was approved for the management of symptoms associated with UF in the EU and UK, as RYEQO, in July and August 2021, respectively ( 20 ). A study (SERENE, NCT04756037 ) assessing the contraceptive efficacy and safety of relugolix-CT in women with UF and EM who are at risk for pregnancy is currently ongoing.

In summary, the comprehensive development program of relugolix led to the approval of the first and only once daily GnRH receptor antagonist combination product indicated for the management of both HMB associated with UF and moderate to severe pain associated with EM.

Relugolix is an antagonist of the human GnRH receptor that competitively binds to the GnRH receptor with subnanomolar binding affinity. In a phase 1 study, in which single 1- to 80-mg doses of relugolix were administered to healthy premenopausal women, rapid (within hours), dose-dependent (with respect to degree and duration) decreases in circulating concentrations of the pituitary (LH, FSH), and ovarian (E2 and P) hormones were observed. At 24 hours postdose, mean E2 concentrations for the 40- and 80-mg doses of relugolix were similar (30.2 pg/mL and 30.3 pg/mL, respectively), suggesting that doses higher than 40 mg are unlikely to provide further suppression of E2 concentrations with once daily administration. The rapid decrease in pituitary and ovarian hormone concentrations after dosing is consistent with the rapid absorption of relugolix and its mechanism of action as a GnRH receptor antagonist. Notably, relugolix trough concentrations at steady state, the lowest concentration during once daily administration, are 7.5 times the half maximal inhibitory concentration (IC 50 ; 0.32 nM) and approximately equivalent to the IC 90 value (2.6 nM) for the GnRH receptor. On multiple-dose administration of relugolix, initial decreases in pituitary and ovarian hormone concentrations are consistently maintained during once daily administration through the 24-hour dosing interval, reflecting a sustained suppression of the hypothalamus-pituitary-gonadal axis. Specifically for E2, mean concentrations on day 14 measured at various postdose time points were consistently low (range: 3.9 to 4.7 pg/mL), demonstrating that after administration of a 40-mg dose of relugolix E2 concentrations are maintained low and stable over the entire 24-hour dosing interval. Collectively, these data demonstrated that decreases in pituitary and ovarian hormone concentrations were achieved at all doses, but doses higher than 40 mg would not achieve greater reductions. Therefore, 10-, 20-, and 40-mg once daily doses were selected for further evaluation in the phase 2 studies in women with UF and EM.