Hormone Add-back Therapy Research Articles

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial

Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200mg twice daily with 1mg estradiol/0.5mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200mg twice daily with add-back therapy, elagolix 200mg twice daily monotherapy for 6months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of-2.43% (lumbar spine),-1.54% (total hip), and-1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of-1.58% to-1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and12. Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5mg as the morning dose and an elagolix 300mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300mg/1mg/0.5mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Oral GnRH Antagonists in Combination with Estradiol and Norethindrone Acetate for Pain Relief Associated with Endometriosis: A Review of Evidence of a Novel Class of Hormonal Agents.

Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

O-027 Efficacy results from a phase 3, randomized, placebo-controlled trial testing two doses of linzagolix in women with endometriosis-associated pain

Abstract Study question Does once-daily linzagolix for up to 6 months reduce the pain symptoms in women with endometriosis? Summary answer Once-daily oral use of the GnRH agonist linzagolix alone or in combination with combined hormonal add-back therapy (ABT) for 24 weeks improved endometriosis-associated pain symptoms. What is known already Linzagolix is an oral GnRH antagonist under development to treat endometriosis-associated pain (EAP). In the EDELWEISS 3 study linzagolix 200mg+ABT met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) in a clinically meaningful fashion along with a stable or decreased use of analgesics. Linzagolix 75mg significantly reduced DYS but not NMPP. Secondary endpoints were DYS, NMPP, overall pelvic pain, dyschezia, and dyspareunia at 6 months assessed with a numeric and/or verbal rating scale (NRS and/or VRS), and interference of pain with daily activities assessed with the Endometriosis-Health-Profile-30 (EHP-30) pain domain. Study design, size, duration EDELWEISS 3 was a randomized, double-blind, placebo-controlled Phase 3 study, investigating efficacy and safety of linzagolix 75mg and linzagolix 200mg with ABT (1mg estradiol/0.5mg norethindrone acetate) for up to 24 weeks in women with moderate to severe EAP. To qualify, subject had to demonstrate over 2 menstrual cycles at least moderate DYS and NMPP for ≥2 days each and at least moderate overall pelvic pain for ≥5 days. Participants/materials, setting, methods Eligible women with moderate to severe EAP were equally randomized to once daily oral: placebo, linzagolix 75mg or linzagolix 200mg+ABT. Efficacy assessments included DYS, NMPP, dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain). The co-primary endpoint was a responder analysis at Month 3. We present secondary endpoints at Month 6. Main results and the role of chance Participants (n = 484) had a mean age of 35 years, a BMI of 24kg/m2 with 99% of subjects being White. At Month 6, compared to placebo significant improvements in DYS and NMPP (VRS) were observed in the 200mg+ABT group, with an estimated mean change from baseline (CfB) of -1.83 (95%CI: 1.96, 1.70; difference with placebo p &amp;lt; 0.001) and 0.92 (95%CI: 1.03, 0.82; p = 0.002), respectively. For the 75mg group, the mean CfB was 1.10 (95%CI: 1.23; 0.97; p &amp;lt; 0.001) and 0.84 (95%CI: 0.95; 0.73; p = 0.048), respectively. For overall pelvic pain (NRS), marked improvements were observed with an estimated mean CfB of 3.39 (95%CI: 3.74, 3.03; p &amp;lt; 0.001) for 200mg+ABT and 2.84 (95%CI: 3.20, 2.48; p = 0.024) for 75mg. Similarly, dyschezia (NRS) was significantly improved for both groups with a mean CfB of 1.99 (95%CI: 2.29, 1.70; p = 0.012) for 200mg+ABT and -1.98 (95%CI: 2.28, 1.69; p = 0.015) for 75mg. Both doses offered a marked, statistically significant improvement in the interference of pain with daily activities as measured on the EHP-30 Pain Dimension, with an estimated mean CfB of 35.60 (95%CI: 38.73, 32.48; p &amp;lt; 0.001) and -27.37 (95%CI: 30.50, 24.25; p = 0.001) for the 200mg+ABT and 75mg group, respectively. Both doses did not provide significant improvements in dyspareunia. Limitations, reasons for caution We report data of the EDELWEISS 3 study for up to Month 6. An extension study of this trial will provide more information on the sustained effect and potential symptom recurrence after stopping treatment. Wider implications of the findings The linzagolix 200mg+ABT group provided substantial improvement in endometriosis-associated pain symptoms. The 75mg dose was less effective but demonstrated still marked improvements. There exists an substantial need for different treatment regimens in women suffering from endometriosis. Trial registration number NCT03992846

Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling.

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150mg once daily and 200mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.

Clinical development of the oral gonadotropin-releasing hormone antagonist elagolix

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.

Linzagolix With and Without Hormonal Add-Back Therapy for the Treatment of Symptomatic Uterine Fibroids: Two Randomized, Placebo-Controlled, Phase 3 Trials

(Abstracted from Lancet 2022;400:896–907) Uterine fibroids occur in 50% to 60% of women and are symptomatic in 30% of patients by causing abnormal uterine bleeding and pelvic pressure. Treatment of uterine fibroids involves surgical and radiological interventions, as well as progestogens and other medical therapies.

IMPACT OF ELAGOLIX WITH ADD-BACK ON BONE MINERAL DENSITY AT 24 MONTHS: INTERIM RESULTS OF A RANDOMIZED, PLACEBO-CONTROLLED TRIAL IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS

To evaluate the effect of oral gonadotropin-releasing hormone receptor elagolix (ELA) with hormonal add-back therapy (AB) on bone mineral density (BMD) in women with heavy menstrual bleeding (HMB) associated with uterine fibroids (UF).

INTERIM RESULTS OF A PHASE 3b, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL EVALUATING 24-MONTH SAFETY OF ELAGOLIX WITH ADD-BACK FOR HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS

To evaluate the long-term safety of oral gonadotropin-releasing hormone receptor elagolix (ELA) with hormonal add-back therapy (AB) in women with heavy menstrual bleeding (HMB) associated with uterine fibroids (UF).

Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials

Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups). Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. ObsEva.

O-306 LINZAGOLIX FOR ENDOMETRIOSIS-ASSOCIATED PAIN: SAFETY RESULTS FROM EDELWEISS 3, A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Abstract Study question Is once-daily linzagolix treatment for women with moderate to severe endometriosis-associated pain (EAP) safe for use for up to 6 months of treatment? Summary answer Both doses of linzagolix were well-tolerated with minimal BMD decrease and few TEAEs &amp;gt;5% in either linzagolix arm. What is known already Linzagolix (LGX) is an investigational once-daily oral GnRH receptor antagonist that reduces serum estradiol in a dose-dependent manner and is being developed in two dosages for the treatment of endometriosis-associated pain (EAP): 75 mg, and 200 mg dose with hormonal add-back therapy (ABT). Study design, size, duration EDELWEISS 3 is a randomized, double-blind, placebo-controlled, multicenter Phase 3 trial of linzagolix in women with moderate to severe EAP. The trial includes 3 treatment arms: 75 mg LGX, 200 mg LGX with ABT (E2 1 mg/ NETA 0.5 mg), or placebo. Here we present safety results up to 6 months (24 weeks) of treatment. Participants/materials, setting, methods Eligible reproductive-aged women with moderate-to-severe EAP were randomized and treated (n = 484) for 6 months with 75 mg LGX, 200 mg LGX with ABT (E2 1 mg/ NETA 0.5 mg), or placebo. Safety and tolerability objectives reported here include 6-month results for treatment emergent adverse events (TEAEs), assessment of mean percent change from baseline (CfB) in lumbar spine (LS) bone mineral density (BMD) and Z-scores. The safety analysis set included 484 subjects across the 3 treatment groups. Main results and the role of chance The overall incidence of TEAEs was similar between the placebo and LGX 75 mg group (46.9%) and slightly higher (56.8%) in the LGX 200 mg + ABT group. There were few (3) serious TEAEs, and none were related to LGX. TEAEs that occurred in over 5% of patients in either active treatment arm included headache (10.5%, 8.1%, and 8.0%), hot flush (6.8%, 7.5%, and 2.5%), and fatigue (6.8%, 3.8%, and 2.5%) for the 200 mg LGX with ABT, 75 mg LGX, and placebo groups, respectively. Mean percent CfB (95% CI) in LS BMD was -0.79% (-1.15, -0.43%), -0.89% (-1.31, -0.47%), and +0.78% (0.41, 1.15%) for the 200 mg LGX with ABT, 75 mg LGX, and placebo groups, respectively. Z-scores at 6 months remained within the same range as baseline in all groups. Limitations, reasons for caution Additional efficacy and safety results from the trial's 24 weeks (6 mo) extension phase are pending. (Edelweiss 6 protocol: NCT04335591) Wider implications of the findings These results support further development of ABT and non-ABT doses of linzagolix that have potential to provide flexibility and choice for women seeking treatment for EAP. A non-ABT option is important for women who have a contraindication to, are at increased risk for complications, or prefer not to use ABT. Trial registration number ClinicalTrials.gov: NCT02778399

Long-Term Safety of Elagolix With Hormonal Add-Back Therapy in Women With Endometriosis-Associated Pain: 24-Month Results [A86

INTRODUCTION: Elagolix is an oral GnRH antagonist approved for the treatment of moderate to severe endometriosis-associated pain (EAP) in the US, Canada, and Israel. Hormonal add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate QD) may alleviate the hypoestrogenic effects (including bone mineral density [BMD] loss) associated with elagolix. The long-term safety of elagolix 200mg BID+add-back are currently under investigation in an ongoing phase 3, 48-month (M) study for EAP; this report focuses on open label safety results to 24M. METHODS: Premenopausal women with moderate-to-severe EAP were initially randomized 4:1:2 to receive elagolix 200 mg BID+add-back, elagolix 200 mg BID, or placebo for 12M, followed by open-label elagolix 200 mg BID+add-back for 36M. This 24M analysis assessed long-term safety including BMD. RESULTS: BMD measurements remained stable during the open label treatment period. At 24M, mean percent change from baseline in BMD for patients who initially received elagolix 200 mg BID+add-back (n=123), elagolix 200 mg BID (n=29), or placebo (n=60) was −0.85%, −1.21%, and −0.43% (spine); −0.23%, −0.58%, and −0.20%, (total hip); and −1.05%, −0.98%, and 0.14% (femoral neck). During the open-label period, safety profiles were generally similar across all three original treatment groups at 24M; rates of serious adverse events were generally low (less than 5%) and balanced across groups. CONCLUSION: Elagolix 200 mg BID+add-back therapy for 24M continues to have a favorable safety profile with minimal long-term impact on BMD. Combined with previously reported improvements in dysmenorrhea and non-menstrual pelvic pain, these safety data suggest elagolix 200 mg BID+add-back may provide a longer-term therapeutic option for women with EAP.

Effect of the Oral GnRH Antagonist Linzagolix on Uterine Fibroid-Related Severe Anemia [A105

INTRODUCTION: Iron-deficiency anemia is common in women with uterine fibroid (UF)-related heavy menstrual bleeding. Severe anemia is defined as hemoglobin (Hb) levels &lt;10g/dL. The effect of linzagolix, an oral GnRH antagonist, on UF-related severe anemia was assessed in two Phase 3 trials. METHODS: PRIMROSE 1 and 2 are randomized, double-blind, placebo-controlled Phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, with or without hormonal add-back therapy (ABT) in the treatment of UF. Subjects were considered responders if an increase of ≥2g/dL from baseline was achieved. Patients with severe anemia were given iron supplements until they reached the Hb levels &gt;12g/dL. RESULTS: In PRIMROSE 1, of 165 subjects with severe anemia, 57.9%, 61.5%, 82.1% and 65.2% of patients were responders at 24 weeks, in the respective treatment groups (100 mg, 100 mg+ABT, 200 mg and 200 mg+ABT), compared to 50% in the placebo group. In PRIMROSE 2, of 93 patients with severe anemia, 62.5%, 75%, 60% and 73.7%, respectively, were responders, compared to 46.2% for placebo. Given the small sample sizes, statistical significance was not reached. Improvements were maintained at week 52: in PRIMROSE 1, 69.2%, 62.5%, 81.3% and 75% of patients were responders in the respective treatment groups, compared to 40% in placebo, in PRIMROSE 2, 66.7%, 100%, 80%, 87% were responders, respectively. CONCLUSION: High and low doses of linzagolix improved Hb levels in patients with UF suffering from severe anemia.

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

ABSTRACT Introduction Uterine Fibroids (UFs) are the most predominant benign tumor in women who are coming of reproductive age, and causes intense economic load priced in billions of US dollars. Historically, surgery has been the main definitive treatment, albeit less attractive nowadays, especially for women with future fertility plans. Therefore, studies to explore the pharmacological treatment options are increasing especially as those that are currently available are limited for short-term use only. Areas covered This drug evaluation features the clinical results from previous and ongoing studies of relugolix, in combination with the add back therapy of estradiol (E2) and norethindrone acetate (NETA), as a novel, orally administered, nonpeptide antagonist of gonadotropin-releasing hormone (GnRH) for the management of heavy menstrual bleeding (HMB) in premenopausal women with UFs. Expert opinion The combination of relugolix/E2/NETA is an encouraging, well-tolerated and noninvasive pharmacological option for UFs patients. Relugolix induced a concentration-dependent decrease in HMB. However, it should be used with hormonal add-back therapy (E2+ NETA) to avoid induced hypoestrogenic side effects, importantly bone mineral density loss. Moreover, symptoms will likely resume shortly after the termination of the relugolix combination administration.

Population Pharmacokinetics of Elagolix in Combination with Low-Dose Estradiol/Norethindrone Acetate in Women with Uterine Fibroids.

Background and ObjectivesElagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids.MethodsData from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach.ResultsElagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids.ConclusionsElagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids.Clinical Trial RegistrationClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01096-w.

O-135 Long term secondary efficacy of linzagolix for heavy menstrual bleeding (HMB) due to uterine fibroids (UF): 52-week results from two placebo-controlled, randomized, phase 3 trials

Abstract Study question Are symptomatic improvements in women with UF observed after 24 weeks of linzagolix treatment with or without add-back therapy (ABT) maintained over 52 weeks? Summary answer Improvements in anemia, pain and quality of life previously reported at 24 weeks were maintained at 52 weeks. What is known already We previously reported that partial or full suppression of estradiol (E2) with once daily doses of either 100 or 200 mg linzagolix for 24 weeks, with or without ABT, were effective in reducing heavy menstrual bleeding associated with uterine fibroids, improving other symptoms such as pain and anemia and improving quality of life. Here we report the maintenance of effect on secondary endpoints after 52 weeks of treatment. Study design, size, duration Linzagolix is an investigational, oral GnRH antagonist being developed to treat HMB due to UF. PRIMROSE 1 (P1, USA, NCT03070899) and PRIMROSE 2 (P2, Europe and USA, NCT03070951) are randomized, double-blind, placebo-controlled Phase 3 trials, with essentially identical design, investigating the efficacy and safety of linzagolix with and without hormonal add-back therapy (ABT: 1 mg estradiol/0.5 mg norethindrone acetate) once daily for 52 weeks. Participants/materials, setting, methods Participants had HMB due to UF (&amp;gt;80mL menstrual blood loss (MBL)/cycle) and were equally randomized to: placebo, linzagolix 100mg, linzagolix 100mg+ABT, linzagolix 200mg, or linzagolix 200mg+ABT. After 24 weeks, subjects originally randomized to placebo or linzagolix 200mg were switched to linzagolix 200mg+ABT except in P1 where 50% placebo subjects continued placebo until 52 weeks. Secondary efficacy assessments included hemoglobin, pain (0–10 numeric rating scale) and health related quality of life (HRQL) on the UF-QoL questionnaire. Main results and the role of chance P1 trial subjects (n = 526) had a mean age of 42 years, pain score of 6.6 and HRQL total score (0–100) of 36.4 and 63% were Black. P2 trial subjects (n = 511) had a mean age of 43 years, pain score 4.8 and HRQL total score of 46.1 and 5% were Black. Mean baseline MBL was about 200 mL per cycle in both studies. In both trials, significant improvements compared to placebo observed at week 24 for secondary endpoints, including pain, anemia and QoL in all linzagolix treatment groups were maintained at 52 weeks. Mean±SD hemoglobin levels in anemic patients (&amp;lt;12 g/dL) increased from baseline by 1.7±1.9, 1.9±1.7, 2.2±2.4, 2.7±1.9 in P1 and 1.2±1.9, 2.9±1.8, 2.4±2.1, 3.0±1.4 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to 0.6±1.8 with placebo (P1). Mean±SD change from baseline in pain scores were -3.3±3.1, -2.7±3.2, -2.6±3.0, -3.9±3.2 in P1 and -2.6±3.1, -2.6±2.8, -3.0±2.6, -2.8±3.0 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to -0.4±2.5 with placebo (P1). Mean±SD change in HRQL total scores were 25.0±26.2, 34.2±30.1, 29.7±29.2, 38.3±29.2 in P1 and 16.8±24.0, 29.6±23.2, 31.9±26.8, 30.7±26.0 in P2 in the 100mg, 100mg+ABT, 200mg/200mg+ABT, 200mg+ABT groups, respectively, compared to 14.6±23.9 with placebo (P1). Limitations, reasons for caution Here we report data in both trials up to 52 weeks of treatment. No statistical comparisons were done at 52 weeks (the primary analysis was done after 24 weeks treatment). Post-treatment follow-up will provide more information in symptom recurrence after stopping treatment. Wider implications of the findings All linzagolix treatments provided sustained benefit. Two regimens previously identified for potential long-term treatment, 200mg with ABT and 100mg without ABT, provided sustained improvements of anemia, pain and associated quality of life. These different treatment regimens could be important to address the diverse needs of women suffering from uterine fibroids. Trial registration number ClinicalTrials.gov: NCT03070899, NCT03070951

Efficacy and safety of elagolix with add-back therapy in women with uterine fibroids and coexisting adenomyosis

ObjectiveTo determine if coexisting adenomyosis limits the efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy in reducing heavy menstrual bleeding in women with uterine fibroids.DesignPooled analysis of two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids [UF]-1 and UF-2).SettingA total of 153 gynecological clinical care settings in the United States and Canada.Patient(s)Premenopausal women (18–51 years) with >80 mL of menstrual blood loss (MBL)/cycle and uterine fibroids with and without coexisting adenomyosis diagnosed by ultrasound and/or magnetic resonance imaging at baseline.Intervention(s)Participants were randomized 1:1:2 to placebo, elagolix 300 mg twice daily alone, or elagolix 300 mg twice daily with estradiol 1 mg/norethindrone acetate 0.5 mg once daily.Main Outcome Measure(s)The primary endpoint was the proportion of women who had <80 mL of MBL during the final month and ≥50% reduction in MBL from baseline to the final month. Adverse events were monitored.Result(s)Of 786 women treated across the two trials, 16% (126 women) had coexisting adenomyosis. Among this subset, a significantly greater proportion of women who received elagolix with add-back therapy (77.1% [95% confidence interval, 66.2, 88.0]) met both primary endpoint criteria compared with women who received placebo (12.2% [95% confidence interval, 1.0, 23.4]). Adverse events most frequently reported in the elagolix with add-back adenomyosis subset were hot flushes (18.3%), nausea (11.7%), and night sweats (8.3%).Conclusion(s)Elagolix with add-back therapy significantly reduced heavy menstrual bleeding in women with uterine fibroids and coexisting adenomyosis, suggesting that elagolix efficacy was not adversely affected by the presence of adenomyosis (Elaris UF-1 and UF-2 Clinical-Trials.gov numbers, NCT02654054 and NCT02691494).

Quality of Life in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids: Baseline Disease Burden from Elaris UF-1 and UF-2

Study ObjectiveReport baseline Uterine Fibroid Symptoms Quality of Life Questionnaire (UFS-QoL) data from Elaris UF-1 and UF-2 to characterize disease burden from heavy menstrual bleeding (HMB) associated with uterine fibroids (UF).DesignElaris UF-1 (NCT02654054) and UF-2 (NCT02691494) were identical, phase 3, double-blind, randomized, placebo-controlled studies investigating safety and efficacy of elagolix alone or combined with hormonal add-back therapy for HMB associated with UF.SettingOutpatient in clinic/office.Patients or ParticipantsPremenopausal women (n=790) aged 18–51 years with diagnosed UF and HMB (menstrual blood loss [MBL] >80 mL/cycle for ≥2 menses).InterventionsN/AMeasurements and Main ResultsA modified UFS-QoL (4-week recall) was conducted before study drug administration. UFS-QoL is a self-administered, 37-item, disease-specific questionnaire that measures symptom severity and health-related QoL (HRQoL; calculated from 6 subscales and scored 0–100). Lower HRQoL scores indicate worse QoL. At baseline, mean (standard deviation [SD]) age was 42.4 (5.4) years, and MBL was 239.7 (158.7) mL. Baseline total HRQoL score was low, reflecting low QoL (mean [SD], 42.9 [23.2]). Mean (SD) scores were generally low across HRQoL domains (concern, 28.1 [24.6]; activities, 40.9 [27.0]; energy/mood, 47.4 [25.3]; control, 54.2 [28.3]; self-consciousness, 39.9 [30.7]; sexual function, 47.5 [35.4]). In each HRQoL domain, the questions most frequently answered ‘most’ or ‘all’ of the time were how often symptoms made patients: feel concerned about soiling underclothes (80%; concern), decrease the amount of time on exercise or other physical activities (59%; activities), feel tired or worn out (68%; energy/mood), feel less productive (50%; control), feel conscious about the size and appearance of their stomach (57%; self-consciousness), and avoid sexual relations (46%; sexual function).ConclusionThere was considerable baseline disease burden. Patients reported the greatest impacts to concern and self-consciousness. Common issues included concerns about soiling underclothes and feeling tired or worn out.

EFFICACY AND SAFETY OF LINZAGOLIX (LGX) FOR THE TREATMENT OF HEAVY MENSTRUAL BLEEDING (HMB) DUE TO UTERINE FIBROIDS (UF): RESULTS FROM TWO PHASE 3 RANDOMIZED CLINICAL TRIALS

To assess the efficacy and safety of LGX, an oral GnRH receptor antagonist, administered with and without hormonal add-back therapy (ABT: 1 mg estradiol/0.5 mg norethindrone acetate), for the treatment of HMB and other symptoms of UF.