Linzagolix – new perspectives in the pharmacotherapeutic management of uterine fibroids and endometriosis

Introduction

Uterine fibroids and endometriosis are among the most common conditions encountered in gynaecological practice [1, 2]. Uterine fibroids affect 30–70% of women, with up to half experiencing symptoms that significantly impair quality of life (QoL), including anaemia, pain, and pressure-related symptoms. For decades, efforts have been underway to develop pharmacological treatments for these conditions that would offer both high efficacy and good tolerability [3–6]. Since the common feature of these disorders is their pathogenetic oestrogen-dependent nature, the most promising therapeutic approach is based on gonadotropin-releasing hormone (GnRH) analogues. These agents act through modulation of the hypothalamic-pituitary-gonadal axis to suppress ovarian endocrine function [1, 2, 6, 7]. The first GnRH analogues used in the treatment of uterine fibroids and endometriosis were GnRH agonists. However, their use is associated with several disadvantages, including the need for intramuscular administration, bone mineral density (BMD) loss, and an initial surge in ovarian hormones (known as the flare-up effect). A significant advancement in the treatment of oestrogen-dependent diseases was the introduction into clinical practice of non-peptide, small-molecule GnRH antagonists. Their advantages compared to GnRH agonists are presented in Table 1 [1, 2, 8–11].

Hypoestrogenic side effects of GnRH antagonists such as vasomotor symptoms or bone loss pose a major safety and tolerability issue. The oestrogen threshold hypothesis proposed by Robert Barbieri in 1992 lead to the introduction of add-back therapy (ABT) as an adjunct to long-term treatment with GnRH analogues [12]. In patients with risk factors for osteoporosis or bone loss, a dual X-ray absorptiometry scan is recommended prior to starting treatment with GnRH antagonist, and continued BMD monitoring should be considered during long-term treatment.

Although ABT with low-dose oestrogen and progestogen has been proven to alleviate hypoestrogenic side effects of GnRH analogues, it may reduce the effectiveness of these drugs. Furthermore, there are several safety issues concerning oestrogen therapy such as cardiovascular or oncological risks [13]. Therefore, the decision on whether to use ABT should be made taking into account personalised goals of therapy and its planned duration as well as individual risk profile of a patient.

There are 3 currently available non-peptide oral GnRH antagonists approved for the treatment of uterine fibroids and/or endometriosis: elagolix, relugolix, and linzagolix (LGX) [2, 11, 14]. The basic characteristics of these drugs are presented in Table 2.

The newest drug in this group, attracting growing interest among clinicians, is LGX [2, 7, 9, 10, 15–18]. It is an oral, small-molecule, non-peptide GnRH antagonist that induces dose-dependent suppression of ovarian function. With a 15-hour half-life, LGX is suitable for once-daily dosing. The bioavailability of the active substance of the drug is not affected by food intake. Linzagolix in its choline salt formulation is available in 2 oral doses (100 mg and 200 mg), enabling dose and treatment regimen customisation according to individual therapeutic goals.

The aim of this literature review was to evaluate current evidence on the potential applications of LGX for the treatment of uterine fibroids and endometriosis.

Material and methods

A comprehensive search of the PubMed, Google Scholar, and MEDLINE databases was conducted using the keywords ‘linzagolix’, ‘uterine fibroids’, and ‘endometriosis’. For the purpose of the review, studies with the highest clinical relevance, published in peer-reviewed journals within the last 10 years, were selected.

Uterine fibroids

Uterine fibroids affect 30–70% of women, with up to half experiencing symptoms that significantly impaired QoL, including anaemia, pain, and pressure-related symptoms. Fibroids represent the third most common cause of gynaecological hospital admissions and the leading indication for major surgical procedures performed by gynaecologists. These tumours are also among the most frequent contributors to anaemia in women. Additionally, fibroids are the sole cause of infertility in 1–3% of women [2, 4, 6, 19].

Treatment goals for uterine fibroids vary depending on the patient’s individual symptom profile, preferences, and expectations. They may include the following:

With growing interest in conservative management of fibroid symptoms, non-surgical therapies, including drug treatments, have been introduced in recent decades. Given the highly oestrogen-dependent nature of both fibroid growth and activity, modern pharmacological therapies are based on suppression of ovarian endocrine function. GnRH antagonists are regarded as the most promising group of therapeutic agents in this field [2, 4, 6, 10]. The most recent GnRH antagonist approved for the treatment of symptomatic uterine fibroids is LGX. The approval of LGX for this indication was based on the results of 2 phase III clinical trials, PRIMROSE 1 and 2, published in 2022 [18]. These identically designed, 52-week, randomised, double-blind, placebo-controlled studies were conducted in the US (PRIMROSE 1) and in Europe/US (PRIMROSE 2). The trials enrolled female patients with uterine fibroids experiencing heavy menstrual bleeding (menstrual blood loss [MBL] > 80 ml). Participants were randomised into 5 treatment arms for 52 weeks, receiving one of the following:

Patients randomised to the placebo or the 200 mg LGX without ABT groups received 200 mg LGX once daily with ABT from week 25 to week 52, except in the PRIMROSE 2 trial, where half of the patients in the placebo group continued to receive placebo during that period.

The primary endpoint of the study was treatment response defined as MBL ≤ 80 ml and at least 50% reduction in MBL during the 28-day period prior to week 24 of treatment. The full analysis included 511 women in the PRIMROSE 1 trial and 501 in the PRIMROSE 2 trial. In both studies, patients receiving LGX with or without ABT achieved a significantly higher rate of satisfactory treatment response compared to the placebo group (p < 0.003). The proportions of women with a satisfactory treatment response in the respective arms of the PRIMROSE 1 trial were: 56.4% (LGX 100 mg), 66.4% (LGX 100 mg + ABT), 71.4% (LGX 200 mg), and 75.5% (LGX 200 mg + ABT). In the placebo group, the corresponding proportion was 35.0%. In the PRIMROSE 2 trial, the response rates were 56.7%, 77.2%, 77.7%, and 93.9% for the respective treatment groups (vs. 29.4% in the placebo group). Analyses of patient subgroups with submucosal fibroids or fibroids larger than 3 cm demonstrated treatment response rates comparable to those observed in the overall populations of these studies.

A significant improvement was observed in all patient groups regarding secondary study endpoints, such as time to achieve MBL reduction, the percentage of patients with amenorrhoea, and an increase in haemoglobin levels (in the latter case, except for the LGX 100 mg group in the PRIMROSE 1 trial). Regarding all endpoints in both studies, the treatment response was significantly stronger in patients receiving 200 mg of LGX compared to patients treated with the 100 mg dose, regardless of whether ABT was used.

The findings at 52 weeks presented in recently published PRIMROSE 1 and 2 long-term extension and withdrawal study confirmed the benefits of LGX treatment observed at 24 weeks [20].

The most frequent adverse event observed in PRIMROSE 1 and 2 trials was hot flashes, occurring in 35% of participants receiving LGX 200 mg without ABT in PRIMROSE 1 and in 32% of the corresponding participants in PRIMROSE 2. This symptom was observed in the remaining study groups with a frequency ranging from 3% to 14%. Patients receiving LGX + ABT were followed up to week 52 of treatment. All therapeutic response indicators assessed after 52 weeks of treatment did not differ significantly from those recorded after 24 weeks of therapy.

Linzagolix therapy proved to be effective in reducing the volume of both the dominant fibroid and the uterus. After 24 weeks of treatment, in the group receiving LGX 200 mg without ABT, the fibroid volume decreased by an average of 45% in the PRIMROSE 1 trial and 49% in the PRIMROSE 2 trial. In the LGX 100 mg and LGX 200 mg + ABT groups, a significant reduction in fibroid volume was observed in 13–25%, while in the LGX 100 mg + ABT group, this change was statistically insignificant compared to the placebo group. Similar results were observed regarding changes in uterine volume. In patients who continued LGX and ABT treatment beyond 24 weeks, the therapeutic effect on reducing both fibroid and total uterine volume remained unchanged at 52 weeks.

An analysis was also conducted on how LGX treatment influenced patients’ quality of life. A significant improvement in QoL was observed in all studied groups across all analysed domains.

Serum oestradiol levels below 20 pg/ml were noted only in the 200 mg LGX group without ABT. In the remaining groups, oestradiol levels remained within the 30–50 pg/ml range throughout the 24-week observation period.

The PRIMROSE 1 and 2 trials evaluated changes in BMD in the lumbar spine, femoral neck, and hip. These changes were found to be most pronounced in the lumbar spine in patients receiving 200 mg of LGX without ABT, with a reduction of 3.3% in the PRIMROSE 1 trial and 4.1% in the PRIMROSE 2 trial. Due to the risk of BMD decrease with prolonged use, the 200 mg dose without concomitant ABT should not be prescribed for longer than 6 months.

Reductions in BMD in the remaining groups were 2.0–2.1% in the 100 mg LGX group and 0.8–1.4% in the 100 mg LGX + ABT and 200 mg LGX + ABT groups, compared to increases in BMD of 0.4–0.5% in the placebo groups. After 52 weeks of treatment with LGX and ABT, reductions in lumbar spine BMD compared to baseline did not exceed 2.4%. Throughout the 52-week observation period, no study subgroup exhibited significant changes in mean z-score values.

In their summary of the PRIMROSE 1 and PRIMROSE 2 trial results, the authors concluded that LGX (100 mg or 200 mg), with or without ABT, significantly reduces uterine fibroid symptoms. This drug enables personalised treatment tailored to both short- and long-term therapeutic goals, allowing for dosage selection as well as the inclusion or omission of adjuvant oestrogen therapy.

The results of the PRIMROSE 1 and PRIMROSE 2 trials have been supplemented by a recently published analysis of a secondary endpoint evaluating the time to achieve therapeutic goals in the treatment of uterine fibroids with LGX [21]. The median time from treatment initiation to achieving a clinically significant reduction in MBL sustained through week 24 was 3 days in the LGX 200 mg + ABT group and 12 days in the LGX 100 mg + ABT group. The rapid therapeutic effect of LGX demonstrated in this study makes it a particularly useful treatment option in clinical practice for patients with heavy uterine bleeding caused by fibroids.

There are major differences between the 2 currently available GnRH antagonists approved for the treatment of symptomatic uterine fibroids (Table 2). The effectiveness and safety/tolerability profiles of relugolix and LGX used for this indication have not been compared in head-to-head trials.

Because the medicinal product that contains LGX is available in 2 doses (100 and 200 mg), treatment can be tailored to the therapeutic goal by selecting one of the following therapeutic regimens [18]:

Endometriosis

Endometriosis is the most common gynaecological cause of chronic pelvic pain syndrome and one of the leading causes of infertility. This condition affects between 2% and 10% of women, leading to symptoms that often have a detrimental impact on QoL [1].

The goals of endometriosis treatment depend on the individual clinical situation and the patient’s expectations, and may include the following:

According to current guidelines, endometriosis should be regarded as a chronic disease that requires a lifelong treatment plan, with the goal of maximising pharmacotherapy and avoiding repeated surgical interventions [1].

Recognising endometriosis as an oestrogen-dependent condition has led many researchers to seek methods for effectively controlling the activity of focal lesions by suppressing ovarian endocrine function while minimising the unwanted effects of hypoestrogenaemia. These studies paved the way for the use of GnRH analogues in treating endometriosis, with GnRH antagonists emerging as the most promising class of medications [8, 9, 11, 12, 22]. The European Society of Human Reproduction and Embryology (ESHRE), in its 2022 position statement, recommends GnRH antagonists as second-line pharmacotherapy for the relief of endometriosis-related pain when oestrogen-progestogen or progestogen-only treatments prove ineffective [1].

Among emerging therapies for endometriosis, a particularly promising candidate is LGX, as shown by findings from the prospective, randomised, double-blind, placebo-controlled phase III EDELWEISS 3 trial [16]. The aim of the study was to assess the effectiveness of LGX in alleviating moderate to severe pain associated with endometriosis over a period of up to 6 months. The study enrolled a total of 486 women who were randomised into 3 groups receiving either 75 mg of LGX, 200 mg of LGX with ABT (1 mg oestradiol + 0.5 mg norethisterone acetate), or placebo. Pain intensity was assessed daily using the VAS scale. After 3 months of therapy, patients receiving 200 mg of LGX + ABT experienced a clinically significant and statistically meaningful reduction in both menstrual and non-menstrual pain, along with a decrease in analgesic use. The proportion of women in this group who achieved a satisfactory response in up to 3 months of treatment for dysmenorrhoea was 72.9%, compared to 23.5% in the placebo group (p < 0.001). With respect to non-menstrual pain, these rates were 47.3% and 30.9%, respectively (p = 0.007). A significant – but less pronounced – improvement in dysmenorrhoea was also noted with the use of 75 mg LGX without ABT. In this group, the proportion of patients with a satisfactory response to treatment for menstrual pain was 44%, compared to 23.5% in the placebo group (p < 0.001). The reduction in the severity of non-menstrual pain did not meet the criteria for statistical significance (p = 0.279). The therapeutic effect of LGX in alleviating pain caused by endometriosis was reported by patients after just one month of treatment. The effectiveness of LGX in treating dysmenorrhoea was also maintained after 6 months of treatment in both therapeutic groups. The reduction in pain symptoms was accompanied by a significant improvement in the multidimensionally assessed QoL of patients over a 6-month period.

The serum oestradiol levels in both study arms ranged between 20 and 60 pg/ml, which is typical for the early follicular phase of the menstrual cycle. Hypoestrogenic adverse effects, such as hot flushes and a decrease in BMD, were observed in both study arms at a level of less than 1%. The most common adverse effects included headaches, hot flushes, and fatigue. In approximately 98% of cases, these symptoms were mild or moderate.

There are 3 currently available GnRH antagonists approved for the treatment of endometriosis-related symptoms (Table 2). Although the effectiveness and safety/tolerability profiles of elagolix, relugolix, and LGX used for this indication have not been compared in head-to-head trials, network meta-analyses showed that all these drugs are effective for endometriosis-associated pain and dysmenorrhoea with a dose-dependent incidence of hypoestrogenic side-effects [11, 14].

The results of the EDELWEISS 3 study demonstrated that LGX constitutes a valuable addition to existing methods for treating endometriosis, providing the option for flexible dosing and personalised therapy regimens.

Conclusions

In recent years, publications have demonstrated the promising therapeutic potential of LGX in the management of uterine fibroids and endometriosis. This drug enables treatment personalisation based on short- and long-term therapeutic goals, allowing for dose adjustment and the optional use of ABT.