Elinzanetant: a phase III therapy for postmenopausal patients with vasomotor symptoms

ABSTRACT

Introduction

Menopausal vasomotor symptoms (VMS) are experienced by most women and are often debilitating and can last for years. While hormone replacement therapy is effective, it carries risks that have impacted its wider use, and it can be contraindicated. There is a large unmet need for a safe, effective non-hormonal therapy.

Areas covered

The importance of the neurokinin (NK) system in the hypothalamic regulation of the vasomotor center has become clear. NK antagonists, previously developed for other indications, have therefore been investigated for the treatment of VMS. Elinzanetant is a potent antagonist at both NK1 (endogenous ligand Substance P) and NK3 (neurokinin B) receptors, whereas other related drugs in development are selective NK3 antagonists. Elinzanetant has been investigated in 2 Phase II trials for menopausal VMS, demonstrating rapid onset and dose-dependant efficacy for the relief of VMS and improvement in quality of life for up to 12 weeks. Phase III trials are underway in women both with physiological menopause and after treatment for breast cancer.

Expert opinion

Elinzanetant is a very promising non-hormonal approach to a highly prevalent symptom constellation, with rapid onset and high efficacy. Wider indications are being explored in current Phase III trials.

KEYWORDS:

• Hot flushes
• vasomotor symptoms
• neurokinin
• Substance P
• menopause

1. Introduction

Women account for more than half of the world’s population, and menopause is a biological inevitability. In addition to amenorrhea, the most common symptoms, experienced by 75–80% of women, are hot flushes and night sweats [1]. These are generally referred to as vasomotor symptoms (VMS); they vary in severity and last around 7.5 years on average [2] but with wide variation. Other symptoms include sleep disturbance, vaginal dryness, reduced libido, pain with sex, mood changes (anxiety and depression), fatigue, and joint pain [1].

Estrogen replacement, in the form of hormone replacement therapy (HRT, also termed menopause hormone therapy, MHT), is the most commonly used treatment for managing menopausal symptoms and is the most effective intervention in this context [3], although it can take several weeks for maximal efficacy to develop [4]. It is thought to be safe, and even beneficial, for most women aged less than 60 years old or fewer than 10 years from menopause [3,5]. However, many women still choose to avoid HRT [6], since there may be small but serious health risks for some, e.g. those with preexisting cardiovascular disease or at increased risk of stroke or venous thromboembolism. HRT is also contraindicated after hormone sensitive cancers where estrogen poses a theoretical risk in tumors that express estrogen receptors (ER) and/or where anti-estrogen treatments are used. In this situation, menopausal symptoms and joint pains have been identified as a major contributor to discontinuation of adjuvant endocrine therapy [7], which has been reported in as many as 50% of women, with a possible 20% increase in mortality [8].

VMS have been listed as the highest treatment priority among women with menopause symptoms after cancer [9,10], with breast cancer patients more likely to prioritize VMS than women with other cancers [9].

Prescribable alternatives to HRT are available but are primarily aimed at improving VMS only. These include SSRIs/SNRIs, gabapentin/pregabalin, clonidine, and more recently oxybutynin [11,12]. This short list of alternatives consisting of repurposed drugs are generally less effective than HRT and very often limited by side effects.

The potential therapeutic value of neurokinin receptor antagonists for menopausal VMS arose from investigation of novel regulatory pathways in reproductive function. NK receptors are rhodopsin-like 7 transmembrane Gq-coupled receptors, activated by the neurokinin/tachykinin family of neurotransmitter peptides consisting of NKs A, B, and Substance P. These have highest affinity for the NK2, NK3 and NK1 receptors respectively [13]. Following genetic evidence for an essential role of initially kisspeptin and subsequently NKB and its receptor NK3R for human puberty and adult reproductive function in both sexes [14–16], these two neuropeptides were demonstrated to partially co-localize in a group of hypothalamic neurons. Additional co-localization with the opioid neuropeptide dynorphin (Dy) led to these being termed ‘KNDy’ neurons, with a wealth of studies exploring their role in the control of gonadotropin releasing hormone (GnRH) and thus as master regulators of mammalian reproduction [17,18]. Neurokinin pathways are widely distributed in the central nervous system, including in the cortex and the basolateral amygdaloid nucleus [19], and peripherally, notably in the gut and pancreas [20]. NKB (and Substance P) had previously been shown to be overexpressed in the hypothalamus of postmenopausal women [21], as was kisspeptin [22]. In addition to regulating the activity of GnRH-containing neurons, KNDy neurons also project to the preoptic thermoregulatory area, known to express NK3R and with evidence of a functional role for NKB. This led to the hypothesis that these KNDy neurons also mediated the VMS associated with menopausal estrogen deficiency, providing a basis for the use of NKB/NK3 antagonists as a treatment of VMS [23]. Further evidence was provided by the demonstration that infusion of NKB in premenopausal women resulted in the rapid onset of VMS [24], and genome wide association studies revealed that variations in TAC3R (encoding NK3R) may contribute to VMS risk [25]. Animal studies have confirmed that effects of projections from the KNDy neurons of the hypothalamic arcuate nucleus to the median preoptic nucleus are mediated by NKB/NK3R, whereas those to the GnRH neurons are mediated by kisspeptin [26]. NKB and dynorphin are also involved in local autoregulation with stimulatory and inhibitory signals respectively (Figure 1).

Figure 1. Schematic of the links between KNDy neurons, the regulation of GnRH secretion, and the vasomotor area in the hypothalamus.

Several companies had previously developed NK3R antagonists as potential treatments of schizophrenia, but clinical trials did not confirm efficacy. Those trials had, however, identified suppression of testosterone levels in men as an adverse effect, and with the new understanding of the role of NKB in the central control of reproduction, repurposing of these agents led to studies in both reproductive and menopausal VMS contexts, initially with the AstraZeneca selective NK3R antagonist AZ4901 (palvinetant; originally AZD2624, subsequently licensed to Millendo Therapeutics and renamed MLE4901). In a cross-over design RCT, MLE4901 reduced VMS frequency by 78.4% vs 45.6% 5% with placebo after 4 weeks [27]. This effect was remarkably rapid in onset being apparent within 2–3 days for both day and nighttime symptoms [28,29]. Similar efficacy and speed of onset has been demonstrated for another NK3R antagonist fezolinetant, originally developed by Euroscreen as ESN364 and subsequently by Ogeda SA then Astellas Pharma [30,31]. Fezolinetant 45 mg once daily (VEOZAH) has recently (May 2023) been approved by the FDA for the treatment of moderate to severe VMS due to menopause [32].

A key differentiating aspect of elinzanetant (Box 1) is that it is an antagonist of both NK1R and NK3R, whereas the other drugs mentioned above are selective NK3R antagonists. Substance P (SP) is the key endogenous ligand for NK1R, widely distributed in the body and classically associated with pain neurotransmission. In several species, including both mice and humans, infusion of SP/selective NK1 agonist ligands increases gonadotropin secretion; although in mice, this is not seen in kisspeptin receptor knockout animals, indicating that it is at least primarily mediated by that receptor in rodents [33]. Expression of Tac1 (encoding SP and NKA) in neurons of the rodent arcuate nucleus, where it partially colocalises with Kiss1, is reduced by estrogen treatment. Co-expression of SP with kisspeptin and NKB is also seen in the human infundibular nucleus [34], with hypertrophy of SP-expressing neurons in postmenopausal women [21,35]. The expression of SP/NK1R in the median preoptic area is unknown. The SP/NK1 system is also associated with the peripheral aspects of heat dissipation and its pathological equivalent, the hot flush. Flushing is a classic symptom of the carcinoid syndrome, mediated by tachykinins and replicated by SP infusion [36], and perivascular SP-containing terminals regulate local vasomotor tone [37]. It is, therefore, possible that NK1R antagonism may contribute to the treatment of menopausal VMS by activity both within the hypothalamus by reducing the activity of heat-sensing neurons and peripherally by reducing vasodilatation. Additionally, specific NK1R antagonists have shown efficacy in Phase II trials in mood [38] and primary insomnia [39], so a compound with NK1R antagonist properties may have potential for improvements in sleep and other symptoms associated with menopause, in addition to VMS.

Box 1. Drug Summary Box

Drug name (generic): Elinzanetant

Phase (for indication under discussion): Phase III studies in progress

Indication (specific to discussion) Vasomotor symptoms associated

with the menopause

Pharmacology description/mechanism of action: Antagonist at

neurokinin 1 and 3 receptors

Route of administration: oral, once daily

Chemical structure: 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro

-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl) hexahydropyrazino

[2,1 c][1,4]oxazin-8(1 H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide

structure submitted as separate figure file

Pivotal trial(s): RELENT-1 (2 weeks treatment duration) and

SWITCH-1 (12 weeks treatment duration).

2. Introduction to the compound

Elinzanetant was initially developed by GSK as GSK1144814, and subsequently by KaNDy Therapeutics Ltd (KaNDy) and NeRRe Therapeutics Ltd (NeRRe) as NT-814 prior to its formal rINN adoption. Elinzanetant was acquired by Bayer in 2020.

2.1. Pharmacology

Development of NK antagonists with both NK1 and NK3 antagonism (thus blocking Substance P and NKB signaling pathways) is described in [40]. The compounds reported showed insurmountable i.e pseudo-irreversible antagonism, indicating very slow receptor dissociation, ensuring prolonged occupancy of the receptor populations, thereby limiting agonist activation. The insurmountable pharmacology of GSK1144814 was confirmed in human brain receptor occupancy studies [41]; this publication also reported that this is a potent dual antagonist with in vitro pKi values of 9.3 and 8.7 at human NK1R and NK3R respectively. Preclinical data showed that GSK1144814 has high selectivity for the NK1 and NK3 receptors over 88 other non-neurokinin receptors, enzymes, and transporters [42].

2.2. Pharmacodynamics

Menopausal VMS do not have an easy biomarker and thus key trial outcomes are mostly subject-reported. Skin conductance has been used as an objective measure [43] but has technical challenges. Studies developing NKR antagonists have, therefore, often used gonadotropin (specifically LH) secretion as it mirrors GnRH secretion and thus KNDy neuron activity [44–48]. While this may not directly reflect activity at the thermoregulatory area, synchrony between hot flushes, and LH secretion has been reported [43,49]. Studies using LH as pharmacodynamic outcome are most easily performed in men, without the cyclic variation in activity of the female reproductive axis, and show rapid and profound LH suppression within hours of first dose administration [46,47]. Detailed PD studies of elinzanetant in men have not been published, but in premenopausal women, dose-dependent partial suppression of LH was demonstrated, with inhibitory effects on ovulation [48]. In postmenopausal women, the very high rate of LH secretion, reflecting hyperactivity of the KNDy/GnRH system, is relatively resistant to suppression by NK3R antagonism [28].

2.3. Pharmacokinetics and metabolism

In studies of GSK1144814 in healthy volunteers, peak drug concentrations were shown within 1 h with a terminal elimination half-life of approximately 15 h (de Beek, et al., 2013).

The pharmacokinetic relationship between plasma NT-814 concentration and effect was explored in an inhibitory effect model and a sigmoid inhibitory effect model in the RELENT-1 trial. Both models showed a plateau in the relationship between plasma NT-814 concentrations and frequency of VMS that was achieved with doses ≥150 mg [50].

3. Clinical efficacy

3.1. Phase II studies

Two Phase II trials have been completed and reported, RELENT-1 (ClinicalTrials.gov identifier NCT02865538) and SWITCH-1 (NCT03596762). RELENT-1 was a multicentre, US-based double-blind, randomized, placebo-controlled, multiple-ascending-dose study to evaluate the pharmacokinetics and safety of multiple NT-814 dose levels over a 14 day treatment period, as well as exploratory efficacy outcomes [50]. About 76 postmenopausal women with moderate/severe hot flashes were randomized 3:1 to 14 days of once-daily NT814 or placebo within each of four sequential dose cohorts (50, 100, 150, 300 mg) taken in the morning. There was a 2 week baseline phase to establish symptom severity and stability

There were improvements in all efficacy parameters (frequency and severity of VMS, frequency of waking from sleep due to night sweats) in all dose groups (Figure 2). Symptom improvement was of rapid onset, within days, and was greater in the second week of treatment than in the first. There was a dose-response relationship, with greatest improvements in the 150 mg and 300 mg NT-814 groups, which showed 84% and 66% reduction in day-time moderate/severe VMS frequency (vs. 37% for placebo) and 81% and 63% reduction in night-time VMS-related awakening (vs. 32% for placebo), respectively.

Figure 2. Daily frequency of: moderate and severe hot flashes (a), severity of hot flashes (b), daily hot flash severity score (c), and waking at night due to night sweats (d), by day. Data shown are mean ± standard error (severity score = [number of mild hot flashes x 1] + [number of moderate hot flashes x 2] + [number of severe hot flashes x 3]). From [50] under CCBY-NC-ND.

SWITCH-1 was an international Phase IIb double-blind, placebo controlled, dose-finding trial which evaluated the optimal dose of elinzanetant for treatment of VMS symptoms in post-menopausal women [51]. After an initial 2 weeks during which all subjects received placebo, subjects were then randomized to receive elinzanetant (40 mg, 80 mg, 120 mg, or 160 mg soft gel capsules) or placebo once-daily for 12 weeks. In an adaptive design, randomization to the 40 mg and 80 mg doses was later stopped. The primary outcomes were efficacy in reducing frequency and severity of moderate to severe VMS, and safety and tolerability, with secondary outcomes including evaluation of efficacy in affecting mental well being, quality of life, and measures of sleep.

Across centers in the US, UK, and Canada, 760 women were screened and 199 randomized, of whom 180 completed treatment. As with RELENT-1 and in studies with selective NK3 antagonists, reductions in symptoms were rapid, occurring within the first week. Treatment with 120 mg elinzanetant resulted in improvements in VMS frequency at both 4 and 12 weeks, with a significant improvement only at week 4 in the 160 mg group (Figure 3). The effects of lower doses were small and not statistically significant. Overall, improvements tended to increase during the 12 weeks of treatment with restoration toward baseline over 4 weeks of post-treatment follow-up. Effects on VMS severity were less clear, although the overall trend was similar. Awakening from sleep, sleep quality and quality of life (by MenQoL-I) were significantly improved in the 120 mg and 160 mg doses at some time points, although changes regarded as clinically meaningful were more consistent.

Figure 3. Change from baseline in mean daily frequency (a, c) and weekly severity (b, d) of moderate and severe VMS by Treatment Group. Abbreviations: EZN, elinzanetant; LS, least square; SE, standard error. From [51] under CCBY-NC-ND.

3.2. Phase III studies

A series of Phase III studies are underway, the OASIS 1–4 trials (NCT05042362, NCT05099159, NCT05030584 and NCT05030584). OASIS 1, 2, and 3 are double blind, randomized, placebo controlled trials of the effects of elinzanetant on VMS in postmenopausal women, of 26 weeks (OASIS 1 and 2) and 52 weeks (OASIS 3) treatment duration with anticipated combined recruitment of approximately 1300 women. OASIS 4 is of similar design, also of 52 weeks treatment duration, in approximately 400 women with VMS caused by adjuvant endocrine therapy for the treatment of hormone receptor-positive breast cancer.

4. Safety and tolerability

In RELENT-1 [50], there were no serious AEs or AEs leading to discontinuation from the study; also, there no adverse changes during extensive 24 hours ECG Holter monitoring. The most common AEs were somnolence and headache (excluding contact dermatitis from ECG lead attachment) (Table 1). Somnolence was always mild and usually intermittent and was most commonly reported during the first week of treatment. Overall AE incidence was similar in the placebo and 50, 100, and 150 mg elinzanetant groups and slightly higher in 300 mg group. The Columbia Suicide Severity Rating Scale was also used in both RELENT-1 and SWITCH-1 with no adverse signals. Markers of bone turnover were also assessed in SWITCH-1 but data were not reported.

Table 1. Most common adverse events (reported in ≥ 10% of subjects in any treatment group) in RELENT-1.

System Organ Class Preferred Term	Placebo N = 18 n (%)	Elinzanetant once-daily dose
		50 mg N = 15 n (%)	100 mg N = 15 n (%)	150 mg N = 15 n (%)	300 mg N = 13 n (%)
Any adverse event	13 (72.2)	7 (46.7)	11 (73.3)	10 (66.7)	11 (84.6)
Somnolence	3 (16.7)	5 (33.3)	2 (13.3)	5 (33.3)	9 (69.2)
Headache	3 (16.7)	0	5 (33.3)	1 (6.7)	6 (46.2)
Diarrhea	0	1 (6.7)	0	1 (6.7)	3 (23.1)
Pelvic pain	2 (11.1)	3 (20.0)	0	0	0
Dyspepsia	2 (11.1)	0	0	1 (6.7)	0
Alanine aminotransferase increased	0	0	2 (13.3)^a	0	0

^aAlanine aminotransferase (ALT) increased to 1.3 × upper limit of normal (ULN) on Day 8, decreasing to 1.1×ULN on Day 14 in one subject; and to 2.6 × ULN on Day 8, decreasing to 1.4 × ULN on Day 14 in the other subject. Four other subjects (2 receiving placebo and 2 receiving 300 mg NT-814) had similar changes in ALT that were not reported as adverse events.

From [50] under CCBY-NC-ND.

In SWITCH-1 [51], treatment-emergent adverse events (TEAEs) were reported in 67.8% of participants in the elinzanetant groups and in 60% of the placebo group. The most frequently reported were headache, somnolence and diarrhea, and most were mild or moderate, and there was no clear relationship with drug dose (Table 2). Increases in liver transaminases of less than 3 × ULN occurred in 11% of the placebo group and 8.8% of the elinzanetant group. Rises of > 3 × ULN were found in two women in the 80 mg elinzanetant group, but as neither had detectable amounts of drug present in their plasma at the time, this was not attributable to drug ingestion.

Table 2. Treatment-emergent adverse events by treatment group in SWITCH-1.

AE category	Placebo group, No. (%) (N = 47)	Elinzanetant group, No. (%)
		40 mg (n = 31)	80 mg (n = 17)	120 mg (n = 52)	160 mg (n = 52)	Total (N = 152)
Any TEAE	28 (60)	17 (55)	14 (82)	34 (65)	38 (73)	103 (67.8)
Serious TEAEs	2 (4)	0	1 (6)	1 (2)	1 (2)	3 (2.0)
TEAEs leading to discontinuation of study treatment	1 (2)	0	2 (12)	0	5 (10)	7 (4.6)
Most common TEAEs (occurring in ≥ 3 participants in any treatment group)
Headache	6 (13)	3 (10)	2 (12)	6 (12)	4 (8)	15 (9.9)
Somnolence	1 (2)	3 (10)	1 (6)	2 (4)	6 (12)	12 (7.9)
Dizziness	0	0	0	3 (6)	3 (6)	6 (3.9)
Nasopharyngitis	4 (9)	1 (3)	0	3 (6)	0	4 (2.6)
Diarrhea	3 (6)	2 (6)	2 (12)	3 (6)	3 (6)	10 (6.6)
Blood creatine phosphatase increased	1 (2)	1 (3)	1 (6)	3 (6)	1 (2)	6 (3.9)
Fatigue	0	3 (10)	1 (6)	1 (2)	4 (8)	9 (5.9)

Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.

From [51] under CCBY-NC-ND.

5. Regulatory affairs

Only one drug with this mechanism of action has been approved for the treatment of menopausal VMS, fezolinetant (VEOZAH). Hepatic toxicity has been a concern, since the withdrawal of palvinetant/MLE4901 from further development for that reason. In the key trial of fezolinetant, including 2205 women, the incidence of liver enzyme elevations was low (fezolinetant 30 mg n = 2; fezolinetant 45 mg n = 0; placebo n = 1), and these events were generally asymptomatic, transient, and resolved on treatment or after discontinuation [31]. Current initial FDA requirements for prescription of VEOZAH include to check liver function tests pretreatment and at 3, 6, and 9 months after initiation of therapy.

6. Conclusion

Elinzanetant has shown clinical efficacy in Phase II trials for the treatment of menopausal VMS, with once daily dosing. As with other NKR antagonists, this effect has remarkable speed of onset and substantial reductions in VMS frequency and severity, with improvements in quality of life scores. At present, efficacy has been demonstrated for a treatment duration of up to 12 weeks, with ongoing Phase III studies of up to 52 weeks, and there is no indication of significant safety concerns, including liver toxicity. Side effects include somnolence, which may be dose-dependent, and may be mitigated by nighttime administration, potentially increasing its effectiveness against nighttime awakening, a troublesome VMS-related menopausal symptom.

7. Expert opinion

VMS of the menopause are common, frequently debilitating and can last for several years. This compromises women’s wellbeing and has significant social and economic impact. While VMS are a ubiquitous physiological process at ages from the mid-forties onwards, they can also be experienced at younger ages, e.g after ovary-damaging cancer treatments. While HRT is effective for many women, its use fell dramatically after the publication of large trials notably the Women’s Health Initiative, although the well-publicized risks have subsequently been re-evaluated [52]. Nevertheless many women remain concerned and HRT is contra-indicated in some women. Effective and safe alternatives are therefore needed, and current non-hormonal therapies are generally of limited use.

The advent of the NKR antagonists has great promise for the treatment of menopausal VMS. The first drug in the field, fezolinetant, has recently been approved by the FDA, and no doubt approval by other regulatory agencies will follow shortly. Elinzanetant has also shown good efficacy in Phase II trials, without problematic side-effects for most women and with no adverse safety issues identified. Symptom relief is rapid, thus comparing favorably to the slower onset of effect of HRT [4]. Elinzanetant is currently being investigated in a series of Phase III studies, notably including one specifically addressing its potential in women with past breast cancer. This widening of the patient base is welcome and it is hoped that other patient groups (such as men treated with androgen deprivation for prostate cancer [53]) may also be investigated in the future. Conversely, as a non-hormonal approach these drugs will not address other important aspects of postmenopausal health such as vaginal dryness, dyspareunia, and loss of bone density. The absence of hormonal activity does though bring the advantage of not carrying a risk of endometrial stimulation, which may result in abnormal vaginal bleeding and endometrial hyperplasia/malignancy.

The key safety concern with this class of drugs has been liver toxicity, which resulted in the cessation of development of one drug, and the imposition of the need for specific testing in routine clinical use for fezolinetant, although the Phase III trials showed no evidence for concern. Likewise, elinzanetant has also shown no evidence of liver toxicity, but the current Phase III trials will be pivotal in this regard.

Elinzanetant differs from other comparable drugs in development in its antagonism of NK1 as well as NK3 receptors. At present, evidence supports the involvement of NK3R but not NK1R in the central regulation of thermoregulation, although NK1 receptors are also involved in the other main hypothalamic regulatory pathway involving NK activity, the regulation of GnRH secretion, and SP is over-expressed in the human postmenopausal hypothalamus [21]. Further relevant central NK1R-related pathways may remain to be identified. There is also evidence for an important role for SP/NK1R signaling in peripheral vasodilatation, which may be increased in women with VMS [54]. While activity of elinzanetant at this locus has not been specifically explored, it is likely to contribute to the overall symptom benefit in VMS. NK1R antagonists may also have therapeutic value in primary insomnia [39] which may be of relevance to the poor sleep often associated with VMS. Both pathways may contribute to the regulation of reproductive function in both men and women. This has been explored for NK3R antagonists for partial suppression of the reproductive axis in women with polycystic ovary syndrome [55,56], but this general approach is also widely used for treatment of women with fibroids and endometriosis. Its possible that the antagonism of SP/NK1R pain signaling and fibrosis may be of additional value in the treatment of endometriosis [57,58], and partial reproductive suppression with prevention of ovulation may also be a potential NK antagonism-based non-hormonal approach to contraception [48,59].

In summary, the value of elinzanetant for the treatment of menopausal VMS is emerging. This is a global therapeutic area with significant and inadequately-met need, and the development of elinzanetant and related NKR antagonists has substantial promise. In addition, there are likely to be other therapeutic areas in reproductive health that may be targets for this approach.

Declaration of interest

J Sassarini has received honoraria from Theramex, Gedeon Richter and Astellas. RA Anderson has a role in data monitoring for Bayer in Phase III studies of elinzanetant.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.