Commentary on “Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men”

A “Rapidly-Moving” Field: Tachykinins as a Therapeutic Target

Tachykinins are a family of peptides so-named due to their contractile action on gut tissue. TAC1 and TAC3 are the tachykinin genes in humans (equivalent to Tac1 and Tac2 in rodents); TAC1 encodes for Neurokinin A (NKA) and Substance P (SP), whereas TAC3 encodes for Neurokinin B (NKB). Neurokinin A and SP are major excitatory neurotransmitters in the peripheral nervous system, whereas NKB has a principally central action. The three G-protein coupled receptors: NK1R, NK2R, and NK3R primarily bind SP, NKA, and NKB, respectively; however, the tachykinins can cross-activate other NKRs, albeit with lower affinity. Antagonists for NK1R have been developed as antiemetics, for NK2R as anxiolytics, and historically for NK3R as antipsychotics.

In recent years, the critical role of the decapeptide NKB in reproductive neuroendocrinology has come to the fore. Inactivating variants in the TAC3R gene cause congenital hypogonadotropic hypogonadism. Neurokinin B is co-expressed with kisspeptin and dynorphin in the hypothalamus of animal models in Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons. Neurokinin B acts upstream of kisspeptin to increase GnRH pulsatility in higher species, whereas dynorphin has an inhibitory action. Thus, these neuropeptides act in concert to regulate the release of kisspeptin and thus determine the pulsatile nature of GnRH secretion. Accordingly, the NK3R antagonist (MLE4901, previously known as AZD4901) ameliorates the raised Luteinizing Hormone (LH) levels (reflective of underlying increased GnRH pulsatility) and resultant hyperandrogenism in women with polycystic ovary syndrome (PCOS) (1).

Over recent years, another major role for NKB has emerged in the pathophysiology of postmenopausal flushing. Naomi Rance’s group first proposed that NK3R mediates the occurrence of postmenopausal vasomotor symptoms (VMS) (2). Neurokinin B–containing neurons are hypertrophied in postmenopausal women due to the lack of the usual physiological constraint by estradiol. Further, NK3R agonist administration into the median preoptic nucleus (MnPO) of the anterior hypothalamus induced heat dissipation in rodents, whereas ablation of KNDy neurons prevented a corollary of postmenopausal flushing (2). Thus, NK3R on MnPO neurons were shown to be key conduits of the thermoregulatory control center, with a central role in mediating postmenopausal VMS. Moreover, 14 single nucleotide polymorphisms in the gene encoding for NK3R were identified in a large Genome Wide Association Study meta-analysis to associate with the occurrence of VMS in postmenopausal women. Although not significantly affecting gonadotropin secretion, administration of higher doses of NKB induced vasomotor flushing in healthy women. Conclusively, in 28 postmenopausal women, the NK3R antagonist MLE4901 (40 mg twice daily (BID) orally) was shown to induce rapid and significant reductions in flushing frequency by 45% compared with placebo (3).

To date, all NK3R antagonists investigated in postmenopausal women have been efficacious in controlling VMS, including 2 selective NK3R antagonists, namely, MLE4901 (pavinetant), and ESN364 (fezolinetant), in addition to the dual NK1R/NK3R antagonist, NT-814. NK1R has been proposed to also contribute to VMS, with NK1R desensitisation attenuating cutaneous vasodilatation and SP administration inducing flushing. Although NK1R antagonism alone is ineffectual in alleviating VMS, NK1R antagonists also have putative anxiolytic effects and can relieve insomnia, as well as anti-emetic effects. Thus, while NT-814 could theoretically offer an additional benefit on sleep quality in postmenopausal women, its predominant action on VMS is mediated via NK3R antagonism.

NK3R antagonists are significantly more effective (by at least 2-fold) than other nonhormonal agents, eg, SSRI, at relieving VMS in postmenopausal women. In a Phase 2A trial of 87 postmenopausal women over 12 weeks, ESN364 (90 mg BID) significantly reduced VMS by 5 episodes per day (4). In the subsequent Phase 2B trial of 287 postmenopausal women randomly assigned to doses of ESN364 between 15 mg once daily (QD) to 90 mg BID, 81% to 95% had an at least a 50% reduction in VMS frequency (5). ESN364 was well-tolerated (21 women discontinued due to adverse effects), with side-effects including headache, nausea, diarrhea, and fatigue.

NT-814 was initially studied in RELENT-1, in which 76 postmenopausal women were randomized to NT-814 at doses between 50 and 300 mg once daily for 2 weeks; NT-814 reduced VMS frequency by 84% (39% placebo), and reduced waking due to night sweats by 81% (32% placebo), with significant improvements at doses of 150 mg or 300 mg (6). Side-effects of NT-814 included somnolence, headaches, and diarrhea. In SWITCH-1, a 12-week Phase 2B randomized, dose-finding (40–160 mg QD) study in 199 postmenopausal women, NT-814 doses of 120 and 160 mg significantly reduced VMS frequency and improved sleep, mood, and quality of life (7).

The half-lives of MLE4901, ESN364, and NT-814 were ~8.5 hours, 4–7 hours, and ~15 hours (but as long as 26 hours at higher doses) (6), respectively, with rapid absorption following oral administration (t_max 1–8 hours, 3–4 hours, and 4–5 hours, respectively). Based on the short half-life of ESN364, twice daily dosing would be expected to achieve better symptom control than once daily dosing; however, this was only of marginal benefit when using equivalent total daily doses (5).

In this issue of The Journal of Clinical Endocrinology & Metabolism, Anderson and colleagues report a Phase 1, double-blind, dose-ascending study in 28 healthy men who received a single oral dose (0.5–90 mg) of the novel competitive NK3R antagonist, SJX-653 (n = 4 per group), and 14 who received placebo (8). SJX-653 is based on an isoquinolinone scaffold and is chemically distinct from other NK3 antagonists, with 100- to 1000-fold selectivity for NK3R (8). SJX-653 induced a dose-dependent, reversible reduction in LH and testosterone levels. SJX-653 had a narrow dosing range, with 4.5 mg being ineffective but 15 mg having close to maximal effects. SJX-653 had a half-life of 9.8 to 12.5 hours, t_max of 3 to 6 hours, a dose-proportional C_max and IC₅₀ for LH reduction of 33 ng/ml. Maximal suppression of LH by 70% (vs 10% placebo) occurred at 6 hours after 30 mg and of testosterone by 68% (vs 18% placebo) at 8 hours after 60 mg (8). Notably, maximal suppression of LH and testosterone occurred at 6 to 12 hours but was lost by 24 to 36 hours, despite ongoing high levels of SJX-653 at higher doses (8). SJX-653 was well-tolerated at all doses investigated in this single-dose study; however, confirmation of its safety profile in multidose studies, especially with respect to liver dysfunction, will be of relevance in later larger phase studies. Although investigated in healthy men, similar dose ranges of MLE4901 (40 mg BD) and of ESN364 (15–180 mg per day) were as efficacious in supressing LH levels in healthy individuals as on reducing VMS in postmenopausal women with other agents in the class. Thus, these data suggest that SJX-653 could have the potential to be efficacious in the suppression of VMS in postmenopausal women and other sex hormone–dependent conditions, pending further study of safety and efficacy.

In summary, NK3R antagonists have demonstrated clear effectiveness for the management of postmenopausal flushing and are likely to revolutionise the management of VMS in the clinic in the near future. Although significant efficacy is found using all agents in the class, the side-effect profile appears to be specific to each agent: MLE4901 was associated with an idiosyncratic transient rise in ALT of up to 6xULN in 3/28 women, and thus development was discontinued. However, recent data for ESN364⁵ and NT-814⁷ showed minimal or no clinically significant changes in liver enzymes, respectively. Hence, Phase 3 trials with ESN364 (Astellas) and NT-814 (Bayer) are underway, given this reassuring early data. Aside from alleviating VMS, NK3R antagonists may also have utility in a range of other reproductive conditions due to their ability to induce noncastrate suppression of sex-steroid levels, including endometriosis, fibroids, PCOS, and potentially even as a nonhormonal contraceptive if reliable gonadotropin suppression can be demonstrated. While the therapeutic benefit of these drugs appears to be a class effect, side-effects such as liver injury may not be, thus the development of multiple agents with NK3 antagonist activity, such as SJX-653, is desirable to maximize the therapeutic potential of this class of drugs.

Acknowledgments

Financial Support: A.A. is supported by National Institute of Health Research (NIHR) Clinician Scientist Award CS-2018-18-ST2-002. W.S.D. is supported by an NIHR Research Professorship NIHR-RP-2014-05-001.

Additional Information

Disclosure Summary: A.A. and W.S.D. have conducted consulting work for Myovant Sciences Ltd. W.S.D. has conducted consulting work for Millendo Therapeutics and KaNDy Therapeutics.

Data Availability

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

References