Fezolinetant in the treatment of vasomotor symptoms associated with menopause

Figures & data

Table 1. Comparison of fezolinetant to first-generation NK3R antagonists osanetant and talnetant in rat. (A) Minimum effective dose correlates to brain receptor occupancy (e.g. unbound (‘free’) concentration of drug relative to receptor potency), (B) in vivo efficacy of NK3R antagonists measured by dose-dependent inhibition of plasma LH in castrate rat

Panel A
Rat data	Fezolinetant	Osanetant	Talnetant
NK3R potency Ki (nM)	219	56	193
CLu (mL/min/kg)	2.3	9500	6700
Brain free fraction (%)	52.5	0.1	1.0
Cbrain,u (nM)	343	0.15	4.74
(Cbrain,u)/Ki	1.566	0.003	0.025
MED (mg/kg, oral)	3	>100	>100
Panel B

CL_u: unbound clearance; C_brain,u: unbound concentration of drug in brain; LH: luteinizing hormone; MED: minimum effective dose (relative to baseline; P < 0.05).  PO: oral dosing. Data in panel B are mean ±SEM; LH at 90 min after dosing. Unbound plasma clearance (CLu) and unbound brain concentrations were based on measurements following doses of each compound at 1 mg/kg (iv) in rat.

Data from Hoveyda HR et al. ACS Med Chem Lett 2015; 6: 736–740, Hoveyda HR et al. J Med Chem 2015; 58: 3060–3082, and Astellas data on file.

Table 2. Receptor binding potency and selectivity at the human isoforms of the neurokinin receptor subtypes for fezolinetant, osanetant, and talnetant

Compound	NK1R^a (Ki, nM)	NK2R^b (Ki, nM)	NK3R^c (Ki, nM)
Fezolinetant	<50% displacement @ 30 μM	<50% displacement @ 30 μM	21.8
Osanetant	330	85	1.9
Talnetant	<50% displacement @ 10 μM	3,700	7.4

Radioligand binding experiments were performed using recombinant, human clones of the NK receptor subtypes individually expressed in Chinese hamster ovary cells. All data reported as the median value from three independent experiments. Binding potencies determined for each receptor subtype by competitive displacement [³H]Substance P^a, [¹²⁵I]Neurokinin A^b, and [³H]-SB222200^c, respectively.

NK1R: neurokinin-1 receptor; NK2R: neurokinin-2 receptor; NK3R: neurokinin-3 receptor.

Data from Hoyveda HR, Roy M-O, Blanc S, et al. Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor. Bioorganic & Medicinal Chemistry Letters 21 (2011) 1991–1996, Hoveyda HR et al. ACS Med Chem Lett 2015; 6: 736–40, Hoveyda HR et al. J Med Chem 2015; 58: 3060–3082, and Astellas data on file.

Figure 1. Mechanism of action of NK3R antagonists in VMS ERα: estrogen receptor alpha; FEZ: fezolinetant (NK3R antagonist); KNDy: Kisspeptin/Neurokinin B/Dynorphin; NKB: neurokinin B; NK3R: neurokinin-3 receptor; VMS: vasomotor symptoms

Table 3. Treatment-emergent adverse events in the phase IIb study

		Fezolinetant, n (%)
	Placebo (n = 43), n (%)	15 mg BID (n = 45)	30 mg BID (n = 43)	60 mg BID (n = 45)	90 mg BID (n = 44)	30 mg QD (n = 43)	60 mg QD (n = 45)	120 mg QD (n = 44)
TEAEs	21 (48.8)	20 (44.4)	18 (41.9)	21 (46.7)	19 (43.2)	23 (53.5)	28 (62.2)	22 (50.0)
Serious TEAEs	0	0	0	0	0	0	1 (2.2)^a	0
TEAEs leading to permanent discontinuation	1 (2.3)	0	4 (9.3)	5 (11.1)	3 (6.8)	2 (4.7)	3 (6.7)	3 (6.8)
TEAEs leading to treatment interruption	1 (2.3)	0	0	2 (4.4)	3 (6.8)	0	0	1 (2.3)
Any treatment-related TEAEs	3 (7.0)	1 (2.2)	9 (20.9)	8 (17.8)	9 (20.5)	10 (23.3)	12 (26.7)	11 (25.0)
TEAEs occurring in ≥5% in any treatment arm
Headache	2 (4.7)	3 (6.7)	2 (4.7)	2 (4.4)	1 (2.2)	6 (14.0)	3 (6.7)	4 (9.1)
Nausea	1 (2.3)	1 (2.2)	3 (7.0)	3 (6.7)	1 (2.3)	2 (4.7)	3 (6.7)	2 (4.5)
Urinary tract infection	1 (2.3)	2 (4.4)	1 (2.3)	2 (4.4)	2 (4.5)	2 (4.7)	2 (4.4)	3 (6.8)
Diarrhea	1 (2.3)	0	1 (2.3)	2 (4.4)	2 (4.5)	1 (2.3)	3 (6.7)	2 (4.5)
Upper respiratory tract infection	1 (2.3)	2 (4.4)	1 (2.3)	1 (2.2)	1 (2.3)	3 (7.0)	1 (2.2)	1 (2.3)
Fatigue	0	1 (2.2)	1 (2.3)	1 (2.2)	2 (4.5)	0	3 (6.7)	1 (2.3)
Viral upper respiratory tract infection	0	2 (4.4)	1 (2.3)	1 (2.2)	3 (6.8)	0	0	0
Sinusitis	0	0	0	3 (6.7)	0	1 (2.3)	2 (4.4)	0
Cough	0	1 (2.2)	0	1 (2.2)	0	0	3 (6.7)	0

TEAE: treatment-emergent adverse event.

^aSkin squamous cell carcinoma in a participant who had a preexisting skin mass; not considered treatment related.

Adapted from Fraser GL, Lederman S, Waldbaum A, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020;27(4):382–392. https://journals.lww.com/menopausejournal/pages/default.aspx. Menopause is published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society (NAMS).

Figure 2. Effect of fezolinetant on VMS over time. (A) Daily total VMS score during week 4 and week 12. (B) Frequency of moderate/severe hot flashes during the duration of the study. (C) Moderate/severe VMS score during the duration of the study. Data are presented as mean ± 95% CI (mITT population, observed data). BID: twice daily; CI: confidence interval; FUP: follow-up; HF: hot flashes; mITT: modified intention to treat; VMS: vasomotor symptoms. Adapted from Depypere H, Timmerman D, Donders G, et al., Treatment of Menopausal Vasomotor Symptoms with Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial, The Journal of Clinical Endocrinology & Metabolism 2019; 104 (12): 5893–5905 doi:10.1210/jc.2019-00677. Reprinted (and adapted) by permission of Oxford University Press on behalf of the Endocrine Society

Figure 3. Effect of fezolinetant on quality of life measures. (A) LSEQ (does not include a total mean score that incorporates all four dimensions assessed). (B) HFRDIS. (C) GCS. (D) SDS. Data are presented as mean ± 95% CI (mITT population). BID; twice daily; CI: confidence interval; GCS: Greene Climacteric Scale; LSEQ: Leeds Sleep Evaluation Questionnaire; mITT: modified intention to treat; SDS: Sheehan Disability Scale. From Depypere H, Timmerman D, Donders G, et al., Treatment of Menopausal Vasomotor Symptoms with Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial, The Journal of Clinical Endocrinology & Metabolism 2019; 104 (12): 5893–5905 doi:10.1210/jc.2019-00677. Reprinted by permission of Oxford University Press on behalf of the Endocrine Society

Table 4. Primary efficacy outcomes: frequency of moderate/severe VMS per 24 h, full analysis set

	Frequency of moderate/severe VMS per 24 h^a
		Difference from placebo
		LS mean (SE)	95% CI	P value^b
Week 4	Fezolinetant treatment group
	15 mg BID (n = 40)	–1.9 (0.84)	–3.56 to –0.25	0.024
	30 mg BID (n = 41)	–3.0 (0.84)	–4.68 to –1.38	0.0004
	60 mg BID (n = 40)	–2.8 (0.84)	–4.44 to –1.14	0.0010
	90 mg BID (n = 37)	–3.5 (0.84)	–5.20 to –1.89	<0.0001
	30 mg QD (n = 40)	–2.3 (0.84)	–4.00 to –0.68	0.0058
	60 mg QD (n = 43)	–3.0 (0.82)	–4.65 to –1.41	0.0003
	120 mg QD (n = 42)	–2.4 (0.84)	–4.06 to –0.76	0.0042
Week 12	Fezolinetant treatment group
	15 mg BID (n = 38)	–1.8 (0.75)	–3.30 to –0.35	0.0154
	30 mg BID (n = 37)	–2.1 (0.74)	–3.60 to –0.67	0.0043
	60 mg BID (n = 31)	–2.3 (0.75)	–3.76 to –0.83	0.0023
	90 mg BID (n = 31)	–2.6 (0.75)	–4.09 to –1.16	0.0005
	30 mg QD (n = 33)	–2.1 (0.75)	–3.52 to –0.58	0.0064
	60 mg QD (n = 36)	–2.6 (0.74)	–4.04 to –1.15	0.0005
	120 mg QD (n = 36)	–2.1 (0.75)	–3.52 to –0.59	0.0063

ANCOVA: analysis of covariance; LS: least squares; SE: standard error; VMS: vasomotor symptoms.

^aFrom ANCOVA model with change from baseline as the dependent variable and treatment group, pooled center, smoking status as factors and baseline measurement and baseline weight as covariates.

^bBased on pairwise comparisons with placebo without adjustment for multiplicity.

Adapted from Fraser GL, Lederman S, Waldbaum A, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020;27(4):382–392. https://journals.lww.com/menopausejournal/pages/default.aspx. Menopause is published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society (NAMS).

Figure 4. Structures of NK3R antagonists advanced into clinical development – (A) osanetant, (B) talnetant, pavinetant and SJX-653, (C) elinzanetant, (D) fezolinetant

Box 1. Drug summary box

Drug name (generic)	Fezolinetant
Phase (for indication under discussion)	III
Indication (specific to discussion)	VMS
Pivotal trial(s)	EudraCT 2015-002578-20, ClinicalTrials.gov NCT03192176
Pharmacology description/mechanism of action	NK3 receptor antagonist
Route of administration	Oral
Chemical structure	(4-fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone

Data availability statement

Researchers may request access to anonymized participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.