Delving into the Latest Updates on Pavinetant with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Pavinetant (USAN/INN)

+ [2]

Target

NK3

Mechanism

NK3 antagonists(Neurokinin 3 receptor antagonists)

Therapeutic Areas

NeoplasmsEndocrinology and Metabolic DiseaseUrogenital Diseases+ [1]

Active Indication-

Inactive Indication

Polycystic Ovary SyndromeSchizophrenia

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

Millendo Therapeutics US, Inc.

AstraZeneca PLC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC26H25N3O3S

InChIKeyQYTBBBAHNIWFOD-NRFANRHFSA-N

CAS Registry941690-55-7

AbstractSTUDY QUESTIONWhat is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)?SUMMARY ANSWERAdministration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained.WHAT IS KNOWN ALREADYPCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear.STUDY DESIGN, SIZE, DURATIONThe NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSSubjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion.MAIN RESULTS AND THE ROLE OF CHANCENK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment.LIMITATIONS, REASONS FOR CAUTIONThe study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects.WIDER IMPLICATIONS OF THE FINDINGSThese data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback.STUDY FUNDING/COMPETING INTEREST(S)Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose.TRIAL REGISTRATION NUMBERN/A.

01 Aug 2018·MenopauseQ3 · MEDICINE

Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action

Q3 · MEDICINE

Article

Author: Clarke, Sophie ; Mohideen, Pharis ; Comninos, Alexander N. ; Dhillo, Waljit S. ; Roberts, Rachel E. ; Stern, Theresa P. ; Jayasena, Channa N. ; Panay, Nicholas ; Lin, Vivian H. ; Prague, Julia K. ; Webber, Lorraine C. ; Hunter, Myra S.

AbstractObjective:Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect.Methods:Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing ≥7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty-seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time course analysis was completed.Results:By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, −81.3 to −63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, −46.1 to −29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, −47.5 to −30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, −79.1 to −43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to −44%, −50%, and −70%, respectively by day 28, all P < 0.0001 compared with placebo).Conclusions:NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure.

01 Jan 2018·NeuroendocrinologyQ2 · MEDICINE

Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women

Q2 · MEDICINE

Article

Author: Richard A. Anderson ; Jyothis T. George ; Karolina Skorupskaite ; Johannes D. Veldhuis ; Robert P. Millar

Objectives: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored. Methods: Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration. Results: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist. Conclusions: The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.

100 Deals associated with Pavinetant

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
D11345	Pavinetant	-	DB11692

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Polycystic Ovary Syndrome	Phase 2	US	Millendo Therapeutics US, Inc.	01 Jul 2016
Schizophrenia	Phase 2	US	AstraZeneca PLC	01 May 2008

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02865915 (CTgov)	Phase 2	Polycystic Ovary Syndrome	55	Placebo (Placebo Treatment Arm)	krgnyjyxvo(zssmlqdiiy) = dohbxtknvy ixlwvyygne (vwdqbgrzyg, lmlhwdkovc - acotersqlw) View more	-	16 Jun 2020
				MLE4901 (MLE4901 Treatment Arm)	krgnyjyxvo(zssmlqdiiy) = lhkelqzgfl ixlwvyygne (vwdqbgrzyg, kkhkfzlvkp - tzirotziks) View more
NCT02668185 (Pubmed \| Lancet) Manual	Phase 2	Hot Flashes	37	MLE4901	svcmowqvwx(qmwtkoynwo) = yziaambdwg cdnyhbnlfm (jnlznmguqs, 15.99 - 23.42)	Positive	06 May 2017
				Placebo	svcmowqvwx(qmwtkoynwo) = pmrvytcimw cdnyhbnlfm (jnlznmguqs, 40.81 - 58.56)
NCT01872078 (Pubmed \| J Clin Endocrinol Metab) Manual	Phase 2	Polycystic Ovary Syndrome	67	AZD4901	(ymuddtnpfp) = oolfgsfvci vbylhvsqfw (iqpextcmbw )	Positive	01 Nov 2016
				Placebo	-
NCT00686998 (CTgov)	Phase 2	Schizophrenia	106	AZD2624 (AZD2624)	bekpgpedsn(bngakxnumv) = ygvzsiqkpg uhmyckmatd (pmmesfyndu, istkmiksvk - ojuavnrasd) View more	-	23 Jun 2011
				Placebo (Placebo)	bekpgpedsn(bngakxnumv) = bhbiugqshb uhmyckmatd (pmmesfyndu, llhnyfcfcl - gurkbiabjd) View more