Delving into the Latest Updates on Pavinetant with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Pavinetant (USAN/INN), AZ-12472520, AZD2624

+ [2]

Target

NK3

Mechanism

NK3 antagonists(Neurokinin 3 receptor antagonists)

Therapeutic Areas

NeoplasmsNervous System DiseasesEndocrinology and Metabolic Disease+ [1]

Active Indication-

Inactive Indication

Polycystic Ovary SyndromeSchizophrenia

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

AstraZeneca PLCMillendo Therapeutics US, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC26H25N3O3S

InChIKeyQYTBBBAHNIWFOD-NRFANRHFSA-N

CAS Registry941690-55-7

The 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, METHODS:

Subjects 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 CHANCE:

NK3Ra 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 CAUTION:

The 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 FINDINGS:

These 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 NUMBER:

N/A.

01 Feb 2020·Journal of the Endocrine Society

Neurokinin 3 Receptor Antagonists Do Not Increase FSH or Estradiol Secretion in Menopausal Women

Article

Author: Higham, Claire E ; Adaway, Jo ; Comninos, Alexander N ; Jayasena, Channa N ; Prague, Julia K ; Abbara, Ali ; Dhillo, Waljit S ; Keevil, Brian G ; Veldhuis, Johannes D

Abstract:

Background:

Neurokinin 3 receptor (NK3R) antagonism is a promising novel treatment for menopausal flashes. However, to avoid adverse hormonal effects it is clinically important to first confirm whether gonadotropin and estradiol concentrations change as a result of their administration.

Methods:

Single-center, randomized, double-blind, placebo-controlled, crossover trial of an oral NK3R antagonist (MLE4901) in 28 women aged 40 to 62 years, experiencing >7 hot flashes/24 h; some bothersome or severe (Clinicaltrials.gov, NCT02668185). Weekly serum gonadotropins and estradiol levels were measured using commercially available automated immunoassays a priori. Serum estradiol was also measured post hoc using a highly sensitive direct assay by liquid chromatography tandem mass spectrometry. Hormone levels were compared by the paired sample t tests or by the Wilcoxon matched-pairs signed rank test, as appropriate for the distribution of the data.

Results:

Mean (standard deviation) serum follicle-stimulating hormone (FSH) concentration was not significantly increased when taking MLE4901 (72.07 ± 19.81 IU/L) compared to placebo (70.03 ± 19.56 IU/L), P = .26. Serum estradiol was also not significantly altered, irrespective of which assay method was used (median interquartile range of serum estradiol by immunoassay: placebo 36 ± 3 pmol/L, MLE4901 36 ± 1 pmol/L, P = .21; median serum highly sensitive estradiol: placebo 12 ± 16 pmol/L, MLE4901 13 ± 15 pmol/L, P = .70). However, mean (standard deviation) serum luteinizing hormone concentration significantly decreased with MLE4901 (27.63 ± 9.76 IU/L) compared to placebo (30.26 ± 9.75 IU/L), P = .0024.

Implication:

NK3R antagonists do not increase serum estradiol or FSH despite their reduction in hot flashes. This is clinically significant and highly reassuring for women who have a contraindication to conventional hormone therapy such as prior/existing breast cancer and/or thromboembolism.

01 Aug 2018·Menopause (New York, N.Y.)Q3 · MEDICINE

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

Q3 · MEDICINE

Article

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

Abstract:

Objective::

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.

100 Deals associated with Pavinetant

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External Link

KEGG	Wiki	ATC	Drug Bank
D11345	Pavinetant	-	DB11692

R&D Status

10 top R&D records.

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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

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02865915 (CTgov)	Phase 2	Polycystic Ovary Syndrome	55	Placebo (Placebo Treatment Arm)	ejawkopmhm(inkjiewadu) = ylrhhwiqqu sqonrplhph (ulbcjilqqg, xbyejmhtgz - czacnlgblv) View more	-	16 Jun 2020
				MLE4901 (MLE4901 Treatment Arm)	ejawkopmhm(inkjiewadu) = uhrdjoyiop sqonrplhph (ulbcjilqqg, unepxpkygy - dxqvacwtjc) View more
NCT02668185 (Pubmed)	Phase 2	Andropause	28	NK3R antagonist (MLE4901)	kzdbbnbwaj(izlexgkglu) = bdcswalmtf gmahzkupag (cbqhtzvera )	Positive	01 Feb 2020
				Placebo	kzdbbnbwaj(izlexgkglu) = tyocaeywlv gmahzkupag (cbqhtzvera )
NCT02668185 (Pubmed \| Lancet) Manual	Phase 2	Hot Flashes	37	MLE4901	xsqyqemthc(yxxlmqermz) = azluffgxqt zahuwnuqxw (xnqkdufpbs, 15.99 - 23.42)	Positive	06 May 2017
				Placebo	xsqyqemthc(yxxlmqermz) = mmlguvcfna zahuwnuqxw (xnqkdufpbs, 40.81 - 58.56)
NCT01872078 (Pubmed \| J Clin Endocrinol Metab) Manual	Phase 2	Polycystic Ovary Syndrome	67	AZD4901	rwetruaifc(xbneheimry) = dvlgpeduqz quhmdabyoh (tzsfzetiqa )	Positive	01 Nov 2016
				Placebo	-
NCT01872078 (CTgov)	Phase 2	Polycystic Ovary Syndrome	67	placebo (Placebo)	saailjsdqw(kugrgsrbys) = eieawfzmuf jmwgzzedlm (cczsuczyjf, grvomljlbe - inakudmpxo) View more	-	12 Oct 2015
				AZD4901 (20 mg AZD4901 qd)	saailjsdqw(kugrgsrbys) = coycqnzvqt jmwgzzedlm (cczsuczyjf, bhrmyrpfls - etzerxcmoq)
NCT00686998 (CTgov)	Phase 2	Schizophrenia	106	AZD2624 (AZD2624)	itqaoaxpzv(rpnzgrnyoq) = rszalrnpsn zvnprryusd (gyhxhklvfu, hbvdazznhc - vhknsynfhv) View more	-	23 Jun 2011
				Placebo (Placebo)	itqaoaxpzv(rpnzgrnyoq) = ifzolcdslz zvnprryusd (gyhxhklvfu, xjservtrxt - ljoajsdxov) View more