Unlocking significant potential
NT-814 has successfully completed a Phase 2a proof of concept study demonstrating its potential to rapidly and profoundly reduce two key symptoms of the Menopause: hot flashes and night time awakening. NT-814 is being prepared to enter a multi-country Phase 2b study in this anchor Women’s Health indication, starting in Q4 2018.
In menstruating women, release of the sex hormone oestrogen, is regulated through the hypothalamic-pituitary-gonadotrophin (HPG) axis that controls reproductive function and health. Located in the hypothalamus are a group of neurons that express kisspeptin-neurokinin B-dynorphin – the so called ‘KNDy’ neurons. The KNDy neurons play a pivotal role in the HPG axis as they are the Gonadotropin Releasing Hormone (GnRH) pulsatile ‘generator’ – and thereby are the master controller of the release of the gonadotropins (Luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) that stimulate the ovaries to produce oestrogen. In turn the oestrogen has a feedback effect on the activity of the KNDy neurons. Importantly, recent evidence indicates that the KNDy neurons can also influence the regulation of body temperature (via hypothalamic heat dissipation effector mechanisms).
In post-menopausal women, the HPG axis breaks down as there is a loss of oestrogen production by the ovaries and therefore absence of feedback and regulation onto the KNDy neurons, causing them to become enlarged (hypertrophic) and hyperactive. These events are believed to disrupt the normal functioning of the thermoregulatory heat dissipation effector mechanisms resulting in the debilitating symptoms of hot flashes.
The rationale for NT-814 as a potential therapy for hot flashes is based on an ever-growing body of scientific evidence* that points to an obligate regulatory role for the NK-3 receptor system on the functioning of the KNDy neuronal networks. The same emerging body of data also indicates a direct influence this receptor system on the hypothalamic heat-dissipation neurons themselves.
Thus the NK-3 receptor system has a controlling influence on at least two major pathways: the heat dissipating Thermoregulatory Pathway and the Gonadotropin Releasing Hormone (GnRH) Pathway as shown in this figure.
The KNDy neurons have also been shown to express NK-1 receptors and its ligand Substance P, suggesting this receptor system may be involved in the functioning of this neuronal circuitry. Furthermore the NK-1 receptor system may make a contribution to heat loss in the periphery via induction of cutaneous vasodilatation (hot flashes); indeed arm-vein infusion of Substance P causes the flushing of the face and neck that is characteristic of post-menopausal vasomotor symptoms.
The dual NK-1,3 receptor antagonist NT-814 thus has the potential to reduce the hyperactivity of the KNDy neuronal network in menopausal women by inhibition of NK-3 receptor signalling centrally on both the KNDy and heat dissipation neurons, thereby returning the heat dissipation effectors to normal functioning and address the dysregulation that is driving hot flash symptoms.
In addition, blockade of NK-1 receptors in the periphery on the cutaneous vasculature by NT-814 may also result in a lessening of the vasodilatory response, thereby contributing to reducing the intensity of hot flashes.
The NK-1 antagonism offered by NT-814 could also make a broader contribution to the amelioration of other bothersome symptoms of the menopause, including sleep and mood disturbance. NK-1 receptor antagonists have demonstrated proof of concept in both primary insomnia and in depression. Hence, there is a strong clinical rationale that NT-814’s unique dual mechanism combination of NK-1 and NK-3 receptor antagonism could treat multiple symptoms of the menopause; thus it potentially represents a truly transformational, non-hormonal alternative to HRT.
*Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ.
Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes.
Front Neuroendocrinol. 2013 Aug;34(3):211-27.
Padilla SL, Johnson CW, Barker FD, Patterson MA, Palmiter RD.
A Neural Circuit Underlying the Generation of Hot Flushes.
Cell Rep. 2018 Jul 10;24(2):271-277.