NT-814 has successfully completed a Phase 2a proof of concept study demonstrating its potential to reduce the frequency and severity of hot flashes, and is now being prepared to enter an international Phase 2b study in this anchor indication.
The rationale for NT-814 as a potential therapy for hot flashes is based on emerging science that points to an obligate regulatory role for the NK-3 receptor system on the centrally located (hypothalamus) “KNDy” (kisspeptin-neurokinin B-dynorphin) neuronal network. There is also evidence to indicate a direct influence on the hypothalamic heat-dissipation neurons.
The NK-3 receptor system thus has a controlling influence on at least two major pathways: the heat dissipating Thermoregulatory Pathway and the Gonadotropin Releasing Hormone (GnRH) Pathway that is part of the hypothalamic-pituitary-gonadotrophin (HPG) axis, which regulates sex steroid hormone release.
In addition, the NK-1 receptor system has also been shown to be expressed on KNDy neurons in humans and may also make a contribution to heat loss in the periphery via promoting cutaneous vasodilation (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.
In menstruating women, oestrogen produced from the ovaries has a feedback effect on the KNDy neurons located in the hypothalamus which thereby regulates the reproductive cycle via the GnRH Pathway/HPG axis.
In post-menopausal women, the absence of oestrogen and therefore the loss of the regulation by this sex steroid onto the KNDy neurons causes them to become enlarged (hypertrophic) and hyperactive.
These events are believed to disrupt the normal functioning of the heat dissipation effector mechanisms resulting in the debilitating symptoms of hot flashes.
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. This should return 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 making a contribution to reducing hot flash intensity.