The mechanism of action of fezolinetant is strongly supported by human genomics, extensive pre-clinical pharmacology and clinical data from independent scientists confirming the importance of the NK3 receptor in the modulation of Women’s Health Disorders.
In women (and men), the KNDy neuron in the brain senses levels of estrogen and thereby regulates sex hormone levels in the body.
For example, high levels of estrogen decrease KNDy neuron activity, reducing further synthesis of sex hormones. Fezolinetant acts directly on the KNDy neuron to decrease its activity, thereby providing a non-hormonal approach to mimic the effects of estrogen.
This means that fezolinetant can be used therapeutically in conditions where estrogen levels, or the response to estrogen, are dysregulated.
Menopausal Hot Flashes: In menopause, the ovaries fail and estrogen levels decline. As a result, KNDy neuron activity rises to signal increased estrogen synthesis, but this demand cannot be fulfilled because the ovaries are unable to replenish estrogen levels. The result is uncontrolled KNDy neuron firing. The problem is that the KNDy neuron also signals to the thermoregulatory center in the brain, where uncontrolled KNDy neuron activity leads to the sensation of hot flashes. The potential solution is to decrease KNDy neuron activity using fezolinetant.
- Hormone Replacement Therapy (‘HRT’; e.g. estrogen therapy) effectively treats hot flashes. However, the Women’s Health Initiative Study advises against chronic treatment with HRT due to safety concerns pertaining to cancer and cardiovascular effects. Fezolinetant provides a potential non-hormonal alternative for the treatment of hot flashes.
- The treatment of sex hormone-dependent cancers (e.g. breast cancer and prostate cancer) requires the use of drugs that severely lower sex hormones (estrogen, testosterone) where hot flashes are a major side effect of cancer therapy. Fezolinetant provides a potential non-hormonal solution for the treatment of hot flashes caused by sex hormone-dependent cancer therapy.
Polycystic Ovary Syndrome (PCOS): In PCOS, patients are typically characterized by high levels of testosterone, an infrequent/irregular menstrual cycle and low fertility. The problem is caused by an imbalance in the hormones LH and FSH, where the LH:FSH ratio is key to the regulation of the different stages of the menstrual cycle. The potential solution is fezolinetant treatment to decrease KNDy neuron activity, thereby causing a re-balancing of the LH:FSH ratio, permitting the efficient conversion of androgens (i.e. testosterone) to estrogen and ultimately restoration of the menstrual cycle and fertility.
Uterine Fibroids (UF): In UF, estrogen and progesterone are clearly implicated in the growth of the fibroid. This is proven by the fact that castrating agents, such as GnRH antagonists, effectively treat UF. But the problem is that these castrating agents provoke menopause-like symptoms in premenopausal UF patients. The potential solution is treatment with fezolinetant, which is scientifically proven to cause a more gradual rise of estrogen levels over the menstrual cycle, such that the adverse events but fibroid growth is mitigated.
Endometriosis: Estrogen is clearly a key driver of excessive endometrial tissue growth. Thus, GnRH antagonists do treat endometriosis, but with the unfortunate side effect of castration. Fezolinetant is expected to offer therapeutic benefit in the treatment of endometriosis by causing a more gradual modulation of estrogen levels over the menstrual cycle without risk of menopause like adverse events.