Fezolinetant: First FDA Approved Treatment for Moderate-to-Severe Vasomotor Symptoms Associated with Menopause
Time to read: 4 minutes
The U.S. Food and Drug Administration approved Veozah (Fezolinetant), an oral medication for the treatment of moderate to severe vasomotor symptoms, or hot flashes, caused by menopause.
Veozah is the first neurokinin 3 (NK3) receptor antagonist approved by the FDA to treat moderate to severe hot flashes (flushes) from menopause.
Vasomotor symptoms, including hot flashes and night sweats, significantly impact the quality of life for many women experiencing menopause. Current treatment approaches primarily involve hormone replacement therapy (HRT), but alternative options are needed due to contraindications or individual preferences. Fezolinetant, a neurokinin 3 (NK3) receptor antagonist, presents a novel and promising avenue for addressing these symptoms.
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KNDy NEURONS AND THE ROLE OF NKB
The neuropeptides kisspeptin (discovered in 2001), Neurokinin B (NKB) and Dynorphin A, which were discovered in 1983 and 1979, respectively, are essential molecules that regulate the HPA axis and control reproduction in mammals.
They control reproduction via controlling pulsatile gonadotropin-releasing hormone (GnRH) release.
This summary highlights the key findings from the phase 3 randomized controlled study, “SKYLIGHT 1,” which investigated the efficacy of fezolinetant in the treatment of moderate-to-severe vasomotor symptoms (VMS) associated with menopause.
The hypothalamic arcuate nucleus (ARC) neurons co-expressing kisspeptin/neurokinin B/dynorphin A, referred to as “KNDy neurons”. [Uenoyama et al, 2021]
- NKB is a neuropeptide belonging to the tachykinin family encoded by the TAC3 gene.
- The PDYN gene encodes Dynorphin.
- The KISS1 gene encodes Kisspeptin.
The KNDy neurones project to the hypothalamic thermoregulatory centre.
Kisspeptin:
- Kisspeptin acts as a critical regulator of GnRH release. It binds to its receptor, the kisspeptin receptor (KISS1R or GPR54), expressed on GnRH neurons.
NKB:
- NKB binds to its receptor, the neurokinin 3 receptor (NK3R), which is expressed on GnRH neurons and initiates and/or accelerates synchronised KNDy neuronal activity to release kisspeptin.
- It thus acts in coordination with kisspeptin to regulate GnRH release.
Dynorphin:
- Dynorphin A released from KNDy neurons acts as an inhibitory regulator of GnRH release by binding to inhibitory κ-opioid receptors expressed on GnRH neurons.
The interplay between these neuropeptides and their receptors can be summarised as follows:
- Kisspeptin stimulates GnRH release through the activation of KISS1R on GnRH neurons.
- NKB acts synergistically with kisspeptin to enhance GnRH release. The binding of NKB to NK3R on GnRH neurons potentiates the effect of kisspeptin on GnRH release.
- Dynorphin, on the other hand, inhibits GnRH release. The binding of Dynorphin to KOR on GnRH neurons counteracts the stimulatory effects of kisspeptin and NKB.
The balance between these neuropeptides and their receptors ultimately determines the pulsatile secretion of GnRH, which is critical for regulating reproductive functions.
PATHOPHYSIOLOGY OF HOT FLASHES IN MENOPAUSE AND MECHANISM OF FEZOLINETANT (NKB ANTAGONIST)
- During menopause, lack of Estradiol (E2) negative feedback results in increased expression of Kisspeptin and NKB along with decreased Dynorphin activity.
- The increased NKB signalling and overstimulation of KNDy neurons increases activity in the thermoregulatory centre, which becomes hypersensitive to external cues from peripheral sensors, activating heat dissipation effectors. [Uenoyama et al, 2021]
- Thus blockade of NKB signalling with the use of an NK3R antagonist (NK3Ra) is proposed to normalise KNDy neurone activity and thus may help alleviate HFs (Hot flushes/flashes) in menopausal women. [Lederman et al., 2023]
FEZOLINETANT IN HOT FLUSHES - RANDOMISED CONTROLLED TRIAL
Neurokinin 3 receptor antagonists are potential non-hormonal therapies for treating vasomotor symptoms in menopausal women who cannot or do not want to take hormone therapy.
Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause.
The “SKYLIGHT 1” RCT investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause.
The study participants were menopausal women experiencing moderate-to-severe VMS. The primary endpoints focused on the change in frequency and severity of hot flashes from baseline. [Lederman et al., 2023]
Results:
- Fezolinetant exhibited a significant reduction in the frequency and severity of hot flashes compared to placebo at 30 mg and 45 mg.
- The improvement was observed as early as four weeks into treatment and sustained throughout the study.
- Fezolinetant was generally well-tolerated, with minimal adverse effects reported.
Before using Veozah, patients should have blood work done to test for liver damage.
While on Veozah, routine bloodwork should be performed every three months for the first nine months of using the medication. Patients experiencing symptoms related to liver damage—such as nausea, vomiting, or yellowing of the skin and eyes—should contact a physician. Veozah cannot be used with CYP1A2 inhibitors. Patients with known cirrhosis, severe renal damage or end-stage renal disease should not take Veozah.
The most common side effects of Veozah include abdominal pain, diarrhea, insomnia, back pain, hot flush and elevated hepatic transaminases. [FDA NEWS]
CONCLUSION
The U.S. Food and Drug Administration approved Veozah (Fezolinetant), an oral medication for treating moderate to severe vasomotor symptoms, or hot flashes, caused by menopause.
Veozah is the first neurokinin 3 (NK3) receptor antagonist approved by the FDA to treat moderate to severe hot flashes (flushes) from menopause.
In conclusion, the phase 3 randomized controlled study, “SKYLIGHT 1,” supported the potential of fezolinetant as a valuable therapeutic option for women experiencing moderate-to-severe vasomotor symptoms during menopause.
The study’s findings contribute to the growing body of evidence highlighting the clinical utility of neurokinin 3 receptor antagonists in addressing this common menopausal symptomatology.
Further research and long-term follow-up studies are necessary to establish the efficacy, safety, and optimal dosing regimens of fezolinetant, ultimately providing women with a broader range of treatment choices to manage vasomotor symptoms effectively including symptoms of mood and sexual well-being,