VMS Symptoms and Neurokinin Receptor Antagonists

Episode 2

The following transcript has been edited for clarity, style, and lenght.

Mary Jane Minkin, MD: Can you talk more about the role of estrogen in blocking the neurokinins? And can you elaborate on the different neurokinin receptor activities, such as neurokinin-1 (NK1) and neurokinin-3 (NK3)?

Lisa Larkin, MD: In the absence of estrogen, KNDy neurons become hyperactive. When estrogen binds to estrogen receptors on these neurons, it reduces their activity. So, it's this dance between the binding, but there’s not just 1 receptor, right? There are different receptors on KNDy neurons, which have differential impact in terms of function. For instance, NK3 receptors are primarily associated with hot flashes, while NK1 receptors are believed to play a role in sleep. But again, it's the balance between estrogen and the neurokinin B (NKB) molecule, and the binding to these receptors that leads to the end organ effect. And that's where the exciting science is, in terms of leading to targeted drug development.

Minkin: Yes, and as you mentioned earlier, Naomi Rance, MD, PhD, a neuropathologist, led this field. She studied an area of the hypothalamus involved with neurokinin activity. Interestingly, she found that postmenopausal women exhibited significant hypertrophy in this region, likely due to increased neurokinin stimulation in the absence of estrogen. This discovery has spurred the development of medications to act as surrogates for estrogen in blocking these receptors. Can you tell us about the neurokinin receptor antagonist currently available?

Larkin: Of course. The medication is called fezolinetant and it is now FDA-approved. Before we continue, I want to say that this is why this is an exiting time in research. Prior to the approval of fezolinetant, treatment options for vasomotor symptoms were limited. The only FDA-approved medication was an SSRI, with other therapies relying on off-label use of drugs approved for different conditions. These weren’t targeted treatments, and we lacked robust clinical data or a thorough understanding of the underlying pathophysiology.

So fast forward—Dr Rance's work has clarified the role of KNDy neurons in the hypothalamus and the interaction between estrogen and NKB. This led to the development of fezolinetant, an NK3 receptor blocker in the hypothalamus which, in the pivotal trials that led to its approval, had significant improvement in vasomotor symptoms. It represents a new era of targeted therapy supported by clinical science.

Minkin: Absolutely. It’s worth noting that fezolinetant has a much stronger binding affinity for NK3 receptors compared to NK1 receptors—about 450 times stronger. While its focus is on hot flashes, there’s potential for expanding its application to other areas of the hypothalamus, like sleep. Sleep disturbances are a major issue for our patients, so addressing both vasomotor symptoms and sleep could be a game-changer. You mentioned that other drugs in development might address these dual concerns. Can you elaborate?

Larkin: Yes, with advances in understanding pathophysiology, we’re seeing new generations of targeted therapies. While vasomotor symptoms are crucial, many patients also struggle with sleep disruptions. For a long time, we thought sleep issues were secondary to vasomotor symptoms, but we now know it’s more complex. As you said, it’s a “chicken or the egg” scenario.

Looking at the difference in receptors, it appears the NK1 receptor is predominantly involved in sleep maintenance and sleep issues. One drug that is far along in the pipeline targets both the NK3 and NK1 receptor and has shown improvement in sleep in addition to vasomotor symptoms in clinical trials. It is very exciting that this whole understanding of the science is leading to great new drug development.

Minkin: The drug you are referring to is elinzanetant, which is currently being reviewed for FDA approval. There are ongoing trials exploring the effects of elinzanetant on sleep using tools like polysomnography to measure sleep quality. This ongoing research is critical, as improving sleep can profoundly enhance patients’ quality of life. This is such an exciting time for advancing care in this field, with the potential to significantly improve the lives of women experiencing menopause.