A New Drug is in the Pipeline for Hot Flashes

Let's Take a Look at the Study

There is a new area of drug research for hot flashes and night sweats, collectively known as vasomotor symptoms or VMS. These drugs work on KNDy neurons, which are specialized nerves that send signals to the hypothalamus, a region in the brain that helps control many functions. KNDy neurons are involved in timing the pulses of the hormone called GnRH (gonadotropin-releasing hormone), which is released by the hypothalamus. These pulses of GnRH drive the release of the hormones from the pituitary that govern the menstrual cycle. KNDy neurons are also involved in regulating temperature. 

This is the “Aha!” moment for the hot flash connection, because this means that ovulation and temperature basically use the same switch board. These shared connections are important, for example, body temperature rises slightly with ovulation, creating a better environment for implantation. Estrogen released during the menstrual cycle helps to control output from the KNDy neurons, essentially controlling the thermostat. Estrogen is like my dad always muttering about the heating bills and turning down the temperature on the thermostat. With menopause, when levels of estrogen drop, the KNDy neurons have lost one of the control mechanisms. Think what the thermostat on your furnace would be like if the temperature sensing mechanisms went wonky? It might kick in when it’s boiling hot inside. 

Enter, the hot flash.

This is essentially what happens in menopause. The KNDy neurons lose one of their internal control mechanisms, higher levels of estrogen in the blood, and so they are now free to tell the brain that you are hot when you are not. And because everything that is experienced happens in your brain, the person affected feels hot. Core temperature doesn’t rise, meaning your body temperature stays the same, but it feels like it has and that’s all that matters. What does your body do when you are hot? It deploys cooling mechanisms, such as sweating and flushing (so you turn red because blood vessels dilate, taking more blood to the skin where heat can dissipate). Why the sensation of heat seems to be most concentrated in the upper body and head isn’t known.

One way to treat hot flashes and night sweats is with estrogen, which helps to quiet the KNDy neurons' over enthusiastic heat signaling. But recently, we have seen work looking at other ways to control this system. One of these drugs, fezolinetant, has been submitted to the FDA. The data from the final trials has yet to be published in a peer-reviewed format, so it’s still not known exactly how well this medication performs. The press release from the company states that fezolinetant, which is a neurokinin 3 inhibitor, results in a “significant reduction from baseline in the severity of moderate to severe vasomotor symptoms”. The data from the press release states the highest dose, 45 mg, results in a mean reduction in the average number of hot flashes per day of 2.55 and 2.53 at weeks four and twelve. It seems as though the severity of the hot flashes is also reduced, but the way this was reported seems very clunky. This always makes me worried that the study is emphasizing statistical significance over clinical significance, meaning does this drug provide a meaningful improvement for someone suffering from hot flashes? Regardless, it reduces the number of hot flashes, and when we have the full peer-reviewed data we’ll be able to say more, meaning how this drug compares with estrogen and the other non-estrogen medications for VMS.

Another new drug that is being studied is called Q-122. Before drugs are given fancy names with lots of z’s, v’s, x’s and y’s (the seemingly trendy letters in Pharma) they have numbers. After all, why name something you aren’t sure you are going to keep? Like fenzolinetant, Q-122 affects signaling from the KNDy neurons, but it works by a different mechanism than neurokinin 3. And this new drug has recently been studied for women with breast cancer who have hormone responsive cancer who were also taking either tamoxifen or an aromatase-inhibitor. It’s great to see studies specifically enrolling women with a history of breast cancer as their symptoms are often the most severe and they have fewer safe options.  

[As a side note, if your provider tells you it is safe to take estrogen and you have had a hormone receptor positive breast cancer, get another opinion. No menopause society or oncology (cancer) society recommends estrogen in this situation. This idea that estrogen matters for every person in menopause is simply not supported by science, but apparently it generates money.

Back to the study.]

Q-122 was tested against placebo, the dose was 100 mg twice a day for 28 days, and at baseline these women were having at least 50 hot flashes a week. One outcome was how the severity of hot flashes changed, and by the scale used, the severity reduced by 39%. And while that sounds fantastic, the placebo resulted in a 26% reduction in severity. The difference was statistically significant, meaning the reduction in severity with Q-122 wasn’t likely due to chance. However, the 26% placebo response rate is something that is very important to consider because this can easily explain anecdotal claims for so-called natural products for hot flashes, which are never tested against a control group.

What about the frequency of hot flashes? There was an average of two fewer hot flashes per day for people with a baseline of more than 50 hot flashes a week, which seems approximately on par with fenzolinetant. Neither group, active drug or placebo, had a 50% reduction in moderate to severe VSM.

Interestingly, the trend at 28 days suggested the benefits of Q-122 increased over time and so we don’t know if the medication had continued for a longer duration or if even more of a benefit would have been seen. 

The study was stopped at 28 days because basically the researchers were asking, “Does this drug do anything meaningful and is it safe?” It was well tolerated. Overall, 3% of people stopped the drug due to side effects. While 55% had some kind of side effect, so did 65% of people who took the placebo. Again this demonstrates the power of the mind and the importance of having every drug tested against a placebo where ethically possible. 

It looks like Q-122 does something meaningful, but whether it’s enough to help people requires more studies. It’s possible that some people might find a reduction of two hot flashes a day meaningful. And it’s also possible that some people will have a greater reduction in hot flashes and for some it won’t do much at all, meaning some people will be responders and others will not. That’s exactly why we need more data.

So why discuss a small study that doesn’t give anyone any practical information? 

First, it’s a good opportunity to discuss how the KNDy neurons work as we will undoubtedly be seeing more here as I am betting that fenzolinetant will get FDA approval.

Second, I hear from many women with hormone receptor positive breast cancer, who often suffer the most, that they feel left out treatment-wise, so I thought it might be nice for them to know that this research exists. Also, not everyone can take estrogen for other reasons or they feel awful while taking it, so more options benefit everyone except perhaps the providers who order unnecessary hormone levels to “manage” hormone therapy. If your provider is managing the doses you are taking by testing your hormones, you are sadly being scammed. (And yes, I will find a way to put that in almost every article).

And finally, I thought people might be interested in the placebo response rate, considering how many unstudied so-called “natural” products exist for hot flashes in menopause.

In summary, It seems from this study that Q-122 looks like it’s worth studying and hopefully sometime soon we will have the final data on fenzolinetant and approval from the FDA, which will give more options for hot flashes and something that can be safely taken by those with breast cancer.

References

1. Amanda Vrselja, Ardian Latifi, Prof Rodney J Baber, et al. Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2022;400;1704-1711.

2. Carolyn J. Crandall, Patricia A. Ganz. Phase 2 data on a new treatment for hot flashes in women with breast cancer. Lancet 2022;400;1659-1661.

3. Press release, Astellas https://www.astellas.com/en/system/files/news/2022-09/20220905_en_1.pdf