By Ann Marie McQueen
The US Food and Drug Administration approved Astellas Pharma’s non-hormonal drug for hot flashes this week. This means a 45mg daily dose of Veozah – which contains fezolinetant, which is what we’ve been calling it until this sudden new name appeared Friday – is the first such medication to make it to market. The Japanese drugmaker, which has also applied for regulatory review in EU, Switzerland and Australia, says Veozah could be in US pharmacies within weeks.
Previously the only non-hormonal, FDA-approved treatment for hot flashes was the anti-depressant paroxetine. If you want to read the FDA’s report for yourself, you will find it here.
How does it work?
Scientists believe hot flashes happen when the balance between estrogen and certain brain chemicals are disrupted. This leads to an enlargement in the KNDy (kisspeptin, neurokinin and dynorphinneural) complex in the hypothalamus, which in turn sparks disregulation in the nearby temperature control center. Fezolinetant is part of a class of drugs known as neurokinin 3 (NK3R) receptor antagonists, which aim to block neurokinin from receptors in the thermoregulatory center, and stop the hot flash in its tracks.
This class of drugs was previously used in the treatment of schizophrenia.
Who is it for?
People who can’t take menopause hormone therapy, women who are weighing their risks of having been on hormone therapy for a long time, or those who choose not to take hormone therapy.
Does it work?
There have been three year-long, phase 3 clinical trials involving 3,000 women in Canada and the US, all with reductions noted. In one, for example, fezolintant reduced hot flashes by up to 50 percent after 12 weeks. Women also reported feeling positive effects much sooner. However, in a fourth clinical trial in Asia involving 302 women that doesn’t get mentioned much anymore, fezolinetant failed to beat the placebo – raising questions about how it impacts other populations.
‘The Institute for Clinical and Economic Review, (ICER) an independent US medicines effectiveness watchdog, released a report on fezolinetant in December after conducting a review that found evidence of a net health benefit “insufficient”. The report called for more data to be released from the three clinical trials, along with full peer review and publishing. They also pointed out that there have been no formal studies comparing fezolinetant to other interventions we know a lot more about, such as hormone therapy.
In March, Acer Therapeutics sent its stock down by 40 percent on the announcement the company had paused trials on its NK3R antagonist, osanetant. While its version passed safety tests, Acer said it failed to reduce the frequency and severity of hot flashes.’The Institute for Clinical and Economic Review, (ICER) an independent US medicines effectiveness watchdog, released a report on fezolinetant in December after conducting a review that found evidence of a net health benefit “insufficient”.
The report called for more data to be released from the three clinical trials, along with full peer review and publishing. They also pointed out that there have been no formal studies comparing fezolinetant to other interventions we know a lot more about, such as hormone therapy. In March, Acer Therapeutics sent its stock down by 40 percent on the announcement the company had paused trials on its NK3R antagonist, osanetant. While its version passed safety tests, Acer said it failed to reduce the frequency and severity of hot flashes.
Meanwhile, there have been indications that fezolinetant improved sleep, although that will need further study.
Is it safe?
Astellas, doctors who worked with Astellas, and the FDA, say yes. However it takes a drug hitting the market and being taken by tens of thousands of people for contraindications and adverse events to turn up in meaningful amounts. (This is why one doctor I’ve spoken with doesn’t prescribe any new drug for at least five years). As Dr Stephanie Faubion, medical director of the North American Menopause Society, told the New York Times yesterday, there’s a lot of unknowns, including how it impacts “heart health, bone health, sexual health, mood symptoms or weight”.
What about the liver?
The FDA’s report indicates liver enzymes three times the upper limit of normal were found in 25 women (2.3 percent) who took fezolinetant across the Astellas clinical trials, compared to 8 (0.9 percent) of those on placebo. The FDA recommends normal baseline liver bloodwork prior to treatment, followed by bloodwork every three months for the first nine months.
One has to wonder how fit this drug is for people with non-alcoholic fatty liver disease, which has been estimated to be up to 30 percent of the US population. Worth noting is Millendo Therapeutics, which in 2017 paused Phase 2 trials of its NK3R antagonist, pavinetant, after several women developed abnormal liver function.
What about other adverse reactions?
Clinical trial data cited headaches, while the FDA lists abdominal pain, diarrhea, insomnia, back pain, and, in a confusing turn of events considering what women will be taking it for, “hot flush”.
Astellas has said the Veozah drug will cost US$550 for a 30-day supply, or $6,600 per year. Will insurance cover that? Can anyone afford that kind of out-of-pocket expense if they don’t? In its December report, ICER said fezolinetant would be cost-effective at $2,000 to $2,600 per year.
Astellas stock rose almost 10 percent in the month leading up to the announcement.
A Jefferies report put fezolinetant’s annual potential value at up to US $2.3 billion, while Astellas has put it at $3.7 billion.
Astellas has put a lot into this approval. So far there has been What’s VMS? campaign, which in January included the first-ever menopause ad to appear during a Super Bowl pre-game; last August they became the first pharmaceutical brand to use TikTok’s advertising solution TikTok Pulse, with ob-gyn Dr Kerry-Anne Perkins (1.1 million followers) and positive aging expert Susan Feldman. Astellas partially funded the UK’s All Party Parliamentary Group on menopause for the last year, an arrangement due to end in June. They are also sponsoring summits and panels right left and center, on both sides of the Atlantic, efforts that are sure to ramp up.
This is a weird one: The most ardent HRT enthusiasts out there hate this drug. As far as I can tell from social media, they seem to dislike any option that might steer a woman away from their favorite topic: how HRT fixes everything and protects us from all disease and also death. (I’m joking, it doesn’t.)
Bayer recently announced it would proceed with trials on its NK3R antagonist, elinzanetant, and at the moment, it appears to be the only one left in what was once a bit of an NK3R race. AstraZeneca had a version, but there’s been no news for ages.
Another alternative: Pycnogenol
If you don’t feel like paying $550 each month for a drug to reduce but not eliminate hot flashes, which has hot flashes listed as one of its possible side effects, you don’t live in the US, or you aren’t quite ready to ingest a pharmaceutical that targets your brain’s thermoregulatory center, consider Pycnogenol. This is a plant-based, standardized extract derived from the bark of the French maritime pine tree, which grows in the Mediterranean and has uses dating back to Hippocrates.
It’s been found to be effective at reducing hot flashes and night sweats in a number of placebo-controlled, double-blind studies. There were significant reductions in other menopause symptoms, including mood swings, vaginal dryness and loss of libido, according to other research, including a study published in a 2011 issue of Panminerva Medica journal. So, how does it work? Pycnogenol boosts production of nitric oxide in the endothelial system – the cell layer that lines blood vessels – to enhance blood flow, without demonstrated side effects.
And it’s not just menopause stuff, either. There have been hundreds of trials in animals and humans looking into how this extract impacts everything from blood sugar, blood flow and artery composition to traumatic brain injury. One 2019 meta-analysis published in the Journal of Pharmacology Research indicated Pycnogenol has a role in preventing cardiometabolic disease; that same year another meta-analysis published in Frontiers in Pharmacology demonstrated improvements in cognitive function.
**Author’s note: Pycnogenol eliminated my hot flashes.
Find out more about Ann Marie’s work at HotFlash Inc.