Menopause treatments will be revolutionised by a drug that acts directly on the brain to prevent hot flushes, leading doctors have predicted.
Speaking after the US approved the first non-hormonal menopause drug, made by Astellas Pharma, experts said the treatment could be transformative for the hundreds of thousands of women in the UK for whom hormone replacement drugs (HRT) are not suitable. The drug, fezolinetant, was licensed in the US on 12 May and could be approved for use in the UK by the end of the year.
“This is going to be a completely blockbuster drug,” said Prof Waljit Dhillo, an endocrinologist at Imperial College London who led a pioneering trial in 2017 that paved the way for the drug’s development. “It’s like a switch. Within a day or two the flushes go away. It’s unbelievable how well these drugs work. It’s going to be completely gamechanging for a lot of women.”
The drug, which is being assessed by the European Medicines Agency (EMA), works by blocking a brain protein called neurokinin-3 that plays a unique role in regulating body temperature in menopausal women.
A large clinical trial of fezolinetant published in March showed that, after 12 weeks of use, it reduced the frequency of hot flushes by about 60% in women with moderate or severe symptoms, compared with a 45% reduction in those who received a placebo. Women also said the drug reduced the severity of hot flushes and improved the quality of their sleep.
“What’s really amazing about these drugs is how quickly they work and how big an effect they have,” said Prof Richard Anderson, a co-director of the Centre for Reproductive Health at the University of Edinburgh. “Typically, oestrogen takes several weeks to have an effect. With these, women are reporting effects from the first tablet.”
About 70% of women going through the menopause experience hot flushes and 10-20% describe them as “near intolerable”, severely affecting daily life, exercise and sleep, and it is the symptom that most often prompts women to seek treatment. It can feel as though a wave of heat has washed over the upper body, leaving the face, neck and chest flushed and sweaty. Some people feel light-headed or have a racing heart.
In England, nearly 2 million women were prescribed at least one HRT medication last year, but these drugs are not suitable for those with a history of breast or ovarian cancer, blood clots or who have untreated high blood pressure. There are also women who experience side-effects or who would prefer a non-hormonal alternative.
“If you can’t take HRT there isn’t much in the way of really effective options,” said Prof Annice Mukherjee, a consultant endocrinologist and visiting professor at the University of Coventry. “Women need options.”
Since the new drug acts directly on the temperature control pathway it does not replace oestrogen, which declines steeply at the menopause, and so would not address the wider range of symptoms that some women experience, including fatigue, muscle and bone weakness, vaginal atrophy and mood swings. Astellas has submitted an application to the EMA, which is expected to make a decision towards the end of 2023, with the UK decision expected to follow a few months after.
Experts said the latest generation of drugs – Bayer is due to complete a phase 3 trial of a similar drug candidate later this year – underlines the critical role of investment in basic research into the menopause. They come after decades of painstaking research by the US neuropathologist Prof Naomi Rance, who identified a specific group of neurons that become enlarged in the brains of menopausal women. She went on to reveal, by measuring tiny temperature variations in the tails of rats, that these neurons release the protein neurokinin-B, which can trigger hot flushes.
“I realised that understanding the brain circuitry controlling hot flushes could be useful for designing new treatments, but I never imagined that it would happen during my life,” said Rance, of the University of Arizona. “I was thrilled to learn about the FDA approval, in part because it illustrates how basic science research can lead to clinical applications.”
Rance’s discovery prompted a trial, led by Dhillo at Imperial College London, which showed that a compound similar to fezolinetant was highly effective at blocking hot flushes in women.
“From our grant being awarded by NIHR [the National Institute for Health and Care Research] and MRC [the Medical Research Council], within two years we could show it had a 73% reduction in hot flushes – that wouldn’t have happened without taxpayers’ funding of medical research,” Dhillo said. “Since doing our studies, we’ve had women all over the world writing to us saying: ‘How can I get this drug?’”
He added: “There’s been this attitude that obesity kills, heart disease kills, diabetes kills, women’s health doesn’t kill. We can’t be in a western society and say 51% of the population’s problems – if they don’t kill them immediately – aren’t important.”
He welcomed a positive shift in the last few years, including the creation of the government’s women’s health strategy, the appointment of a women’s health minister and an increase into research on topics including menopause and endometriosis.
