Fluctuating oestrogen levels may alter how drugs enter women’s brains

The experimental drug davunetide was showing promise for degenerative brain conditions until, more than 10 years ago, a pivotal late-stage trial fell flat. Allon Therapeutics, the company behind davunetide, subsequently halted its development. But upon closer inspection, scientists found the drug may actually be effective in women. Digging deeper, they have now revealed that fluctuating oestrogen levels may influence how much of the drug reaches the brain, raising the possibility that its effectiveness – and those of other treatments – varies depending on our levels of hormones like oestrogen, which fluctuate throughout the menstrual cycle.

“It’s very common that brain disease is regulated by steroid hormones [such as oestrogen, progesterone and testosterone] and that’s not taken into consideration very often, which is a massive, massive problem,” says Jens Pahnke at the University of Oslo, Norway, who wasn’t involved in the research.

More than 20 years ago, Illana Gozes at Tel Aviv University in Israel derived davunetide from a naturally occurring brain protein called activity-dependent neuroprotective protein (ADNP), which we now know is regulated by sex hormones. Davunetide reinforced microtubules, part of the brain’s transport system, in animal studies. This suggests that microtubules could then more efficiently prevent the toxic build-up of abnormal tau proteins within cells, such as those that form tangles in Alzheimer’s. But in 2014, when an intranasal formulation was put to the test in a late-stage trial for progressive supranuclear palsy – a rare neurological condition driven by abnormal tau accumulation – it didn’t appear to have an effect.

This prompted Gozes, who was involved in the trial, to look back at studies that had differences between the sexes in their results, but the overall findings were mixed together. To see if this could apply to davunetide, Gozes and her colleagues first analysed the genetic activity of male and female mice with an ADNP mutation, which caused Gozes to experience “what really was like a lightbulb coming into my brain”. They found that the sets of genes altered in each sex had “almost nothing in common”, she says.

They also reanalysed davunetide studies, separating the results according to sex, and found that in women with progressive supranuclear palsy, it seemed to slow their disease progression and protect against symptoms linked to brain damage, such as difficulty swallowing and speaking. “I saw that if you look at males and females separately, the results are not the same,” she says.

Now, the researchers have given fluorescently labelled davunetide to male and female mice and found that among the females, more of the drug reached their head when their oestrogen levels were highest. And when analysing eight adult volunteers, made up of six women and two men, they found that the women tended to have higher peak concentrations of the drug in their circulating plasma than the men.

This may be because oestrogen can influence blood flow, drug metabolism and the permeability of the blood-brain barrier, says Gozes, which could affect how drugs are absorbed.

Hormones like oestrogen are potent biological regulators that influence many aspects of brain function, making it plausible that they affect how drugs behave, says Pahnke. But it’s not just about their presence or absence, “it’s also how much of each hormone we have in the brain at specific locations”, says Pahnke, who is developing an imaging technique to map this. “Different locations may react differently to hormones.”

Pahnke previously found that the multiple sclerosis drug fingolimod has markedly better effects in female mouse models of Huntington’s disease than male ones. But he cautions that Gozes’s latest research has been done on mice and a small group of people. “These [results] could be used for raising hypotheses about sex‑dependent intranasal davunetide bioavailability, but the conclusions should be treated with big caution.”

Still, both Pahnke and Gozes make the same broader point: that hormonal status is rarely measured in trials, even when the results are separated by sex, which may mean an important source of biological variation is being overlooked.

“What [the researchers] are saying is both that [neurodegenerative] diseases are different in each sex, and though the drug is the same drug, hormonal status is going to affect how this particular drug acts,” says Gozes.

Davunetide is now licensed for development to ExoNavis Therapeutics in Tel Aviv. “We are currently planning to continue sex-stratified clinical trials in the ADNP syndrome [a neurodevelopmental condition caused by a mutation to this gene], progressive supranuclear palsy and more,” says Gozes, who is VP of drug development at the company.