How Estrogen Level Fluctuations Impact Drug Absorption in Women’s Brains

The experimental drug davunetide showed potential against degenerative brain diseases until a significant late-stage trial failure over a decade ago. Though Aron Therapeutics, the company behind davunetide, halted its development, new findings suggest that: this drug could actually benefit women. Research revealed that fluctuations in estrogen levels significantly influence the drug’s brain penetration, suggesting that the effectiveness of davunetide and similar treatments could vary greatly based on hormonal levels—especially estrogen fluctuations throughout the menstrual cycle.

As noted by Jens Pahnke from the University of Oslo, who did not participate in the study, “Steroid hormones, such as estrogen, progesterone, and testosterone, commonly regulate brain diseases, yet this is often overlooked, posing a significant issue.”

Over two decades ago, Ilana Gozes and her team at Tel Aviv University extracted davunetide from a naturally occurring brain protein known as activity-dependent neuroprotective protein (ADNP). It is now known that ADNP is influenced by sex hormones. In animal studies, davunetide-enhanced microtubules—which are part of the brain’s transport system—effectively prevent toxic build-up, including the abnormal tau proteins associated with Alzheimer’s disease. However, an intranasal version failed to show efficacy in a late-stage trial for progressive supranuclear palsy, a rare neurological disorder correlated with abnormal tau accumulation back in 2014.

This trial’s outcome prompted Gozes to reassess her findings. Differences in treatment outcomes between genders were evident, but results remained ambiguous overall. To explore this, Gozes and her colleagues first analyzed gene activity in male and female mice with the ADNP mutation. Gozes described this revelation as “like a light bulb igniting in the brain,” discovering that the gene sets altered between sexes were only minimally overlapping.

They reexamined the davunetide trial, segregating results by gender, and found that for women with progressive supranuclear palsy, the drug appeared to slow disease progression and alleviate symptoms linked with brain damage, such as swallowing and speech difficulties. “Our findings revealed distinct results when we analyzed men and women separately,” she remarked.

Recent research showed that when fluorescently labeled davunetide was administered to male and female mice, a higher concentration of the drug reached the brains of females during peak estrogen levels. An analysis of eight adult volunteers—six women and two men—also indicated that women experienced greater peak concentrations of the drug in circulating plasma compared to men.

This discrepancy may be influenced by estrogen’s ability to modify blood flow, drug metabolism, and blood-brain barrier permeability, affecting absorption rates, according to Gozes. Hormones like estrogen are powerful biological regulators that significantly impact brain functions and drug efficacy, explains Pahnke. He emphasizes that it’s not merely the presence of hormones, but their specific concentrations within different brain regions that matter. “Various brain areas may respond differently to hormonal levels,” Pahnke asserts, as he develops imaging technology aimed at mapping this factor.

Professor Pahnke has previously reported that the multiple sclerosis medication fingolimod exhibited significantly improved efficacy in female mouse models of Huntington’s disease compared to male counterparts. However, he advises that although Gozes’ recent research holds promise, it was conducted on mice and a limited group of humans. “These [results] could help formulate hypotheses regarding the sex-dependent bioavailability of intranasal davunetide, but they should be interpreted with caution,” he cautions.

Still, both Pahnke and Gozes agree on a crucial point: even when results are separated by gender, hormonal status is seldom considered in trials, leading to significant biological variations being neglected.

“What [the researchers] indicate is that [neurodegenerative] diseases manifest differently in each gender, and even if the same medication is used, hormonal status will influence how effectively it works,” Gozes asserts.

Davunetide has received a development license from ExoNavis Therapeutics in Tel Aviv. “We are currently advancing our gender-stratified clinical trial for ADNP syndrome [a neurodevelopmental condition stemming from a gene mutation] and progressive supranuclear palsy,” Gozes, the company’s vice president of drug development, stated.