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

The experimental drug davunetide initially showed significant promise in combating degenerative brain diseases until a pivotal late-stage trial failed over a decade ago. Following this setback, Aron Therapeutics discontinued its development. However, recent analyses suggest that: this drug may be effective for women. Further investigation reveals that fluctuations in estrogen levels may affect the delivery of the drug to the brain, indicating that its efficacy—and that of similar treatments—could vary based on hormonal changes throughout the menstrual cycle.

“It is common for brain diseases to be influenced by steroid hormones, such as estrogen, progesterone, and testosterone,” stated Jens Pahnke from the University of Oslo, who was not involved in the study.

Over 20 years ago, researchers at Tel Aviv University, including Ilana Gozes, derived davunetide from a naturally-occurring brain protein called activity-dependent neuroprotective protein (ADNP). This protein is now known to be regulated by sex hormones. Studies indicate that davunetide enhances microtubules, a crucial component of the brain’s transport system, which in turn helps prevent toxic protein accumulation such as tau, associated with Alzheimer’s disease. However, in 2014, an intranasal formulation was tested in late-stage trials for progressive supranuclear palsy, a rare neurological disorder, but yielded no significant effects.

This realization allowed Gozes, who participated in the clinical trial, to reflect on her previous research on gender differences in clinical outcomes. To assess whether these differences applied to davunetide, Gozes and her team analyzed gene activity in male and female mice with the ADNP mutation, resulting in an epiphany: the gene sets altered between the sexes were “very different.”

Additionally, upon reanalyzing the davunetide study with a gender-focused lens, findings indicated that in women with progressive supranuclear palsy, the drug seemed to slow disease progression, providing protection against brain damage symptoms, such as difficulties with swallowing and speech. “When we separated the data by gender, the outcomes diverged,” Gozes noted.

Recent experiments involving fluorescently labeled davunetide administered to male and female mice revealed that females exhibited higher drug absorption during peak estrogen levels. A study involving eight adult participants, six women and two men, found that women had higher peak concentrations of the drug in their plasma compared to men.

This variability may be attributed to estrogen’s influence on blood flow, drug metabolism, and blood-brain barrier permeability, which affects drug absorption.

Hormones like estrogen serve as critical regulators of various brain functions and can modulate drug efficacy, as highlighted by Pahnke. He emphasized the significance of assessing not only the presence but also the concentration of each hormone in specific brain regions, stating, “Different areas may respond variably to hormonal changes.”

Professor Pahnke previously uncovered that the multiple sclerosis drug fingolimod demonstrates significantly greater efficacy in female mouse models of Huntington’s disease compared to males. Yet, he urges caution regarding Gozes’ findings, noting that the research, conducted primarily in mice and involving a small human sample, merits careful interpretation. “These [findings] can inform hypotheses regarding the sex-dependent bioavailability of intranasal davunetide, but conclusions should be approached with caution.”

Both researchers agree on a critical observation: Despite variations in clinical trials by gender, hormonal status is seldom accounted for, potentially neglecting significant biological diversity.

“What [the researchers] are illustrating is that neurodegenerative diseases manifest differently in males and females, and even with the same medication, hormonal factors modify therapeutic outcomes,” Gozes remarked.

Davunetide has received a development license through ExoNavis Therapeutics in Tel Aviv. “We are currently committed to advancing our gender-stratified clinical trials in individuals with ADNP syndrome, a neurodevelopmental disorder attributed to an ADNP mutation, and progressive supranuclear palsy,” stated Gozes, who holds the position of vice president of drug development at the company.