Fluctuating estrogen levels change how drugs enter the brain. That was the missing variable in davunetide.
An experimental drug meant for degenerative conditions, davunetide, showed early promise. Then, more than ten years ago, a pivotal Phase 3 trial failed. Flat line. Allon Therapeutic stopped development. But the data didn’t disappear. It just sat there. Ignored.
Scientists dug deeper. They looked at women. Specifically, at their cycles. The revelation wasn’t that the drug worked, exactly, but that its effectiveness depended entirely on how much estrogen was circulating at any given moment. A treatment that seems useless might be brilliant depending on the phase of the menstrual cycle. Or lack thereof.
“It’s very common that brain disease [is regulated] by steroid hormones and that’s not taken into account, which is a problem.” —Jens Pahnke
The ghost in the data
Illana Gozes at Tel Aviv Israel University has been working on this protein for two decades. Davunetide comes from a natural brain protein, ADNP, regulated by sex hormones. In animal studies it strengthened microtubules—the transport roads inside cells. This should have prevented tau proteins from building up toxic tangles. Like in Alzheimer’s.
Then came 2014. An intranasal version of the drug was tested for progressive supranuclear pslalsy, a rare disease driven by tau accumulation.
Nothing happened.
Or so it seemed. The data was aggregated. Men and women were dumped into one bucket. Averages hide truth.
Gozes looked at genetic activity in mice with ADNP mutations. The genetic response in males? Almost nothing in common with females. “What really was like a light bulb,” she said.
They pulled apart the human data by sex. For women with the palsy the drug worked. It slowed the disease. Protected against speech loss, swallowing issues, and other signs of damage. Men? Not so much.
Did you ever notice how often results are “mixed” in early papers?
Why it matters
Now, new experiments. Fluorescently tagged davunetide in mice. Females absorbed more drug when their estrogen hit its peak. Same in eight humans (six women two men). Women had higher drug concentrations in their plasma than men.
Estrogen changes the rules. It tweaks blood flow. It alters how the liver processes drugs. It adjusts the permeability of the blood brain barrier. Gozes says. It controls the gate.
Pahnke agrees hormones are potent regulators. But it’s complicated. Not just presence or absence. But concentration. Location matters.
Pahnke previously saw a similar bias. Fingolimod, a multiple sclerosis drug, worked way better in female mouse models for Huntington’s. Yet he warns against overinterpretation. The sample sizes are tiny. The new findings are mice. Eight humans is barely a blip in clinical data. Treat the conclusion with caution. Big caution.
The overlooked variable
Both researchers point to a systemic flaw. Trials rarely measure hormonal status. Even if they separate data by sex later the window of biological context is already gone.
The disease might look different in men and women. The drug is the same pill, but it behaves differently.
“Hormonal status is going to affect how the drug acts, even though it is the same drug.”
Davunetide lives on now licensed to ExoNavis Therapy. Gozes, vice president of drug development, plans new sex-stratified trials for ADNP syndrome and more. The cycle turns again. This time we’ll watch the tide.
