Since earning her Ph.D. from the University of Arizona in 1984, Roberta Diaz Brinton has devoted her career to unlocking the effect of female hormones on the brain and diseases like Alzheimerβs.
Now, sheβs driving a UA technology startup developing a plant-based nutritional supplement to ease the hot flashes experienced by menopausal women β while continuing research on a drug therapy that can help regenerate brain cells to treat Alzheimerβs.
Brinton is director of the UA Health Sciencesβ Center for Innovation in Brain Science, which in 2019 was awarded a $37.5 million grant from the National Institute of Aging to study a drug used to treat postpartum depression as a treatment for Alzheimerβs, a so far incurable neurodegenerative disorder that disproportionately affects women.
And with the help of a $2.5 million research grant from the National Institutes of Healthβs National Institute on Aging, Brintonβs Tucson startup, NeuTherapeutics, recently launched an advanced clinical trial of its hot-flash supplement.
The company says its supplement, called PhytoSERM, promises menopausal women safe, effective relief of hot flashes without the increased risk of breast cancer that has been found to come with traditional hormone therapy.
βWe developed PhytoSERM as a safe, natural and effective approach for menopausal symptoms to address an unmet need in womenβs health,β Brinton said, noting that many women simply endure the symptoms due to their fear of breast cancer.
The grant will fund a Phase 2 clinical trial by NeuTherapeutics to evaluate the impact of its new dietary supplement, PhytoSERM, on more than 100 participants in the HF Relief Clinical Trial at the UAβs Clinical and Translational Sciences Research Center.
Safer treatment
PhytoSERM contains three phytoestrogens β naturally occurring compounds derived from plants that can function like estrogen, the primary female sex hormone, said Brinton, a UA Regents professor in pharmacology.
SERM stands for βselective estrogen receptor modulators,β hormone therapies that manage how estrogen works in the body.
The latest trial follows a double-blind, placebo-controlled Phase 1b/2a clinical trial in 2018 that enrolled 72 women and found that PhytoSERM was safe and well-tolerated while decreasing the number of hot flashes in women experiencing large numbers of hot flashes.
Hormone-replacement therapy with estrogen or progesterone, or both, in is a common treatment for menopausal hot flashes, which are the result of the body trying to cool itself in response to signals from the brain.
But hormone replacement has been linked to increased risk of breast cancer in multiple studies, prompting many women to avoid the therapy, said Brinton, who studied the area for three decades as a research professor at the University of Southern California before returning to the UA in 2016.
βThere is that concern, and a large proportion of women elect not to receive hormone therapy because of fear of breast cancer, and so it became quite clear that in order to promote brain health through the estrogen pathways, I would also have to take on the challenge of sustaining breast health,β she said.
Because of the estrogen receptor in the brain they target, the plant-based phytoestrogens in NeuTherapeuticsβ PhytoSERM donβt increase breast cancer risk, and may in fact reduce it, Brinton said, citing studies already conducted by breast cancer researchers.
PhytoSERM also has been shown in preclinical studies to boost overall brain function, though the recently launched study focuses on the treatment of hot flashes.
Soy and menopause
Soy isoflavones, plant-based compounds that mimic estrogen, have been used in over-the-counter nutritional supplements to treat menopausal symptoms for years, but their efficacy is variable.
Among thousands of molecules studied, Brintonβs research isolated three soy compounds that are most active with the targeted brain estrogen receptor to create PhytoSERM.
Because PhytoSERM is a dietary supplement, the company doesnβt need to conduct clinical trials and win approval from the U.S. Food and Drug Administration, like a new drug.
The FDA simply requires makers of dietary supplements to have evidence their products are safe and that they donβt make misleading claims, though supplement makers typically cite some studies or experts.
But NeuTherapeutics is going the extra step of drug-style clinical trials to instill confidence in the eventual over-the-counter product, which will be in pill form.
βThe reason we are developing a product thatβs over the counter thatβs both safe and effective, is because women were voting with their feet and getting a product over the counter, so I had to go where women are going,β Brinton said.
Decades of work
Brinton, who earned her undergraduate and masterβs degrees from the UA before completing her UA doctorate in neuropharmacology and psychobiology in 1984, has been studying the relationship of estrogen and brain function for decades.
After graduating with her Ph.D. from the UA, Brinton spent four years working as a NIH postdoctoral fellow at The Rockefeller University in New York.
While at Rockefeller observing a clinical trial to determine if estrogen could help treat patients with Alzheimerβs, Brinton befriended a patient who was a psychologist and professor and spent a lot of time getting to know her, walking the campus and chatting.
After returning the patient to her hospital room after a long walk, Brinton said goodbye, closed her door and waited 30 seconds.
βI knocked on the door and entered and asked her, βDo you remember me, and she was such a lovely person, she said, βIβm so sorry, should I?β Brinton recalled. βAnd so what she taught me was, it wasnβt that she didnβt remember me, it was that she never encoded me despite the many hours that we had spent together.β
βAt the time, I was very focused on understanding how the brain encodes new information, and remembers that information, the molecular basis of that,β she said. βAnd in that moment, that one woman with Alzheimerβs just transformed the career of this one neuroscientist, and from there, I really began to investigate.β
Alzheimerβs is the most common form of dementia and the sixth-leading cause of death in the United States, affecting nearly 6 million Americans β roughly two-thirds of whom are women.
While the fact that two-thirds of people with Alzheimerβs disease are women is often attributed mainly to the longer average lifespan of women, Brinton is convinced there is a link to the loss of estrogen in the brain during menopause that weakens the bodyβs defenses.
βItβs because women can start the disease earlier,β she said. βThat disease can start in the female brain during the menopausal transition, when thereβs a loss of estrogen in the brain.β
Brinton is also a chief collaborator on the Womenβs Brain Initiative, an NIH-funded study of how sex differences affect brain aging and risk of Alzheimerβs disease, led by Weill Cornell Medicine in New York.
Brinton said sheβs excited about the prospects for NeuTherapeutics and had high praise for Tech Launch Arizona, the UAβs tech-transfer arm, in helping her start the company, which is also a member of the UA Center for Innovation incubator.
βIβm so grateful for the University of Arizona and its technology transfer team is in supporting this, (helping) with all the caveats and all the regulation and adherence to all of the principles and requirements,β she said.
Regeneration study
Meanwhile, the UA brain center and its research partners are still enrolling patients for a Phase 2b clinical trial of its Alzheimerβs drug at the UA brain center, with the support of a $37.5 million federal research grant in 2019.
The drug, allopregnanolone, or allo, is already approved for use to treat postpartum depression, but the UA researchers say it can also promote regeneration of the brainβs neural networks, to reverse the course of the neurodegenerative disease in its early stage.
During a Phase 1 clinical trial, Brinton and her team found that allo, a natural steroid that is already produced within the brain, increased the generation of new brain cells, reducing the formation of beta-amyloid proteins linked to Alzheimerβs and improving cognitive function.
For information on the Alzheimerβs trial, which includes one Arizona site in Scottsdale, go to regenbrain.org.