San Antonio — George Perry, a scientist at the University of Texas at San Antonio, has long proposed that drug developers and researchers need to look earlier into the roots of Alzheimer’s disease.
Over more than two decades, Perry has studied the possibility that diseases like Alzheimer’s may get their start because the body produces too many variants of oxygen, called free radicals, which cause cell damage, and not enough antioxidants to limit the damage. The process, called oxidative stress, has been associated with aging and neurodegeneration.
A potential discovery that targets the early development of the disease—in his area of research or elsewhere—may help limit incidence in a condition that’s seen little therapeutic progress in the last 30 years, he says.
That’s why Perry agreed to take a paid position on the scientific advisory board of a small San Antonio company, Phoenix Biotechnology, which has been developing a plant-based drug for cancer for more than a decade, but is now pinning its future on preliminary, preclinical data for neurodegenerative disease. In 2016, the company published findings that indicated its drug may be able to produce an antioxidant response in the brain, which followed other early results showing that the drug may stimulate a protein related to memory and learning.
Phoenix is looking for help promoting its drug in part because it is running out of time and money. Since it was founded in 2003, Phoenix has spent $22 million from private investors, who are now getting “a little long in the tooth,” says president and chief science officer Robert Newman.
Instead of seeking more private funding, the company now wants to find a larger drug developer to continue the research. Phoenix’s original cancer research is expected to produce clinical results later this year, but the firm is betting that its Alzheimer’s disease data will tip the scale in attracting suitors.
“I’m going to be 79 years old in a couple of months. I’ve been looking at this particular opportunity for a couple of years,” says Phoenix CEO Crandell Addington. “We intend to do some type of merger or acquisition so we can move this drug along, particularly in light of what we discovered in neurodegenerative diseases.”
Phoenix is facing two big hurdles, however: The data it has are limited, and Alzheimer’s drugs have a terrible track record in clinical trials. A 2014 paper spotlighted a nearly 100 percent failure rate over a decade; there have been more failures since then. In February, Merck (NYSE: MRK) was the latest to disclose a failed trial when its experimental therapy for mild-to-moderate Alzheimer’s, verubecestat, came up short. That followed another Phase 3 failure for Eli Lilly’s (NYSE: LLY) solanezumab.
The Merck and Lilly compounds focused on the prevailing theory about Alzheimer’s: the condition might be treatable with a drug that clears clumps of amyloid protein, called plaques, from the brain. Perry believes that amyloid plaques might be a consequence of the oxidative stress, rather than a signal that the disease is taking root. A debate rages on the value of targeting amyloid, and companies like Biogen (NASDAQ: BIIB) are still pursuing similar related treatments.
In an Alzheimer’s brain, there is loss of function of synapses and neurons, the circuitry essential to short-term memory. A protein called brain-derived neurotrophic factor (BDNF) may play a key role in supporting that circuitry, according to a 2011 published by Mark Tuszynski and Alan Nagahara of the University of California, San Diego (UCSD).
People with the highest levels of BDNF had a 50 percent slower cognitive decline than those who expressed the lowest levels, according to a January 2016 study from researchers at Rush Alzheimer’s Disease Center in Chicago. Other researchers have published similar findings, but BDNF exploration is still quite early, and its role in Alzheimer’s is not fully understood.
When Phoenix was studying its compound PBI-05204 in cancer, patients who received the drug had increased levels of BDNF, the company said. But chief science officer Newman isn’t a neurologist, so he asked a researcher at Duke University, Donald Lo, to examine the implications of stimulating BDNF. Lo was already studying plant-based treatments similar to PBI-05204 in stroke victims. He wanted one that could cross the blood-brain barrier, which Phoenix’s drug can do, Newman says.
In studies published in 2011 and 2014, Lo and a research team wrote that the brains of mice in a stroke model had increased levels of BDNF after receiving PBI-05204. The researchers said the drug, which can be administered orally, also activated a receptor that BDNF binds to, known as TrkB. Neurons in the brain slices were protected from injuries related to a stroke, according to the 2014 study. A third report from 2016 said the drug may induce antioxidants that limit inflammation.
Xconomy asked Nagahara of UCSD to review Phoenix’s published data (he was previously not familiar with the company). Nagahara says the company’s drug is interesting, but there’s not enough data to call it scientifically compelling. He says he would like to see an additional animal study to better understand how the compound gets into and is distributed by the brain.
“The fact that this one does increase BDNF, it’s interesting and may have additional derivative effects,” Nagahara says, noting the potential anti-oxidant effects Phoenix published in 2016. “But I’m not exactly sure if that in itself would be impactful, considering that there are other drugs or things that can stimulate BDNF levels.”
Antidepressant drugs, such as serotonin reuptake inhibitors, have been known to elevate BDNF levels, Nagahara says. He added that the drug would appear more interesting if the company could show it can produce BDNF in a specific region of the brain. The receptors that BDNF binds to are found in multiple regions, elevating the risk of possible side effects. Nagahara and colleagues are pursuing research into a different method of inducing BDNF—delivering BDNF genes through a viral vector into part of the brain that may lead to additional production—in Tuszynski’s UCSD lab.
Phoenix’s Newman says he is open to additional studies, which is part of the reason the company is looking for partners.
With the abysmal clinical record of Alzheimer’s drug, neurologists advocate testing as many methods as possible for treating Alzheimer’s, which affects some 5.5 million people in the U.S., according to the Alzheimer’s Association.
“As a field, we shouldn’t be shy about pushing anything that is based on solid biology and might make sense,” says George Bloom, a professor of biology, cell biology and neuroscience at the University of Virginia. Bloom is studying the underlying reasons that a healthy neuron converts to one with signs of Alzheimer’s or Parkinson’s disease.
Roots in Oleander
The Phoenix drug is an extract of the oleander plant, a flowering shrub that grows around the world and was brought to Texas in the 1840s, according to Texas A&M. Phoenix creates the extract by applying carbon dioxide to it under certain pressure and temperature conditions—a process called supercritical CO2 for which the company has a patent.
There’s one caution to oleander and other similar plant extracts, known as cardiac glycosides: Too much can be toxic. Digoxin, one of the better known drugs developed from an extract of another cardiac glycoside, foxglove, is used to treat heart failure. But it can also cause irregular heartbeat and other side effects. The same is true for oleander.
Phoenix says it developed a safe dosing regimen during the Phase 1 cancer trial, though the same safety standards don’t necessarily apply to neurodegenerative disorders. In cancer, Newman says he wants to test the drug in combination with chemotherapy, but that would cost money that the company doesn’t have, which is a reason Phoenix is looking for a deal.
Phoenix has been getting advice from Fred Frank, a longtime biotech investment banker who was once the vice chairman of Lehman Brothers and is now the chairman of New York- and San Francisco-based Evolution Life Science Partners, says Addington, a former chemical manufacturing and oil and gas executive.
Phoenix says it has received interest from a potential suitor.
Newman says he’s open to any type of deal, but “would like to (stay involved), since this is kind of my baby. I certainly don’t want to see somebody buy it and put it on the shelf.”
Newman is also chief science officer and a shareholder of a Phoenix spinout that sells oleander-based cosmetics and has raised eyebrows in a news publication with claims of clinical proof and “age-defying” ingredients; he says it operates independently of Phoenix.