The scientists at Salk and Abrexa have been working for years to raise money to put this drug candidate to the test. Although the company won’t disclose financial details, its budget is a sliver of the billions spent by the pharmaceutical industry on discovering, developing and testing Alzheimer’s drugs.
Any drug that generally protects against aging should also work against Alzheimer’s, said Salk Institute researcher Dave Schubert, who led the drug’s development along with fellow Salk researcher Pamela Maher and other colleagues. That’s because age is the strongest predictor of Alzheimer’s risk.
This drug, for now called J147, isn’t presented as a fountain of youth or expected to be one. But even a modest effect in delaying age-related brain deterioration could add years of clear thinking and the ability to enjoy life.
Ultimate success could be to simply delay the disease until those at risk of Alzheimer’s die of something else.
What is Alzheimer’s?
The number of Americans with Alzheimer’s is projected to reach 15 million by 2060. And that’s not even considering the impact on the millions more of their friends and family, who must watch their loved ones slowly die while technically remaining alive.
Alzheimer’s represents about three-fourths of age-related dementias, the umbrella term for impaired cognition. Unusual and increasing lapses of memory, confusion, difficulty in finding the right words and altered emotional states are signs of possible dementia.
Alzheimer’s disease causes dementia by physically attacking neurons. It’s distinguished from other causes of dementia by the accumulation of toxic brain protein deposits, called beta amyloid and tau.
Over the years, these protein deposits form harmful plaques that damage and then kill brain cells. In recent years, brain scans have been developed that can detect amyloid and tau in living people. This is now being used to select volunteers for clinical trials of Alzheimer’s drugs.
The ability to detect these toxic brain proteins is important because Alzheimer’s symptoms are similar to those produced by other conditions. Interactions between prescribed drugs can simulate dementia, for example. Adjusting prescriptions to remove the interactions can remove these symptoms.
And other forms of dementia also can be easily mistaken for Alzheimer’s.
For example, narrowing of blood vessels in the brain may precede a series of small strokes that damages the brain. This is called vascular dementia. It can be detected by brain imaging tests that identify areas of poor blood circulation or structural abnormalities. It is believed to account for about 10 percent of dementia cases.
Another form, Lewy body dementia, involves abnormal deposits of a brain protein called alpha-synuclein. Some of its symptoms resemble those of Parkinson’s disease, a movement disorder.
To make things even more complicated, dementia patients may have multiple forms, such as vascular dementia combined with Alzheimer’s.
This is important because unlike Alzheimer’s, there are treatments for vascular dementia that may alleviate that source of cognitive decline.
But Alzheimer’s itself is intractable, and newer research and ideas about the disease indicates why that may be so.
Researchers now say Alzheimer’s begins long before symptoms emerge. In some cases, toxic protein deposits can be detected in people in their twenties. These people have normal cognition for decades before symptoms are detected.
In other words, when people show signs of Alzheimer’s, the disease has been at work for a long time. When symptoms emerge, the damage may be irreversible. However, the Salk scientists and others now say that the early to mid-stage cognitive deficits may be reversible.
So the latest thinking is to attack toxic proteins as early as possible. Clinical trials of amyloid and tau drugs are now being tested in cognitively normal people whose brain imaging scans show the telltale signs that Alzheimer’s is at work.
The great majority of scientists, including the Salk’s Schubert and Maher, accept that amyloid and tau can contribute to Alzheimer’s. But drugs developed to remove these toxic proteins to date haven’t been proven effective.
The failures are numerous, expensive and heartbreaking. One drug in particular, called solanezumab, generated much hope as it was tested by Eli Lilly & Co. The drug removes the protein amyloid before it can stick together in plaques.
Some signs of potential efficacy for solanezumab were seen in midstage trials. But late-stage or phase 3 trials found no benefit. This pattern has been characteristic of Alzheimer’s drug development.
However, some drugs have a limited effect against Alzheimer’s, even though they don’t affect the underlying disease. Some temporarily relieve symptoms before the downward spiral begins again. These drugs, such as Aricept, Exelon and Namenda, affect chemicals produced by the brain called neurotransmitters.
Moreover, the lag between the appearance of biochemical markers for Alzheimer’s and the emergence of symptoms suggests that the brain has the ability to compensate for the loss of function, up to a certain point. This is called “cognitive reserve.”
Some evidence suggests that cognitive reserve can be increased by keeping the brain active during life. The brain is plastic, able to adapt to higher demands, and conversely functions may wither with disuse.
Such non-drug approaches to cushion the blow of Alzheimer’s or other dementias include various brain-training exercises like crosswords or Sudoku.
A recent study in the journal BMJ found both good news and bad news about these exercises.
The bad news is that they don’t stop mental decline.
The good news is that brain function is elevated, so those who practice these exercises lose function from a higher level.
“Overall, findings suggest that high-performing adults engage and those that engage more (are) protected from relative decline,” the study stated.
Another path
Salk scientists Schubert and Maher say such modest results indicate that a direct assault on the toxic proteins behind Alzheimer’s is unlikely to work for most cases, and that indirect approaches are needed. This is how they came up with the anti- brain aging drug, or J147.
The amyloid/tau approach comes from a field called structure-based drug design. It begins by getting sophisticated understanding of diseases at the molecular level, then designing drugs that interfere with the disease process. Structure-based drug design has produced spectacular successes, such as effective drugs against HIV.
Schubert and Maher turned to an older method for drug discovery. That is to sift through vast numbers of potential drugs to find those that reduce symptoms and physical signs of disease. The mechanism of action isn’t important, just the effect. Scientists call this approach a “phenotypic screen.”
After discovering compounds with signs of effectiveness, scientists then do more research to understand how they work, and test variations of those compounds. Then the knowledge can be used to derive even more potent and safer drugs.
The drug J147 that has been licensed to Abrexa is the product of phenotypic screens. It is a synthetic derivative of curcumin, a component of the curry spice turmeric. There is some anecdotal evidence that curry-consuming cultures, such as in India, have lower rates of Alzheimer’s.
Maher led research into another potential drug, a natural component of strawberries called fisetin (pronounced FI-setin). Much like J147, it reduced signs of aging-related cognitive decline, brain inflammation and other symptoms of aging in a strain of mice that age prematurely.
They have also been researching other potential anti-aging drugs, which they call “geroprotectors.” This “geroprotective” hypothesis aims to make sense of anti-aging discoveries made by other scientists.
In addition to J147 and fisetin, the Salk scientists have found anti-aging and Alzheimer’s disease modifying effects in two other synthetic compounds.
A recent study led by Schubert and Maher found that these geroprotective compounds work by a similar mechanism to reduce the effects of aging. They published the results in the Nov. 13 issue of the journal Trends in Pharmacological Sciences.
Schubert said these molecules work like two other drugs believed to have anti-aging properties, the diabetes drug metformin and the cancer drug rapamycin.
Since these drugs converge on the same molecular pathway, large-scale research is warranted, he said.
Worth a try
Two Alzheimer’s researchers said that the strategy outlined by Schubert and Maher that led to J147 is worth clinical testing.
“It makes sense to try different approaches for Alzheimer’s, and because aging is a risk factor for Alzheimer’s, it is possible that drugs that target pathways implicated in aging may have benefits,” said Dr. Douglas Galasko, a UC San Diego neurologist who sees patients with dementias.
“It is hard to place bets on which type of anti-Alzheimer’s therapy will be best, and it may be that combinations of treatment may ultimately be needed,” Galasko said.
Gregory Cole, interim director of the Mary S. Easton Alzheimer Center in Los Angeles, said he likes the phenotypic screen as an alternative approach.
“Developing Alzheimer’s disease involves a complex cascade of events,” Cole said. “Most of the field has targeted beta amyloid because the genetics teaches us that it plays an important role in initiating the disease.”
However, that single-cause theory doesn’t match what occurs in real patients, Cole said.
“In one study, only 9 percent had pure Alzheimer’s disease,” Cole said. “The others also had vascular damage (at least one-third of the cases), or accumulation of other pathological proteins beyond beta amyloid and tau.”
“Based on the multiple causes of cognitive decline and dementia, the phenotypic screen approach selecting for agents that are more broadly neuroprotective makes sense.”
Schubert said money has been a limiting factor in putting these geroprotective drugs to the test.
Just getting J147 to the clinical stage required extensive research and funding support over many years. Tests of the drug in mice have repeatedly demonstrated that the drug protects against aging of the brain, he said, so actual testing in people is the next logical step.
Schubert said he would like to see testing of the other potential Alzheimeer’s drugs, but there’s not enough money for now.
Abrexa, the San Diego company that licensed J147, will begin early or phase 1 human clinical testing early this year said Abrexa CEO Ernie Villafranca. Drugs typically pass through three phases of testing. A successful phase 3 trial may qualify the drug for approval.
“We’re looking to see how much of the compound is absorbed into the blood, and then how long it lasts, how high the levels get, and also how safe it is,” Villafranca said.
The testing should take about six to eight months, he said. If testing goes well, Abrexa will need to fund a second, larger trial, to look for evidence of efficacy.
To reach Abrexa for more information, email abrexa@abrexa.net.