With a little help, Linda Van Eldik made it across the “Valley of Death.”
As the director of the University of Kentucky Alzheimer’s Disease Center, Van Eldik’s life’s work is to find a cure for Alzheimer’s disease. Like most researchers in her field, she has plenty of new ideas for treating a thus-far incurable condition. But unlike many researchers in her field, she has been able to find the necessary funding—including millions of dollars in grants from the National Institutes of Health (NIH) since 1985—to take many of her ideas from the lab to testing in humans.
The gap between preclinical testing and human trials is known colloquially as the Valley of Death. Most newly proposed drugs don’t make it to the other side—due to a lack of funding, a failure to demonstrate efficacy, or some other reason—and therefore never reach the FDA for approval.
“For promising new drugs to go into early-stage trials in people, there’s so much work that is needed—and that work costs money,” says Maria Carrillo, Ph.D., chief science officer for the Alzheimer’s Association.
Van Eldik is one of the lucky ones. Her research on a promising drug designed to reduce brain inflammation moved into early-stage clinical trials thanks in part to funding from Part the Cloud, an Alzheimer’s Association initiative founded by Michaela “Mikey” Hoag in 2012. It’s one of the few nonfederal sources willing to fund early trials in humans.
“You hope that the information that you’ve gotten from all the preclinical work that you’ve done will translate into a human benefit,” says Van Eldik. “That doesn’t always happen.”
The majority of preclinical work, in fact, doesn’t end up translating into treatments; 99 percent of new Alzheimer’s drugs have failed to reach the market. Of the five drugs that are currently FDA-approved—the latest in 2014—only four are actually new. (The fifth is a combination of two previously approved drugs.) And those drug therapies only treat dementia symptoms; there are no approved therapies that change the outcome of the disease. The extreme expense of drug development—more than $2 billion per drug—continues to be an obstacle for researchers looking for new treatments.
According to the Alzheimer’s Association, more than 5 million are living with Alzheimer’s disease, and that number is projected to rise to nearly 14 million by 2050. Alzheimer’s disease will cost the nation $305 billion in 2020, which roughly equates to one in five Medicare dollars. Estimates that include the hidden costs of caretakers for those with Alzheimer’s add $244 billion per year. The combined costs of dementia care dwarf those of other diseases like cancer and heart disease, which respectively cost about $80 billion and $219 billion per year. But the cost of Alzheimer’s has long been disproportionate to the financial attention it receives.
“If you look at the field of cancer research or the field of cardiovascular research, they have been funded at a much higher level than Alzheimer’s for at least the past two decades,” says Eliezer Masliah, M.D., the head of the Division of Neuroscience at the NIH’s National Institute on Aging. “Now we’re starting to catch up.”
source: Alzheimer's Association
source: Alzheimer's Association
Cost and Duration of Each Aspect of Alzheimer’s Drug Development
Today 35 percent of Alzheimer’s research is sponsored by academic medical centers funded by the NIH and other sources. Some funding comes from venture capital firms, but those firms tend to gauge Alzheimer’s research as so risky that they average only 32 deals per year. The majority of funding comes from pharmaceutical companies. But few for-profit entities are willing to take on the financial risk required for early, experimental trials.
As of 2019, researchers found, the number of potential therapies is small compared to other widespread diseases, with 132 therapies being studied in 156 trials. Only 30 new Alzheimer’s and dementia drugs are in Phase I clinical trials, during which researchers test whether the drug can be safely used by healthy people. There are 74 drugs in Phase II clinical trials, the phase at which drugs first start to be tested in patients with the disease, while Phase III has 28 drugs currently in development.
The research landscape is changing. After years of advocacy from the Alzheimer’s Association, funding for dementia research at the national level is growing. In 2019, the NIH spent 6.1 percent of its $39.3 billion budget on research for Alzheimer’s disease and related dementias, a sharp climb from what it spent in previous years. That funding boost has helped bring the number of potential drug targets to more than 500 and expanded the scope of translational research. In coming years, it is expected to increase the number and diversity of drugs in the pipeline.
Those ideas, based on the newest science and the latest understanding of the biology of dementia, will have to go through years of clinical trials before they can potentially reach the public. Van Eldik’s research into inflammation, for example, is only in Phase I, but it reflects one of the emerging approaches to Alzheimer’s disease that look beyond the decades-old and prevailing theory that amyloid plaques in the brain cause dementia.
“I actually feel more hopeful now than I did a few years ago because—this is a little bit of an exaggeration—but everybody was in the amyloid book. Nobody was trying anything else,” says Van Eldik. “Now we’re not just going along that one amyloid road. We’re looking at other avenues.”
Alzheimer’s is a complex disease, and Van Eldik believes that there isn’t a single “magic bullet” waiting to be discovered but rather a combination of approaches that multiple researchers must explore. For that to happen, even more researchers need to make it past the Valley of Death. Carrillo is one of many who are determined to keep fortifying the bridge.
“What we are hoping to accomplish through Part the Cloud is to accelerate the path to a more effective treatment, a potential prevention strategy, and perhaps even a cure,” Carrillo says. “That is what we’re trying to do over the next 10 years.”