SAN DIEGO – Frustrations abound as scientists work feverishly for a curative Alzheimer's disease drug, and business leaders seek ways to fund the research. In the meantime, their parents and grandparents are stuck in the middle of failed or unproven treatments and a real fear that time is running out.

With the aging population, it is estimated that 50 percent of all people who reach age 85 will get Alzheimer's disease (AD). More than that, a third of caregivers report declining health, showing the toll goes beyond the Alzheimer's Association's estimated $259 billion health care cost for AD this year. Today, one out of every five U.S. Medicare dollars is spent on AD, and that is expected to rise to one out of every three by 2050, said MacKay Jimeson, head of corporate affairs at New York-based Pfizer Inc.'s internal medicines unit, who led a panel at BIO called "Public Policy and the Coming Epidemic of Neurodegenerative Disease."

Those diseases include dementia and Parkinson's, but Alzheimer's dominated the conversation. As a 6-year-old, Jimeson watched his grandmother care for his great-grandmother, and many years later, he then watched his mother care for his grandmother.

"Her social life was gone," he said. "All she cared about was being able to brush my grandmother's hair so she had some sense of dignity in her life."

Over the last 100 years, major scientific breakthroughs have included insulin and penicillin, as well as high cholesterol and cardiac disease therapies, but little has changed for AD. During the time that death from heart disease has decreased by 14 percent, death from AD has increased by 89 percent, Jimeson said.

"One of the issues that you've seen so far in the development of Alzheimer's drugs, particularly for amyloid plaque, is you've had some failed trials or maybe you've had failed drugs, and the problem is we don't know which is which," said Ken Verburg, senior vice president of global development at Pfizer.

Pharmaceutical firms have pursued anti-amyloid therapies for some time, but up until Cambridge, Mass.-based Biogen Inc.'s phase Ib trial of aducanumab (BIIB037), which showed an amyloid lowering and a slowing of cognitive decline, the drugs were tested in patients without any amyloid positron emission tomography (PET) imaging, said Lauren Friedman, assistant director of scientific affairs for Alzheimer's Drug Discovery Foundation. (See BioWorld Today, Sept. 1, 2016.)

Friedman's foundation stopped funding amyloid programs once pharma took the baton, and is now focusing on neuroinflammation, neuroprotection, neuronal energy failure, ApoE function and cholesterol metabolism, vascular injury, and neuroimaging and biomarkers.

"We can only learn from our failures for clinical trial design," Friedman said, "but who knows if we're just going after the wrong drugs."

While every Alzheimer's patient has amyloid plaque, not every person with amyloid plaque develops AD, Verburg said, so there is a risk to patients when discussing the possibilities of testing failed drugs at an earlier stage of disease.

In addition to amyloid, another target of interest in recent years is tau, but "neither one of those has been proven," Verburg said. "None of the current agents have proven that they reduce the load of plaque, or whether they are meaningful in terms of cognitive function over time. None of those dots have been tied up at all yet."

Researchers also are pursuing the 5HT6 pathway, but so far, it has not fared much better than amyloid beta or tau. Pfizer stopped a phase II study for PF-05212377 in the fall of 2015 when futility criteria were met, and H. Valby, Denmark's Lundbeck A/S, with Tokyo-based partner Otsuka Pharmaceutical Co. Ltd., reported earlier this year two phase III failures with idalopirdine. Investor reactions to Hamilton, Bermuda-based Axovant Science Ltd.'s prospects for RVT-101 (intepirdine) are split, based on positive phase II data and a failed phase III, although CEO David Hung remained upbeat Tuesday at a BIO fireside chat, anticipating confirmatory results in September that will back up the phase II. (See BioWorld Today, Feb. 9, 2017, and June 21, 2017.)

Beyond amyloid and tau targets

There are serious challenges with recruiting patients for clinical trials, getting them to the clinic, screened and returning for each visit, problems that may be addressed with wearable monitoring devices enabling data to be gathered from patients staying at home, Friedman said.

Companies pursue a variety of approaches, attempting to clear the plaque or prevent the plaque, or move earlier in the disease process, but there is a distinct possibility that the plaque, while associated with the disease, is not the driver. Verburg said the industry has not reached broadly enough, beyond the amyloid and tau targets, to find an answer. Investors are reluctant to invest in AD therapies because of the hit rate vs. other therapeutic areas. They want a return on their investments.

"The more the failures add up, the more underwater you get," he said.

While researchers have "cured Alzheimer's disease in mice a hundred times over," the basic science has not translated to humans, Verburg said. Exploring the vascular system or neuroinflammation as potential drivers of the disease are potential areas of focus. Todd Coleman, director of the Neural Interaction Lab at the University of California, San Diego, suggested at a different BIO convention panel that the gastrointestinal system may be to blame for neurodegenerative diseases, since it delivers 80 percent of the information flow to the brain, with only 20 percent flowing back in the other direction.

"So it is how much time, how much personnel, how much money can you put in to what is really a wide open opportunity," Verburg said. "The question is, 'Can you make the right bets at the right time?'"