When virologists and drug developers were too slow in finding ways to save the lives of people with HIV/AIDS and refused to give patients access to experimental drugs 30 years ago, activists chained themselves to a balcony on the New York Stock Exchange, held demonstrations where scores were arrested, and effectively shut down the Food and Drug Administration for a day.
The lack of progress against Alzheimer’s disease has brought somewhat less outrage. Although the latest analysis of experimental Alzheimer’s drugs finds that literally zero are being tested in late-stage clinical trials to treat moderate to severe Alzheimer’s, no patient advocacy groups uttered a peep in protest.
“We need a Larry Kramer,” said Dr. Sam Gandy, a neurologist and Alzheimer’s expert at Mount Sinai Hospital in New York, referring to the AIDS activist. Instead, he said, patients and their families adopt the fatalistic attitude that dementia is an inevitable consequence of aging, and funders see spending $1 on curing a child as ethically more justified (since it buys more total years of life) than spending $1 on an 80 year old, who’s closer to the grave.
While ageism partly explains why Alzheimer’s patients are being written off, just as gay men were in the 1980s, it’s not the whole story. For more than 20 years drug makers and academic scientists pursued treatments to slow or reverse dementia by targeting amyloid plaques in the brain. Every last one failed. Now companies and investors are instead focused on trying to prevent Alzheimer’s in younger people — potentially a huge, and hugely lucrative, market — or trying to ameliorate agitation and other behavioral symptoms of the disease. Meanwhile, alternative strategies for treating the disease have been largely ignored and underfunded, with little outcry.
“I don’t think most people have really internalized this, or are ready to hear about it,” said chemist Derek Lowe, a longtime pharmaceutical scientist who blogs about drug discovery. “It’s painful, and no one is going to come out and say flatly that people with existing Alzheimer’s damage are probably never going to get any better, and that it would take a major advance just to stop them from getting any worse. It sounds defeatist.”
Not every company has given up on the 5.5 million people in the U.S. who already have Alzheimer’s, all of whose disease will become tragically, mind-robbingly, identity-destroyingly severe if it isn’t already — and if they don’t die first.
“These are the very patients we have to help,” said Dr. Daniel Alkon, president and chief science officer of Neurotrope (NTRP), which is running a Phase 2 clinical trial of a compound called bryostatin in patients with moderate to severe Alzheimer’s. That makes it literally the only Phase 2 or Phase 3 study of whether a drug can alter the course of disease in patients with severe dementia. “I absolutely do not think it’s hopeless.”
Alkon’s optimism (not shared by most experts) reflects his preclinical research showing that bryostatin boosts two kinds of molecules: those that degrade amyloid and those that increase synapse formation. The first mechanism of action might prevent the formation of synapse-destroying amyloid plaques, while the second might preserve and create synapses, whose destruction underlies the cognitive losses in Alzheimer’s. In lab mice, bryostatin reversed brain damage and improved memory. Neurotrope’s small Phase 2 trial suggests it might do the same for patients with moderate-to-severe Alzheimer’s, but the results still have to be confirmed in a larger trial.
Neurotrope is a complete outlier, however, and even Alkon can understand both the scientific and business case for drug developers’ decision to target mild Alzheimer’s, or even pre-symptomatic but at-risk (i.e. healthy) people.
For more than a decade, drug developers have based their experimental compounds on the amyloid hypothesis, convinced that ridding the brain of sticky amyloid plaques, and preventing new amyloid deposits, was the key to fighting the disease. Trouble was, quite a few drugs did reduce the amyloid burden, “but that didn’t do anything for cognition,” Alkon said. “So the thinking became, plaques are too late, we have to get rid of what causes the plaques,” namely, soluble amyloid molecules called oligomers. By definition, people without amyloid plaques do not have Alzheimer’s disease.
“The scientific rationale was, by the time people get moderate dementia, their brain is pretty filled up with amyloid and they’ve lost neurons and synapses,” said Dr. Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation. “And what drug developers want is to get a drug to market,” not waste time and money on noble but quixotic causes.
That means that in addition to a scientific justification for targeting earlier disease (or pre-disease), there was a business one. “No one was making any progress in targeting patients with moderate to severe disease,” Alkon said. Eli Lilly alone spent at least $1 billion, analysts estimate, on what turned out to be a failed antibody against amyloid. Such astronomically expensive failures in even moderate Alzheimer’s, he said, “has been the rationale of the entire industry” for why it has basically given up on patients who are losing their memories and their minds and, eventually, their lives.
“The moderate-to-severe patients got completely left in the dust,” said Fillit. “It’s driven by companies’ need for a success.” Given the 200-plus failed clinical trials of experimental Alzheimer’s drugs, the smart money says that is more likely to come from a drug that prevents the development of full-on dementia in people with mild cognitive impairment or even just risk factors (including genetic ones).
“The moderate-to-severe patients got completely left in the dust. It’s driven by companies’ need for a success.”
Dr. Howard Fillit, Alzheimer’s Drug Discovery Foundation
Not everyone agrees that millions of patients have been abandoned. Nearly three dozen drugs in mid- to late-stage development aim to reduce agitation, sleep disorders, and other behavioral changes that accompany Alzheimer’s. Such drugs, if they work, could make a significant difference in the daily life of patients and caregivers even if they don’t alter the course of the actual disease. Clinical trials for these behavioral symptoms “continue to make up a significant percentage of the total trials,” said Alzheimer’s Association spokesman Niles Frantz.
In addition, federal funding of Alzheimer’s research nearly tripled from $503 million in 2012 to $1.8 billion (if the 2018 congressional appropriation becomes law), partly as a result of advocacy by the Alzheimer’s Association, said Dr. David Knopman of the Mayo Clinic and chair of the group’s Medical and Scientific Advisory Council. Even if those basic biology studies succeed, however, they wouldn’t lead to an effective drug in anything less than a decade.
As for the lack of outrage, “if someone has moderate to severe Alzheimer’s, there is a lot of therapeutic nihilism,” said Fillit. That is, families, caregivers, and even physicians have assimilated the decade-long drumbeat of drug failures. “Most people I see think there’s nothing that can be done and there’s no hope,” said Fillit, who disagrees with that grim assessment. They don’t handcuff themselves to the balcony of the stock exchange because they see no point.
An ethical issue also arises. For the most part, experimental drugs that have shown promise in early clinical trials, before ultimately failing, have merely slowed the rate of cognitive decline. That is, after 18 months on the experimental drug, patients’ scores on standard cognitive tests have fallen 30 percent less than have those of untreated patients. But they’ve still fallen. If a drug that achieves that in a Phase 3 trial (none has) were to win FDA approval, it would be a double-edged sword.
“At the end of 18 months, the patient is still going to be worse” than she was earlier, Fillit said, and it might take expert assessment to even detect that. Many scientists who study Alzheimer’s, as well as clinicians who treat it, therefore wonder if that’s a meaningful outcome, especially since slowing the rate of mental decline almost always means postponing the inevitable and living with a devastating disease for longer.
As for the one outlier in the exodus from drug development for advanced Alzheimer’s, last month Neurotrope said it had begun enrolling what it hopes will be 100 patients in a confirmatory Phase 2 clinical trial of bryostatin. All will have scores on the Mini Mental State Exam of 4 to 15 — moderate to severe Alzheimer’s — and scientists will be looking for signs that patients’ disease doesn’t merely stop worsening but that their cognition and memory improve. The company expects to complete the study around this time next year.