AUGUST 15,
2018
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.
VERTEX
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, 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).
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.
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