JULY 30, 2018
In the
long-running debate over just what causes Alzheimer’s disease, one side looks
to have scored a victory with new results with an in-development drug. But
there’s enough variation in the data to ensure that the squabbling factions of
Alzheimer’s will have plenty to fight about.
At issue
is the so-called amyloid hypothesis, a decades-old theory claiming that
Alzheimer’s gradual degradation of the brain is caused by the accumulation of
sticky plaques. And the new drug is BAN2401, designed by Biogen and Eisai to
prevent those amyloid plaques from clustering and attack the clumps that
already have.
In data
presented last week, one group of patients receiving BAN2401 saw their amyloid
levels plummet, a result that was tied to a significant reduction in cognitive
decline compared with placebo.
To the
amyloid-inclined, like Dr. Howard Fillit of the Alzheimer’s Drug Discovery
Foundation, that marks a clear affirmation of the linkage between plaques and
mental fortitude.
“I mean
if you asked me five or 10 years ago if we’re going to have a drug that can
remove the plaques from the brain, I would have thought this was space
technology,” Fillit said. “And there was definitely a signal, in my opinion, on
clinical outcomes, which is what we’ve all been looking for.”
But to
skeptics, the trial was laden with confounding details that make it impossible
to draw conclusions.
“These
results are a mess,” wrote Baird biotech analyst Brian Skorney. “Not so much
that they indicate an outright failure of the [amyloid] hypothesis, but they
don’t really say anything informative at all.”
In the
trial, every single tested dose had a significant effect on plaques as measured
by a brain scan, and the more BAN2401 patients got, the less amyloid they had
after 18 months. But looking at cognition, only the highest tested dose was
significantly better than placebo at slowing down mental decline. And some of
the patients who received lower doses actually declined faster than those who
received no treatment at all.
If
amyloid really is the driving factor behind Alzheimer’s, why didn’t each
incremental reduction in plaques lead to a corresponding improvement in
cognition?
Dr. Al
Sandrock, Biogen’s chief scientific officer, said there is likely a threshold
of amyloid reduction that must be reached before patients actually benefit. The
low doses, despite their effect on plaques, might not have hit that threshold,
Sandrock said, thus accounting for their poor performance on cognitive decline.
The
divergence in the two curves is what gives Dr. Reisa Sperling, who was overall
encouraged by the results, “the most pause.” But Sperling, director Center for
Alzheimer Research and Treatment at Brigham and Women’s Hospital, noted that
some of the study’s arms had small numbers of patients, making it difficult to
draw conclusions. She said while there is a biological argument that could
underpin the threshold hypothesis, she wanted to see more data from a larger
trial with a more traditional design.
Even if
Sandrock’s theory holds up, what happened to BAN2401 is not a new phenomenon.
This year a drug from Merck, meant to shut off the production of plaques by
blocking an enzyme called BACE, was successful in reducing amyloid but fared so
dismally on cognitive measures that researchers terminated the trial early. A
second BACE drug, from Biogen and Eisai, had similar results in miniature,
hitting the mark on plaque reduction in a Phase 2 trial but failing to
significantly outperform placebo on cognition.
The
underlying issue, according Dr. Lon Schneider, director of the California
Alzheimer’s Disease Center at the University of Southern California, is that
“the plaques are not the target — those are biomarkers.”
“A target
is something that, as a result of hitting it, there will be change downstream
in behavior, cognition, and illness course,” Schneider said. “So, yeah we’re
knocking down amyloid, but so far we’re not changing behavior much.”
Even
BAN2401’s saving grace — that its highest dose appeared to both reduce amyloid
and improve patient’s clinical results — has come under scrutiny.
In the
BAN2401 trial, about 70 percent of patients getting placebo had a genetic
mutation that triples the risk of Alzheimer’s. But in the high-dose BAN2401
group, just 30 percent of patients had the mutation, called APOE4.
That
could explain why BAN2401 seemed to outperform a saline injection in the
high-dose group, skeptics say, as past trials suggest that APOE4 carriers have
more rapidly progressing Alzheimer’s than patients without the mutation.
And it
could mean that the drug’s seeming promise is a mirage.
Dr. Paul
Aisen, who runs the Alzheimer’s Therapeutic Research Institute at the
University of Southern California, said the discrepancy “does create a
potential bias.” But in trials where patients are confirmed to have amyloid in
their brains at the outset, as was the case with BAN2401, “the impact of
[APOE4] on progression is modest,” Aisen wrote in an email. “I don’t think this
accounts for the apparent slowing of cognitive decline in the high-dose arm.”
Sperling
agreed that she did not think the arms’ different populations skewed the data,
in part because the group that received the second highest dose of the drug had
a larger share of APOE4 carriers and saw results that were similar — though not
as substantial — as the high dose group.
“It’s a
similar pattern,” she said. “For me that partially mitigates that concern.”
Biogen
and Eisai have promised to dig into the data and parse out the effect APOE4 had
on whether patients responded to BAN2401, but those results likely won’t be
ready for months.
In the
meantime, companies are still queueing up to take cracks at amyloid.
Eli
Lilly, which has spent billions on failed Alzheimer’s drugs in recent years,
has designed a trial that will test the amyloid hypothesis “in the most
definitive way possible,” said Mark Mintun, the company’s vice president of
neurodegeneration.
The plan
is to take a BACE inhibitor and pair it with an injected treatment that targets
amyloid already in the brain. That should address the two major concerns with
each approach, Mintun said: BACE inhibitors prevent amyloid but don’t address
plaques that already exist, while amyloid-targeting therapies don’t stem the
flow of new toxic clumps.
“I equate
it to going down to your basement and finding three feet of water and there’s
been a slow drip for four weeks,” Mintun said. “You can turn off the spigot,
but it won’t feel like you’ve made much progress, so you’ve got to pump it out,
too.”
That
study is enrolling 375 patients into three groups, planning to study whether
the combination can improve cognition compared with placebo over 18 months.
Andrew
Joseph contributed reporting.
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