news

Genentech’s Alzheimer’s antibody trial to

study disease prevention
The first clinical trial
of a drug’s ability to
forestall Alzheimer’s
disease in cognitively
healthy individu-
als is preparing to
launch. Genentech
of S. San Francisco,
California, the
Banner Alzheimer’s
Institute in Phoenix,
Arizona, and the US
National Institutes of
Health will together
spend $96 mil-
lion in an interna-
Genentech

tional effort testing

© 2012 Nature America, Inc. All rights reserved.

Genentech’s experi-
mental drug crene-
zumab, a humanized Genentech’s crenezumab, binds amyloid beta in plaques. A landmark trial
monoclonal antibody planned in Colombia using this antibody will determine if the amyloid
(mAb) that binds the hypothesis is correct.
amyloid beta pep-
tide (Aβ), in people certain to develop early mer president of Lilly Research Laboratories in
Alzheimer’s disease owing to autosomal domi- Indianapolis, who now directs an Alzheimer’s
nant gene mutations. Two other drug clinical institute at Weill Cornell Medical College in
trials, one also targeting Aβ in presymptomatic New York. But a conventional prevention trial
familial Alzheimer’s disease and another in the in Alzheimer’s disease would need to follow
general population, also aim to launch in 2013. many thousands of people for a long period
These pioneering studies will also test the to show a drug effect.
amyloid hypothesis and multiple Alzheimer’s So academic researchers began planning
biomarkers and thus shape future drug devel- smaller, shorter trials in populations certain
opment for a field desperate for a success. (or very likely) to suffer Alzheimer’s disease
That’s because clinical trials of agents target- within a relatively short time (Table 1). Such
ing Aβ have so far failed almost completely. drug trials have never before been attempted
npg

(Phase 3 results for Eli Lilly’s solanezumab, in any neurodegenerative disease, says Magali
and Pfizer and Elan’s bapineuzumab were Haas, incoming chief science and technology
imminent as of late July.) The new approach officer for One Mind for Research, a non-
will test drugs before or just after the onset profit in Rutherford, California, focused on
of Alzheimer’s symptoms, thus theoretically multidisciplinary approaches to brain dis-
improving the odds of success. Fraught with eases. Researchers are counting on govern-
their own risks, these trials may offer the best ment funding and philanthropic support, and
chance of making meaningful progress any- have recruited industry partners to provide
time soon against a disease that is projected the drugs. Despite myriad risks, including the
to overwhelm the health systems of the devel- danger of serious side effects in cognitively
oped world within a generation. normal individuals using investigational
One reason for the failure of Aβ-targeted drugs, these trials have the support of regula-
drugs to date is that they may come too late tors in the US and Europe, which in turn has
in the disease course to make a difference. convinced companies to participate. “It’s pretty
Neuropathological studies reveal high brain bold,” says Paul. “But I think this is the way
amyloid burden even before Alzheimer’s that one has to approach the disease.”
symptoms develop. “By that time there’s been The only trial of the three to secure com-
considerable synapse loss, destruction, degen- plete funding by early July is an international
eration of neurons, [so] that it’s unlikely that trial sponsored by the Alzheimer’s Prevention
the current disease-modifying therapies, those Initiative (API), a collaboration organized
that go after amyloid or go after tau, are going by Alzheimer’s researchers Eric Reiman
to be hugely effective,” says Steven Paul, a for- and Pierre Tariot of the Banner Alzheimer’s

nature biotechnology volume 30 number 8 august 2012 731

 NEWS
Table 1 Presymptomatic Alzheimer’s disease clinical trials
Principal sponsor Population
Alzheimer’s Prevention Mainly PS1 mutation carriers in
Initiative Colombia
Dominantly Inherited PS1, PS2 and APP carriers in
Alzheimer’s Network N. America, Europe, Australia
Alzheimer’s Disease Asymptomatic 70+ year olds in
Cooperative Study N. America with high Aβ burden
p-tau, phospho-tau; CSF, cerebrospinal fluid, Aβ: amyloid-β.
Sources: API, DIAN and ADCS.
Institute. This randomized trial will enroll
300 members of an extended family in and
around Medellín, Colombia, many of whom
have a fully penetrant autosomal dominant
mutation in the gene encoding presenilin-1
(PS1) that typically triggers Alzheimer’s
symptoms around age 50. (Some noncarrier
controls and a small number of individuals
in the US with varied mutations will also be
included.) Neurologist Francisco Lopera of the
© 2012 Nature America, Inc. All rights reserved.
Universidad de Antioquia in Medellín, who
identified the family and has been following
it for three decades, will head the Colombian
team. The trial, using crenezumab, will last
five years, with an interim analysis at two
years to gauge the drug’s effect on a variety
of Alzheimer’s biomarkers (Table 1). If one or
more biomarkers move in response to treat-
ment at two years, the trial will proceed. “The
biomarkers may be more sensitive than the
cognitive measures,” explains Reiman. The
trial’s primary endpoint, though, is a positive
difference in cognition.
The second trial is sponsored by the
Dominantly Inherited Alzheimer’s Network
(DIAN), a research partnership funded by the
National Institute on Aging (NIA). DIAN pro-
poses a five year, two-stage randomized trial
npg
in carriers of autosomal dominant mutations
in PS1, PS2 and amyloid precursor protein
(APP). Three drugs, each employing a differ-
ent anti-Aβ mechanism, will be tried in the first
phase. “This could be a window of opportunity
to intervene therapeutically before there’s sub-
stantial brain damage,” says John Morris, a neu-
rologist at Washington University in St. Louis
and DIAN’s program director.
The largest of the three trials is the “Anti-
Amyloid Treatment in Asymptomatic AD,” or
A4 trial. Its 1,000 enrollees will be people in
their 70s and early 80s in the general popu-
lation selected on brain amyloid burden as
measured by amyloid positive emission
tomography (PET) rather than by the pres-
ence of autosomal dominant mutations. But
the randomized trial won’t be large enough to
detect a difference in the number of dementia
cases that develop, just their relative latency.
“What we’re really powered to do, with 500
per arm, is to see a difference in the slope
732 volume 30 number 8 august 2012 nature biotechnology
Biomarkers Start date
FDG and amyloid PET; End 2012 or early 2013
MRI; CSF tau and Ab-42
FDG and amyloid PET; End 2012 or early 2013
MRI; CSF tau and Aβ (NIA funding pending)
Amyloid PET, MRI, CSF Mid-2013 (NIH funding
tau and p-tau in subset pending)
of decline, in the rate of decline,” says Reisa
Sperling, a Harvard neurologist who heads
the A4 trial.
Taken together, these aggressive trials
will test the validity of the amyloid cascade
hypothesis, that Aβ deposition leads to senile
plaques, neurofibrillary tangles, neuronal cell
death and dementia. And tracking biomark-
ers and clinical outcomes in parallel could
enable future trials. “We’re including all of the
best established biomarkers, so that we can
find out which ones might qualify for use as
a reasonably likely surrogate endpoint in the
accelerated approval of… future preclinical
Alzheimer’s treatments,” says Reiman. But
clinical effect is the main goal of all these trials.
Regulators seem prepared to approve drugs
if they’re successful in a single trial, at least for
API and DIAN. Russell Katz, head of the US
Food and Drug Administration (FDA)’s neurol-
ogy products division, said in an April meeting
that a change in a single cognitive test in DIAN
could be enough for registration. “We are open
to that,” Katz said. “We have not signed off on
that formally, but have asked sponsors to flesh
that out for us. We recognize that very early
on, when people are asymptomatic, the usual
rules are tough to apply.” (A typical dementia
trial would also require showing a change in
daily function.) In the case of A4, Sperling says
that the trial by itself would probably not be
enough for drug approval, but that the FDA and
European Medicines Agency have shown flex-
ibility in discussions. “They’ve come an amaz-
ingly long way in thinking about how we could
do this,” Sperling says.
First the drugs must work, hardly a sure
thing. Crucially, the drug mechanism must be
right for the disease. API selected crenezumab
in part because it targets diverse forms of Aβ:
monomers, oligomers and fibrils, and thus is
capable of clearing free Aβ as well as plaques.
Crenezumab also depends in part on microg-
lial engulfment of Aβ. This mechanism differs
from other anti-Aβ antibodies. For example,
Lilly’s solanezumab only binds soluble Aβ and
works by altering the balance between plaque
and plasma Aβ. In theory, crenezumab should
work better in early disease, but no one knows
for sure.
Duration Cost
5 years; interim analysis at $96 million
2 years
2 years for first stage, 5 ~$60 million for first
years total stage
3 years double-blind treat- $109 million
ment, 2 years follow-up
Also, safety is a major concern, because
cognitively normal people will be taking
these drugs. Some anti-Aβ mAbs have caused
vasogenic edema, the leakage of proteinaceous
fluid from blood vessels, and microhemor-
rhages. According to Reiman, as of early July
more than 250 patients had received cren-
ezumab with no reported cases of treatment-
related vasogenic edema or microhemorrhage.
(The antibody was engineered with an IgG4
backbone to limit microglial activation, a likely
contributor to vasogenic edema.)
Other risks are political. Familial
Alzheimer’s disease may be more difficult
to treat than sporadic disease, notes Ronald
Peterson, director of the Mayo Alzheimer’s
Disease Research Center in Rochester,
Minnesota. So failure in API or DIAN
might prematurely doom a drug that would
otherwise work in the general population.
Conversely, success in early-onset Alzheimer’s
does not mean that a drug will work in the
much more common late-onset variety,
Peterson says, as the familial form is caused
by too much Ab deposition, and the late-onset
disease is more about deficient Ab clearance.
“There likely are similarities, but it’s not the
same illness,” agrees Morris.
Joshua Boger, founder and former CEO
of Vertex Pharmaceuticals in Cambridge,
Massachusetts, worries that a drug effective in
API or DIAN, though approved only for rare
cases of familial Alzheimer’s, would cause “a real
stampede” of off-label use in the general popu-
lation. “It could create quite a clamor for what
would still be a very hypothetical and experi-
mental treatment,” Boger says. But everyone’s
first concern is finding a drug that’s effective.
“We sure hope that we see a positive signal from
these studies, because otherwise I think the field
will have a hard time recovering,” says Morris.
Boger feels that all these risks are necessary.
“There’s a bigger risk in not doing anything,”
he says, calling Alzheimer’s “a species emer-
gency.” “We can do the demographics—it’s
ugly. Trillions of dollars a year and crippling
the entire medical system, and crippling fami-
lies. So this is a crisis. Risk taking is prudent
in a crisis.”
Ken Garber Ann Arbor, Michigan