1.

Introduction
2. Anti-b-amyloid monoclonal
antibodies for Alzheimers
disease: failures of Phase III
clinical trials on bapineuzumab
and solanezumab
3. Anti-b-amyloid monoclonal
antibodies for Alzheimers
disease: the era of secondary
prevention trials
4. Expert opinion
Review
Amyloid-directed monoclonal
antibodies for the treatment
of Alzheimers disease: the point
of no return?
Francesco Panza

, Vincenzo Solfrizzi, Bruno P Imbimbo &

Giancarlo Logroscino

University of Bari Aldo Moro, Department of Clinical Research in Neurology, Pia Fondazione
Cardinale G. Panico , Tricase, Lecce, Italy
Introduction: Two humanized monoclonal antibodies, bapineuzumab and
solanezumab, directed against the N terminus and mid-region of b-amyloid
(Ab), respectively, were recently tested in large, long-term Phase III trials in
patients with mild-to-moderate Alzheimers disease (AD).
Areas covered: This review discusses current clinical data on solanezumab,
bapineuzumab and their failure in Phase III trials to show significant clinical
benefits, as well as other monoclonal antibodies under investigation for AD.
Expert opinion: Solanezumab showed some beneficial cognitive effects in
mildly affected AD patients and this subgroup of AD patients is currently
being tested in another Phase III trial to this subgroup of AD patients to con-
firm previous encouraging observations. Two other monoclonal antibodies,
gantenerumab, which preferentially binds to fibrillar Ab, and crenezumab,
which preferentially binds to soluble, oligomeric and fibrillar Ab deposits,
are being tested in secondary prevention trials in presymptomatic subjects
with autosomal dominant AD mutations. Solanezumab is also being tested
in a prevention study in asymptomatic older subjects, who have positive pos-
itron emission tomography scans for brain amyloid deposits. These ongoing
secondary prevention trials will tell us if Ab really plays a crucial role in the
pathophysiology of AD.
Keywords: Alzheimers disease, cognitive disorders, dementia, gantenerumab, monoclonal
antibody, passive immunotherapy, prevention trials, solanezumab
Expert Opin. Biol. Ther. [Early Online]
1. Introduction
The past three decades witnessed great efforts in the search for an effective disease-
modifying treatment for Alzheimers disease (AD) [1], with both active and passive
anti-b-amyloid immunotherapies demonstrated to clear b-amyloid (Ab) deposits
from the brains of AD patients in neuroimaging and neuropathological studies [2]. In
fact, in this progressive, multifactorial and heterogeneous neurodegenerative disease,
the Ab peptide is central to AD pathogenesis, with senile plaques (SPs) that are the
result of misprocessing of the amyloid precursor protein (APP) by b- and g-secretases
to form a toxic Ab peptide of 40 -- 42 amino acids [3]. Therefore, many of these efforts
addressed possible Ab-based AD therapeutics with a disease-modifying potential.
The recent advances in the use of reliable biomarkers of AD, providing in-vivo
evidence of the disease, have proposed new research criteria that re-conceptualize
the diagnosis with the support of both structural/biological evidence of AD pathol-
ogy and a specific pattern of cognitive changes [4]. The 2011 National Institute on
Aging (NIA) and Alzheimers Association (AA) criteria suggested that AD may begin
10.1517/14712598.2014.935332 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 1
All rights reserved: reproduction in whole or in part not permitted
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before the development of clinical symptoms, and that new
diagnostic procedures may identify brain changes before the
development of dementia syndrome [5]. Using the NIA-AA
criteria, an individual with these early brain changes would
be said to have preclinical AD or mild cognitive impairment
(MCI) due to AD [5,6], a possible target population to start
with an Ab-based disease-modifying treatment. Given that
AD pathology starts years or even decades before any appear-
ance of symptoms, interventions should be started at an
asymptomatic/preclinical phase in order to be effective. The
conceptual framework for defining the stages of preclinical
AD based on these recent NIA-AA guidelines included a first
stage characterized by evidence of Ab accumulation on posi-
tron emission tomography (PET) amyloid imaging or cerebro-
spinal fluid (CSF) assays, a second stage with cerebral
amyloidosis and evidence of neurodegeneration (elevated
CSF tau levels or abnormalities on functional or structural
neuroimaging) and a third stage characterized by b-
amyloidosis and neurodegeneration plus evidence of a very
subtle cognitive decline not meeting the MCI criteria [5,7].
This preclinical AD model based on the NIA-AA criteria
received first clinical and neurobiological support by recent
cross-sectional findings on familial AD from the Dominantly
Inherited Alzheimer Network (DIAN) [8], and longitudinal
data on sporadic AD from the Australian Imaging Biomarkers
and Lifestyle [9], the Alzheimers Disease Neuroimaging Initia-
tive [10] and the Mayo Clinic [11]. Recently, following an
operational approach to the NIA-AA criteria, two additional
categories were proposed for the preclinical AD model: stage
0, including cognitively normal subjects with no biomarker
evidence of AD pathophysiology and no evidence of subtle
cognitive impairment; and a category termed Suspected
Non-Alzheimer Pathology (sNAP), including individuals
with normal amyloid PET but one or both neuronal injury
biomarkers abnormal [12]. The sNAP group could not repre-
sent a preclinical stage of AD, but rather a distinct biologically
based category to denote individuals in the preclinical stage of
non-AD pathophysiological processes [12], with a risk for cog-
nitive decline after 1 year that was about the same as preclinical
AD stage 1 and less than 50% the risk of stages 2 or 3 [11].
However, the sNAP group and the preclinical AD stages 2 +
3 group did not differ in any of the imaging biomarkers, vas-
cular risk factors or clinical features [13]. Only the carriage of
apolipoprotein E (APOE) "4 genotype, a key risk factor for
AD, was under-represented in the sNAP group [13], which
was consistent with the lower levels of brain b-amyloidosis in
the sNAP group. Therefore, these findings did not suggest
an increase in features observed in cerebrovascular disease
pathology or a-synucleinopathy, the two other major patho-
physiologies that may cause dementia in older age [13]. Initial
evidence of biomarkers of neurodegeneration occurring in
cognitively normal persons with preclinical AD may not be
dependent on b-amyloidosis, suggesting that a tau/neurode-
generative-positive but amyloid-negative biomarker profile
may represent an alternative path of entry into the AD cascade.
2. Anti-b-amyloid monoclonal antibodies for
Alzheimers disease: failures of Phase III clinical
trials on bapineuzumab and solanezumab
The majority of the current therapeutic approaches under
development for the treatment of AD are aimed to reduce
the brain Ab burden of the patients [14]. Passive anti-Ab
immunization strategies consist in the injection of already pre-
formed and manufactured humanized monoclonal antibodies
to AD patients, avoiding eliciting Th1-mediated autoimmu-
nity [15,16]. Preclinical studies on different murine analogs of
the humanized monoclonal antibodies showed significant
reductions in brain Ab burden and improved cognition in
transgenic mouse models of AD [17,18]. The most widely stud-
ied anti-Ab monoclonal antibodies are bapineuzumab and
solanezumab, which have been evaluated in large Phase III
clinical trials [19-21]. Unfortunately, all these trials did not
match their primary efficacy end-points, although both pro-
vided precious information on AD diagnostic accuracy and
biomarkers [22,23].
2.1 Bapineuzumab
Bapineuzumab (AAB-001) is a fully humanized monoclonal
antibody directed against the N terminus of Ab, recognizing
the Ab
1 -- 5
region [19,21]. Phase II clinical trials on mild-to-
Article highlights.
.
Neuroimaging and neuropathological findings have
demonstrated that both active and passive anti-b-
amyloid immunotherapies in patients with Alzheimers
disease (AD) may stimulate b-amyloid (Ab) clearance
from the brain.
. Second-generation amyloid-directed active vaccines and
several passive monoclonal antibodies against Ab are
under extensive clinical investigation.
. Two large Phase III studies have shown that
bapineuzumab, a humanized monoclonal antibody
recognizing N terminus of Ab, did not improve cognition
or functionality of mild-to-moderate AD patients.
. Two large Phase III trials with solanezumab, a
monoclonal antibody directed at the mid-region of Ab,
also failed but suggested some beneficial cognitive
effects in mildly affected patients. A Phase III study in
mild AD patients is ongoing to confirm these
potential benefits.
.
Some secondary prevention trials on the anti-Ab
monoclonal antibodies solanezumab, gantenerumab and
crenezumab will investigate when exactly AD treatment
has to be started, focusing on therapy in asymptomatic
subjects at risk of AD with positive positron emission
tomography scans for brain Ab or presymptomatic AD
subjects with autosomal dominant AD-causing
genetic mutations.
This box summarizes key points contained in the article.
F. Panza et al.
2 Expert Opin. Biol. Ther. (2014) 14(10)
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moderate AD patients with bapineuzumab showed reduced
brain Ab burden assessed with >
1
>
1
C Pittsburgh compound
B (>
1
>
1
C PiB) PET amyloid imaging [24] and slight differen-
ces between treatment and placebo groups for CSF tau but
not for CSF Ab [25]. An important negative side effect was
the occurrence of amyloid-related imaging abnormalities
(ARIA) detected by MRI [26], particularly vasogenic edema,
in bapineuzumab-treated patients that increased in APOE
"4 carriers [27]. Very recently, in two double-blind, random-
ized, placebo-controlled Phase III trials on mild-to-moderate
AD, one involving 1121 carriers of the APOE "4 allele and
the other involving 1331 noncarriers, bapineuzumab or pla-
cebo, with doses varying by study, was administered by intra-
venous infusion every 13 weeks for 78 weeks [22]. Of these AD
patients, a total of 1090 APOE "4 carriers and 1114 non-
carriers were included in the efficacy analysis. The primary
outcome measures were scores on the 11-item cognitive sub-
scale of the Alzheimers Disease Assessment Scale (ADAS-
cog11) and the Disability Assessment for Dementia (DAD).
Secondary outcome measures included findings on >
1
>
1
C
PiB PET amyloid imaging and CSF phosphorylated tau
(phospho-tau) concentrations. In these two Phase III trials,
there were no significant between-group differences in the
ADAS-cog11 and DAD scores or other clinical end-points
(scores on the Clinical Dementia Rating Scale [CDR]--Sum
of Boxes, Neuropsychological Test Battery, Mini Mental
State Examination [MMSE] or Dependence Scale) [22]. Bapi-
neuzumab treatment was associated with reduced CSF
phospho-tau concentrations and a decreased rate of accumula-
tion of cortical amyloid in the brain on >
1
>
1
C PiB PET only
among APOE "4 carriers [22]. However, there was no measur-
able reduction from baseline of this cortical Ab, so it is
unclear whether SP clearance was stimulated [28]. Although
CSF phospho-tau is believed to be a downstream marker of
neurodegeneration, the bapineuzumab-associated reductions
in this biomarker were not associated to a cognitive or clinical
benefit. On the other hand, data from APP transgenic mice
suggested that CSF tau level may represent a response bio-
marker of Ab deposition rather than an independent measure
of neuronal injury [29]. This suggests that the observed reduc-
tions in CSF phospho-tau levels in bapineuzumab-treated AD
patients compared to those receiving placebo simply reflect
the inhibitory effects of the drug on Ab accumulation in the
brain rather than a real positive effect on neurodegeneration.
This hypothesis seems to be confirmed by the volumetric
MRI analyses that did not show significant differences in
the annual rate of loss of brain volume between the bapineu-
zumab group and the placebo group [22]. On the other hand,
longitudinal individual measurements of CSF tau, phospho-
tau
181
and visinin-like protein-1 in subjects with autosomal
dominant AD (ADAD) in the DIAN study have recently evi-
denced a decrease in these biomarkers after the individual esti-
mated age at onset (AAO) of symptoms [30]. This surprising
observation suggests that we may not have fully understood
the exact link between the individual longitudinal changes
in phospho-tau and other putative biomarkers of neurodegen-
eration in CSF and the corresponding individual cognitive
and clinical longitudinal profile. ARIA with vasogenic edema
among patients receiving bapineuzumab, which increased
with bapineuzumab dose and APOE "4 allele number, was
the major safety finding in these trials, leading to discontinu-
ation of the 2.0 mg/kg dose [22]. These not significant clinical
benefits in a series of primary and secondary cognitive and
functional outcomes reported in these two large Phase III clin-
ical trials have led also to the discontinuation of all Phase III
clinical trials and follow-on extension studies of bapineuzu-
mab in its intravenous form in AD patients on August 6,
2012. Although all Phase III trials on bapineuzumab have
been stopped, one Phase I clinical trial has been completed
in mild-to-moderate AD patients to test the safety and tolera-
bility of a more recent version of bapineuzumab (AAB-003,
PF-05236812) (ClinicalTrials. Identifier: NCT01193608)
[31] that was re-engineered to reduce the risk of ARIAs [16],
while another Phase I trial is still ongoing, but not recruiting
participants (ClinicalTrials. Identifier: NCT01369225) [32].
2.2 Solanezumab
Solanezumab is another anti-Ab monoclonal antibody that has
progressed to large Phase III clinical trials, targeting the central
Ab
13 -- 28
region, and recognizing also various N-terminal
truncated species such as Ab
3 -- 42
that are known to be present
in AD SPs [20,21]. Solanezumab was tested in Phase I and II
clinical trials [33,34], showing distinct CSF plasma elevations
of Ab and an increase of Ab
1 -- 42
and a decrease of Ab
1 -- 40
[34], with also no evidence of the meningoencephalitis reported
with first-generation active amyloid vaccines, ARIA or other
significant drug-related adverse events even after 1 year of
follow-up [33,34]. These encouraging findings led to the launch
of two large randomized, double-blind, controlled Phase III
trials of solanezumab, EXPEDITION1 and EXPEDITION2,
with, respectively, 1012 and 1040 mild-to-moderate AD
patients randomized to 400 mg of solanezumab or placebo
every 4 weeks for 80 weeks [23], and with a follow-up open-
label extension to determine the long-term safety of this
monoclonal antibody (EXPEDITION-EXT, ClinicalTrials.
gov Identifier: NCT01127633) [35]. The primary outcomes
were the changes from baseline to week 80 in scores on the
ADAS-cog11 and the Alzheimers Disease Cooperative Study--
Activities of Daily Living scale (ADCS-ADL). After analysis of
data from EXPEDITION1, while primary cognitive and func-
tional end-points were not met in overall mild-to-moderate
AD patients, a statistically significant reduction in cognitive
decline was shown in a planned secondary subgroup analyses
in patients with mild AD(MMSE score of 20 -- 26) [23]. There-
fore, the primary outcome for EXPEDITION2 was revised to
the change in scores on the 14-item cognitive subscale of the
ADAS (ADAS-cog14). Unfortunately, solanezumab treatment
did not significantly improve ADAS-cog14 scores in the
EXPEDITION2 trial also [23]. Therefore, the two EXPEDI-
TION trials did not meet cognitive and functional primary
Amyloid-directed monoclonal antibodies for the treatment of Alzheimers disease
Expert Opin. Biol. Ther. (2014) 14(10) 3
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end-points. A subgroup analysis of pooled data of both EXPE-
DITION trials showed a statistically significant 34% reduc-
tion in cognitive decline in patients with mild AD (MMSE
score of 20 -- 26), but not in patients with moderate severity
(MMSE score 16 -- 19) [21]. An independent analysis by the
ADCS confirmed these findings [21]. Biomarker analyses
showed an increase of plasma Ab
1 - 40
and Ab
1 - 42
levels, a
reduction of CSF levels of unbound and total (bound and
unbound) Ab
1 - 40
and an increase of CSF total Ab
1 - 42
in
the solanezumab groups in both trials [23]. Furthermore, there
were no significant changes in other AD biomarkers including
CSF tau, CSF phospho-tau, hippocampal volume, whole
brain volume or amyloid burden assessed by
18
F-florbetapir
PET imaging [23]. In the combined safety data set of both
EXPEDITION trials, the incidence of ARIA with edema
were observed in 0.9% of patients who received solanezumab
and in 0.4% of those who received placebo, while ARIA with
hemorrhage were observed in 4.9 and 5.6% of patients, respec-
tively [23]. Two ongoing Phase III trials will continue as
planned: the open-label extension study, EXPEDITION-
EXT (ClinicalTrials.gov Identifier: NCT01127633) [35]; and
the EXPEDITION3 on the progression of mild AD patients
(ClinicalTrials.gov Identifier: NCT01900665) [36], with
changes in the scores on the ADAS-cog14 and the ADCS-
ADL scales as the co-primary outcome measures. In both sets
of trials on bapineuzumab and solanezumab, approximately
25%of mild AD patients had no evidence of amyloid accumu-
lation on PET imaging studies [28], which therefore questioned
the AD diagnosis in these subjects. The involvement in the
EXPEDITION3 trial as an inclusion criteria of the positivity
of Ab accumulation on PET imaging should improve the diag-
nostic accuracy of the AD diagnosis and the potential to show
efficacy in this study. This inclusion criterion does not neces-
sarily imply that solanezumab should produce better results
in patients with Ab-PET positivity at baseline, since previous
Phase III studies with both bapineuzumab and solanezumab
did not show positive cognitive or clinical trends in the sub-
group of AD patients with >
1
>
1
C PiB- or
18
F-florbetapir
PET at baseline. At present, at least five other anti-Ab mono-
clonal antibodies, with properties distinct from bapineuzumab
and solanezumab, are in various stages of development [37,38].
Of these, one is a first-generation antibody (gantenerumab),
while other four (crenezumab, BAN2401, BIIB037/BART
and SAR228810) represent the second generation of anti-Ab
monoclonal antibodies, targeting pathogenic Ab multimers
rather than Ab monomers or fibrils, currently in intensive
clinical development [37,38].
3. Anti-b-amyloid monoclonal antibodies for
Alzheimers disease: the era of secondary
prevention trials
The recent failure of a series of Phase II and III clinical trials
on amyloid-centric drugs for the treatment of AD such as the
g-secretase inhibitors avagacestat [39] and semagacestat [40] and
the monoclonal antibody bapineuzumab [22] and the absence
of marked beneficial effects for solanezumab [23] suggested
that earlier intervention should probably be attempted with
secondary prevention trials in asymptomatic genetic forms
of AD and in individuals with no cognitive dysfunction sus-
pected to be at an asymptomatic stage of sporadic AD. In
fact, passive immunotherapy with anti-Ab monoclonal anti-
bodies may be involved in a preventive way in an attempt at
modifying the AD course prior to widespread brain damage
and clinical symptoms. A number of trials in both genetic
at-risk and biomarker-positive older individuals are under
way, including the Anti-Amyloid Treatment in Asymptom-
atic AD (A4) Study in amyloid-positive older individuals [41];
the DIAN-Trials Unit (DIAN-TU) in families carrying
presenilin-1 (PSEN1), presenilin-2 (PSEN2) or APP muta-
tions [42]; and the Alzheimers Prevention Initiative (API) in
a Colombian PSEN1 kindred (Table 1) [43]. These trials can
be considered secondary prevention initiatives with the
objectives of preventing cognitive decline in individuals show-
ing signs that the disease process has begun in the brain [44], so
investigating when exactly AD therapy has to be started to be
really effective [15]. However, the two alternative definitions of
AD onset, that is, disease starting with neuropathological
changes according to the NIA-AA Workgroup [5] and disease
starting with clinical symptoms according to the International
Working Group for New Research Criteria for the Diagnosis
of AD [4], may lead to different definitions of primary, sec-
ondary and tertiary prevention in AD [45].
The A4 Study is the first prevention trial on older individ-
uals identified as at-risk for progression to AD, without a
dominant genetic predisposition to the disease, who have pos-
itive PET scans for brain amyloid but without clinical AD
symptoms (Table 1) [41]. The A4 is a placebo-controlled, ran-
domized Phase III clinical trial that will test solanezumab for
three years in 1000 people aged 65 -- 85 years (ClinicalTrials.
gov Identifier: NCT02008357) [46]. The A4 Study will begin
to enroll participants at > 60 sites throughout the United
States and Canada and in Australia in the spring of 2014.
More than 5000 cognitively healthy older individuals aged
65 -- 85 years will be screened to be included among the
1000 participants randomized in two treatment arms
(500 on the solanezumab arm and 500 on the placebo arm).
These older subjects must have an increased amyloid burden
assessed by
18
F-florbetapir PET imaging with both visual rat-
ing and a quantitative measurement (standardized uptake
value ratio, SUVr) to be qualified for randomization. Inclu-
sion criteria will be MMSE score of 27 -- 30 (education
adjustment), CDR total score of 0 and Logical Memory II
score of 8 -- 15 for high education. Primary outcome measure
will be rate of decline on the ADCS-Preclinical Alzheimers
Composite Cognitive (ADCS-PACC), a cognitive composite
score including a picture-word list learning test, a logical
memory paragraph recall test and MMSE. Biomarker and
imaging outcomes will include volumetric and functional
F. Panza et al.
4 Expert Opin. Biol. Ther. (2014) 14(10)
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connectivity MRI, repeated amyloid-PET scans and, in a sub-
set of participants, CSF Ab
1 -- 42
, tau, and phospho-tau and
tau-PET scans, with a new ligand binding to the hyperphos-
phorylated tau protein of the neurofibrillary tangles [41].
People who do not show PET scan evidence for brain amyloid
accumulation will not be able to participate, but may be asked
to participate in the natural history observational arm of the
A4 Study, the Longitudinal Evaluation of Amyloid Risk and
Neurodegeneration (LEARN) Study. These subjects will be
on stage 0 or sNAP group of preclinical AD, and they will
not receive solanezumab or placebo, but they will complete
the same cognitive tests every six months to compare changes
in cognition over time, with imaging and biomarker out-
comes collected at the end of the LEARN Study. The LEARN
cohort will provide findings on amyloid-related cognitive
decline and also on nonamyloid factors linked to cognitive
decline in older adults. The A4 Study design will serve as a
platform for future secondary prevention trial on anti-Ab
drugs and for combinations of therapeutic agents with more
than one target in preclinical AD [41].
Among secondary prevention trials, the DIAN-TU was
launched in December 2012 with the aim of analyzing
Table 1. Principal secondary prevention trials of monoclonal antibodies targeting b-amyloid for the treatment of AD.
Trial
Compound
Company
Collaborators
ClinicalTrials.gov Identifier
Binding characteristics Estimated or
completed
enrollment
Characteristics Status Ref.
Anti-amyloid treatment in
Asymptomatic AD (A4)
Solanezumab (Eli Lilly)
(LY2062430)
Humanized monoclonal
IgG1 anti-Ab
1 -- 42
antibody
(Ab
13 -- 28
), binding soluble Ab
NCT02008357 1000 older
individuals at-risk
for progression
to AD (2014 -- 2018)
400 mg i.v.
administered once
every 4 weeks for
168 weeks
Phase III trial
(currently
recruiting)
[46]
Dominantly inherited Alzheimer
Network-trials unit (DIAN-TU)
Solanezumab (Eli Lilly)
(LY2062430)
Humanized monoclonal
IgG1 anti-Ab
1 -- 42
antibody
(Ab
13 -- 28
), binding soluble Ab
Gantenerumab
(Hoffmann-La Roche)
(RO4909832)
Fully human monoclonal
IgG1 antibody against Ab
1 -- 42
(Ab
1 -- 10
and Ab
19 -- 26
), not
binding soluble Ab
Washington University
School of Medicine
Alzheimers Association
National Institute on Aging
Avid Radiopharmaceuticals
NCT01760005 210 subjects
with autosomal
dominant AD
mutations
(2012 -- 2016)
Solanezumab:
400 mg i.v. every
4 weeks for 2 years
Gantenerumab:
225 mg s.c.
every 4 weeks
for 2 years
Phase II/III trial
(currently
recruiting)
[48]
Alzheimers prevention initiative
Crenezumab (Genentech)
(MABT5102A)
Banner Alzheimers Institute
Humanized monoclonal
IgG4 antibody against Ab
1 -- 42
(Ab
12 -- 23
)
NCT01998841 300 individuals
with autosomal
dominant AD-causing
genetic mutations
(2013 -- 2020)
Crenezumab s.c.
injections every
2 weeks for
260 weeks
Phase II trial
(currently
recruiting)
[53]
AD: Alzheimers disease; Ab: b-amyloid.
Amyloid-directed monoclonal antibodies for the treatment of Alzheimers disease
Expert Opin. Biol. Ther. (2014) 14(10) 5
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patients who are carriers of ADAD genetic mutations
(PSEN1, PSEN2 and APP), all destined to develop symptom-
atic AD at an early age [42,47], using two different treatment
options: solanezumab and gantenerumab (ClinicalTrials.gov
Identifier: NCT01760005) (Table 1) [48]. Gantenerumab
(RO4909832, Hoffmann-La Roche, Basel, Switzerland) is
the first fully human monoclonal antibody with sub-
nanomolar affinity to a conformational epitope expressed on
Ab fibrils, resulting in a monoclonal antibody that binds Ab
monomers and fibrils, therefore preferentially interacting
with aggregated Ab in the brain [49,50]. Preclinical findings
of gantenerumab showed a significantly reduced amyloid bur-
den by recruiting microglia, thereby preventing new SP for-
mation without altering plasma Ab [49]. A Phase I clinical
trial with this antibody on AD patients showed a decrease in
cerebral amyloid burden assessed with >
1
>
1
C PiB PET of up
to 30% in a dose-dependent manner [51], while a Phase III
trial on individuals with prodromal AD, amyloid-positive by
PET imaging but not yet cognitively impaired, is presently
in progress (ClinicalTrials.gov Identifier: NCT01224106)
(SCarlet RoAD trial) [52]. The DIAN-TU is a randomized,
double-blind placebo-controlled Phase II/III trial of an anti-
aggregated Ab antibody (gantenerumab), a soluble anti-Ab
antibody (solanezumab) and a pooled placebo group with an
estimated enrollment of a total of 210 asymptomatic to
mildly symptomatic ADAD mutation carriers who are -
15 to +10 years of their estimated AAO. In the DIAN-TU,
primary outcome measures were the amount of fibrillar
amyloid deposition assessed by >
1
>
1
C PiB PET scans for gan-
tenerumab, while for solanezumab they included the concen-
trations of unbound CSF Ab
1 -- 40
(decrease) and unbound
Ab
1 -- 42
(increase/no change) at baseline and at 2 years of fol-
low-up. Secondary outcome measures for solanezumab
included only the change in amyloid deposition as measured
by >
1
>
1
C PiB PET mean composite SUVr, and for gantener-
umab only the change in CSF Ab peptide concentrations.
Other secondary outcome measures were the change of CSF
tau and phospho-tau
181
values compared between subjects
on active drug (gantenerumab or solanezumab) and mutation
carriers in the pooled placebo group, rate of brain atrophy in
treatment groups versus pooled placebo group as measured by
cortical thickness of regions of interest (volumetric MRI) and
change in 2-[18F] fluoro-2-deoxy-D-glucose (FDG) PET
metabolism in specific regions of interest (e.g., precuneus) in
treated group as compared to pooled placebo group. Principal
inclusion criteria were: 18 -- 80 years of age, individuals who
knew they have an AD-causing mutation or were unaware
of their genetic status and had a 50% chance of having an
ADAD mutation (e.g., parent or sibling with a known AD-
causing mutation), individuals that were within
-15 to + 10 years of their parental AAO of symptoms, and
cognitively normal or with MCI or mild dementia with a
CDR of 0 -- 1 (inclusive) [42,47].
The API is a secondary prevention trial with crenezumab
started in 2013 and that will be conducted in 300 individuals
30 -- 60 years of age and who are symptom-free from the
worlds largest early-onset AD kindred in Antioquia, Colom-
bia, with a mutant gene (PSEN1 E280A) associated with a
dominant form of early onset AD (ClinicalTrials.gov Identi-
fier: NCT01998841) (Table 1) [53]. This mutation leads to
early and robust cerebral Ab
1 -- 42
SP deposition at a relatively
young age [54], which is followed at around 50 years of age by
a progressive decline in cognition and clinical function that is
decades earlier than the typical sporadic AD cases [55]. Crene-
zumab (MABT5102A, Genentech, San Francisco, CA, USA)
is a second-generation anti-Ab monoclonal antibody derived
from a mouse antibody binding to Ab
12 -- 23;
recognizing
Ab monomers, oligomers and fibrils with equally elevated
affinity [56]; and designed on an IgG4 backbone to reduce
the risk of microglial-mediated pro-inflammatory effects in
the brain [56]. In fact, a Phase I clinical trial showed that
crenezumab-treated patients had a reduced risk of brain
microhemorrhage and vasogenic edema [56], and this antibody
is presently in Phase II trial (ClinicalTrials.gov Identifier:
NCT01723826) [57]. The extraordinary Colombian kindred
of the API, which has been followed for > 20 years, includes
about 5000 people, with a sufficient number of presymptom-
atic carriers in the targeted age group to make it possible to
relate a treatments effects on both biomarker and clinical
end-points within 2 -- 5 years [43]. In the API, a Phase II
clinical trial, with a 5-year treatment period, 100 PSEN1
mutation carriers will receive subcutaneous injections of cren-
ezumab every 2 weeks, 100 will get placebo, and 100 non-car-
riers will receive placebo to ensure that study participants will
not know whether they carry the pathogenic mutation or
not [43,58]. Primary outcome measure will be change on API
Composite Cognitive Test total score (including Word List:
Recall, Multilingual Naming Test, MMSE, CERAD Con-
structional Praxis and Ravens Progressive Matrices) in a
5-year follow-up. The Collaboration for Alzheimer Preven-
tion (CAP) consortium was formed with the objective of cre-
ating interactions among these secondary prevention trials,
harmonizing the collection of biomarker, imaging and clinical
data [41]. There was a collaboration among the CAP consor-
tium, the US FDA and the European Medicines Agency
that released draft guidelines for potential regulatory pathways
of trial design in early-stage AD [59].
4. Expert opinion
The most advanced Ab-centric immunotherapeutics for AD
treatment are monoclonal antibodies. However, current
therapeutic failures of bapineuzumab and solanezumab in
mild-to-moderate AD patients provided evidence that
amyloid-directed interventions need to be used prior to or
early in the amyloid cascade, when patients are still asymp-
tomatic/preclinical. The NIA-AA criteria and stages for pre-
clinical AD [5,7] and the recent additional categories [12,13]
may help to identify asymptomatic subjects at risk of AD
with biomarker evidence of AD pathology, presymptomatic
F. Panza et al.
6 Expert Opin. Biol. Ther. (2014) 14(10)
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AD subjects carrying ADAD mutations and asymptomatic
individuals with initial biomarker evidence of neurodegenera-
tion but without b-amyloidosis. Given the considerable grow-
ing evidence showing that biomarker changes can be detected
many years before symptom onset, secondary prevention trials
for AD rely on NIA-AA criteria and biomarker data to deter-
mine when it will be best to begin amyloid-modifying thera-
peutics during this long asymptomatic/preclinical phase. On
this basis, three secondary prevention trials with the anti-Ab
monoclonal antibodies solanezumab, gantenerumab and cren-
ezumab are under way with the objective of determining when
exactly AD treatment has to be started. These trials involve
older subjects asymptomatic but with positive PET scans for
brain amyloid (A4 Study) or presymptomatic subjects with
ADAD mutations (DIAN-TU and API).
The failure of several Ab-directed drugs has also proposed
the issue of identifying the right Ab molecular structure to
target with current and future amyloid-modifying treatments.
In fact, many different Ab species with overlapping size and
morphology have been described (low-molecular-weight
oligomers, globulomers, Ab-dimers, Ab-derived diffusible
ligands [ADDLs], amylospheroids and protofibrils) [37]. In
particular, oligomeric Ab and ADDLs have been implicated
in cognitive decline [60,61], becoming the targets of
conformation-specific monoclonal antibodies designed to be
selectively directed towards these Ab species, with the aim of
producing beneficial cognitive effects without altering the
normal physiology of monomeric Ab [62,63]. Furthermore,
other proteins involved in Ab binding and aggregation might
also be a target for passive immunotherapy. In fact, preclinical
studies have reported beneficial effects of monoclonal
antibodies on other Ab-related targets, that is, the
pyroglutamate-3 Ab, a highly pathogenic Ab species, reduc-
ing SP burden in young and old AD transgenic mice, without
increased vascular amyloid or microhemorrhage [64]. Anti-
amyloidogenic effects have been showed also by anti-APOE
antibodies, binding to APOE in the SPs and activating
microglia-mediated amyloid clearance [65]. Furthermore, an
antibody targeting a more parenchymal-plaque-specific epi-
tope (Abp
3 -- 42
) showed robust clearance of pre-existing SPs
without inducing ARIA and microhemorrhage [66]. Finally,
in APP transgenic AD mice, endogenous murine Ab is a
minor Ab SP component, and passive anti-murine Ab immu-
nization cleared Ab SP pathology, including the major human
Ab component, decreasing behavioral deficits [67]. Therefore,
targeting minor endogenous brain SP constituents can also
be beneficial, thereby extending the range of the anti-amyloid
immunotherapeutic targets available for AD treatment
strategies.
Failure in eliminating Ab from brain interstitial fluid is
considered an important factor in AD pathogenesis [68]. Ab
clearance mechanisms include degradation by neprilysin,
absorption into the blood via receptor-mediated mechanisms
and elimination along perivascular pathways, effectively repre-
senting the lymphatic drainage pathways for the brain [68].
Preclinical studies showed that Ab and other solutes may be
eliminated from the brain along the basement membranes of
capillaries and arteries, and these are the pathways that ulti-
mately drain to cervical lymph nodes [69]. In the AD brain,
Ab accumulates not only in SPs but also within the perivascu-
lar drainage pathways as cerebral amyloid angiopathy
(CAA) [70]. Experimental studies have shown that perivascular
drainage of Ab from the brain is altered both in the ageing
brain and as a consequence of CAA [69]. Following active
immunization, post-mortem studies of brains from immu-
nized AD patients have shown that there is a decrease in amy-
loid in the brain parenchyma, but an increase in the severity of
CAA [71]. These findings confirmed the results on immunized
APP transgenic mice showing that as SPs are removed the
CAA severity increases [72]. However, quantitative in vivo
imaging studies in transgenic mice have documented that
clearance of CAA deposits occurred within 1 week after a sin-
gle administration of antibody directly to the brain and that
chronic administration of antibody over 2 weeks led to
more robust clearance without evidence of hemorrhage or
other destructive changes [73]. Human neuropathological
studies in AD patients immunized against Ab
1 - 42
have
shown that 4 -- 5 years after first immunization, patients had
virtually complete absence of both SPs and CAA, raising the
possibility that, given time, Ab is eventually cleared from
the cerebral vasculature [71]. These findings are consistent
with the hypothesis that Ab immunization results in solubili-
zation of Ab plaques, which, at least in part, exit the brain via
the perivascular pathway, causing a transient increase in the
severity of CAA. The extent to which these vascular alterations
following Ab immunization in AD patients are reflected in
changes in cognitive function remains to be determined. In
this respect, studies in transgenic mice have shown that the
behavioral benefits of passive immunotherapy persisted in
spite of the presence of vascular amyloid and small
hemorrhages [72].
Targeting of Ab alone might not be enough to prevent or
slow AD progression. Multiple mechanisms are involved in
AD pathogenesis, such as tau protein hyperphosphorylation,
oxidative stress, neuroinflammation and vascular factors.
Hyperphosphorylated, abnormally folded tau or tau aggre-
gates may exert direct toxic effects on neurons by decreasing
tau affinity for microtubules and subsequently promoting
microtubule network breakdown [74]. Although tau is an
intracellular protein and the deposits occur inside cells, several
immunotherapeutic approaches have recently been tested in
preclinical models for tau antibody-induced tau clearance [75],
with some preliminary data indicating that this may be a via-
ble option for clearing tau deposits in AD. Given that AD
neuropathology is linked to both accumulation of amyloid
SPs and neurofibrillary tangles, it could be reasonable to
assume that a treatment strategy focusing on both targets
may be more beneficial than a strategy focusing only on
one. Chronic inflammatory conditions may cause dysregula-
tion of mechanisms to clear misfolded or damaged neuronal
Amyloid-directed monoclonal antibodies for the treatment of Alzheimers disease
Expert Opin. Biol. Ther. (2014) 14(10) 7
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proteins accumulating with age, and concomitantly lead to
tau-associated impairments of axonal integrity and trans-
port [76]. Moreover, an increased level of the markers for oxi-
dative damage, alterations in the specific activity of
antioxidant system, mutations in specific genes, mitochon-
drial disturbances and several connections between oxidative
stress and SPs have suggested the potential benefits of antiox-
idant therapy also for AD treatment [77]. Finally, an increasing
body of evidence has related risks factor linked to vascular dis-
ease to AD also [78], and the modification of these cardiovas-
cular risk factors may be included in the ongoing secondary
prevention trials with anti-Ab monoclonal antibodies to pos-
sibly promote brain health and lessen the overall burden of
AD. The relative contributions of these different mechanisms
might vary at different stages of the disease [79]. Although the
recent failure of bapineuzumab and solanezumab in mild-to-
moderate AD suggested that anti-Ab therapies may have a
better outcome in the asymptomatic/preclinical phase, there
is also the need of developing treatments for patients in late
stages of the disease. At the dementia stage, successful thera-
peutic management might be achieved by targeting Ab
accumulation and also synaptic dysfunction and tau hyper-
phosphorylation, and providing neuronal protection and cog-
nitive training [79].
Some experimental studies on cultured cells showed that
naturally occurring Ab-reactive autoantibodies isolated from
AD patients, but not from healthy controls, may promote
b-secretase activity, so driving Ab generation [80,81]. Further-
more, using monoclonal antibodies to various regions of Ab,
antibodies generated against the N-terminal region, especially
Ab
1 -- 17
, dose dependently promoted amyloidogenic process-
ing of APP via b-secretase activation [80,81]. This N-terminal
region is largely coincident with the epitope of bapineuzumab
(Ab
1 -- 5
) and one of the epitopes of gantenerumab (Ab
1 -- 10
).
Thus, future passive or active anti-Ab immunotherapies must
consider potential off-target effects resulting from antibodies
targeting the N terminus of Ab. The development of
epitope-selective antibodies targeting the toxic domain of Ab
and favoring peripheral Ab clearance should be preferred.
The results of the recent large Phase III trials with bapi-
neuzumab and solanezumab have evidenced a number of
apparent disconnections between the effects of the drugs on
AD biomarkers and cognition. The most important is repre-
sented by the observation that the inhibitory effects of bapi-
neuzumab on brain Ab deposition and CSF phospho-tau
levels in AD patients were not associated with any cognitive
and clinical benefit. The second apparent disconnection is
that the positive cognitive effects observed in mildly affected
AD patients treated with solanezumab were not associated
with a decrease in brain Ab burden, CSF tau or phospho-
tau levels. Finally, no differential positive effects on cogni-
tion were detected for bapineuzumab or solanezumab in
the subgroup of AD patients with positive Ab-PET scan at
baseline, that is, in patients with pure AD. These apparent
inconsistencies raise doubts in our understanding of the link
between drug effects on AD biomarkers and cognition.
Alternatively, this may indicate that we are not chasing the
right biomarkers to predict positive cognitive and clinical
response to anti-Ab monoclonal antibodies. In this uncertain
situation, the results of the ongoing clinical trials with anti-
Ab monoclonal antibodies in subjects with prodromal AD,
in presymptomatic subjects with ADAD mutations or in
asymptomatic subjects at risk of developing AD, will tell us
if Ab really plays a crucial role in the pathogenesis of AD
or is only an epiphenomenon of an unknown pathological
mechanism.
Declaration of interest
BP Imbimbo is an employee at Chiesi Farmaceutici and is
involved in the development of CHF5074, a microglial mod-
ulator. He is listed amongst the inventors of a number of
Chiesi Farmaceuticis patents of anti-AD drugs. F Panza, V
Solfrizzi and G Logroscino declared no conflicts of interest.
This research was supported by Programmi di Ricerca Scien-
tifica di Rilevante Interesse Nazionale (PRIN) 2009 Grant
2009E4RM4Z. The authors have no other relevant affilia-
tions or financial involvement with any organization or entity
with a financial interest in or financial conflict with the sub-
ject matter or materials discussed in the manuscript apart
from those disclosed.
F. Panza et al.
8 Expert Opin. Biol. Ther. (2014) 14(10)
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Bibliography
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
1. Schneider LS, Mangialasche F,
Andreasen N, et al. Clinical trials and
late-stage drug development for
Alzheimers disease: an appraisal from
1984 to 2014. J Intern Med
2014;275:251-83
2. Panza F, Logroscino G, Imbimbo BP,
Solfrizzi V. Is there still any hope for
amyloid-based immunotherapy for
Alzheimers disease?
Curr Opin Psychiatry 2014;27:128-37
3. Walter J, Kaether C, Steiner H, Haass C.
The cell biology of Alzheimers disease:
uncovering the secrets of secretases.
Curr Opin Neurobiol 2001;11:585-90
4. Dubois B, Feldman HH, Jacova C, et al.
Research criteria for the diagnosis of
Alzheimers disease: revising the
NINCDS-ADRDA criteria.
Lancet Neurol 2007;6:734-46
5. Sperling RA, Aisen PS, Beckett LA, et al.
Toward defining the preclinical stages of
Alzheimers disease: recommendations
from the National Institute on
Aging--Alzheimers Association
workgroups on diagnostic guidelines for
Alzheimers disease. Alzheimers Dement
2011;7:280-92
6. Albert MS, DeKosky ST, Dickson D,
et al. The diagnosis of mild cognitive
impairment due to Alzheimers disease:
recommendations from the National
Institute on Aging--Alzheimers
Association workgroups on diagnostic
guidelines for Alzheimers disease.
Alzheimers Dement 2011;7:270-9
7. Sperling RA, Karlawish J, Johnson KA.
Preclinical Alzheimer disease-the
challenges ahead. Nat Rev Neurol
2013;9:54-8
8. Bateman RJ, Xiong C, Benzinger TL,
et al. Clinical and biomarker changes in
dominantly inherited Alzheimers disease.
N Engl J Med 2012;367:795-804
9. Villemagne VL, Burnham S, Bourgeat P,
et al. Australian Imaging Biomarkers and
Lifestyle (AIBL) Research Group.
Amyloid beta deposition,
neurodegeneration, and cognitive decline
in sporadic Alzheimers disease:
a prospective cohort study.
Lancet Neurol 2013;12:357-67
10. Desikan RS, McEvoy LK,
Thompson WK, et al.
Amyloid-beta-associated clinical decline
occurs only in the presence of elevated
Ptau. Arch Neurol 2012;69:709-13
11. Knopman DS, Jack CR Jr, Wiste HJ,
et al. Short-term clinical outcomes for
stages of NIA--AA preclinical Alzheimer
disease. Neurology 2012;78:1576-82
12. Jack CR Jr, Knopman DS, Weigand SD,
et al. An operational approach to
NIA--AA criteria for preclinical
Alzheimers disease. Ann Neurol
2012;71:765-75
.
The new criteria by the National
Institute on Aging and the Alzheimers
Association subdivided the preclinical
phase of Alzheimers disease (AD) into
stages 1 -- 3. This population-based
study proposed two additional
categories: stage 0 with subjects
including normal AD biomarkers and
no evidence of subtle cognitive
impairment; and Suspected Non-AD
Pathophysiology (sNAP) including
subjects with normal amyloid positron
emission tomography imaging, but
abnormal neurodegeneration
biomarker studies.
13. Knopman DS, Jack CR Jr, Wiste HJ,
et al. Brain injury biomarkers are not
dependent on beta-amyloid in normal
elderly. Ann Neurol 2013;73:472-80
. This population-based study suggested
that cognitively normal persons with
neurodegeneration biomarker
abnormalities, with or without
abnormal levels of b-amyloid, were
indistinguishable on a variety of
imaging markers, clinical features and
risk factors.
14. Frisardi V, Solfrizzi V, Imbimbo BP,
et al. Towards disease-modifying
treatment of Alzheimers disease: drugs
targeting beta-amyloid.
Curr Alzheimer Res 2010;7:40-55
15. Lambracht-Washington D,
Rosenberg RN. Advances in the
development of vaccines for Alzheimers
disease. Discov Med 2013;15:319-26
16. Lemere CA. Immunotherapy for
Alzheimers disease: hoops and hurdles.
Mol Neurodegener 2013;8:36
. Updated and comprehensive review
discussing b-amyloid (Ab)
immunization in Alzheimers disease,
focusing on recent advances on Ab-
directed clinical trials.
17. Bard F, Cannon C, Barbour R, et al.
Peripherally administered antibodies
against amyloid beta-peptide enter the
central nervous system and reduce
pathology in a mouse model of
Alzheimer disease. Nat Med
2000;6:916-19
18. Morgan D. Mechanisms of A beta
plaque clearance following passive A beta
immunization. Neurodegener Dis
2005;2:261-6
19. Panza F, Frisardi V, Imbimbo BP, et al.
Anti-b-amyloid immunotherapy for
Alzheimers disease: focus on
bapineuzumab. Curr Alzheimer Res
2011;8:808-17
20. Imbimbo BP, Ottonello S, Frisardi V,
et al. Solanezumab for the treatment of
mild-to-moderate Alzheimers disease.
Expert Rev Clin Immunol
2012;8:135-49
21. Tayeb HO, Murray ED, Price BH,
Tarazi FI. Bapineuzumab and
solanezumab for Alzheimers disease: is
the amyloid cascade hypothesis still
alive? Expert Opin Biol Ther
2013;13:1075-84
22. Salloway S, Sperling R, Fox NC, et al.
Two phase 3 trials of bapineuzumab in
mild-to-moderate Alzheimers disease.
N Engl J Med 2014;370:322-33
.. Phase III trials of bapineuzumab in
mild-to-moderate Alzheimers disease
patients, showing no treatment benefits
in cognitive and functional measures,
with high incidence of amyloid-related
imaging abnormalities.
23. Doody RS, Thomas RG, Farlow M,
et al. Phase 3 trials of solanezumab for
mild-to-moderate Alzheimers disease.
N Engl J Med 2014;370:311-21
.. Phase III trials of solanezumab in
mild-to-moderate Alzheimers disease
patients, showing no significant
improvement in the primary outcomes
and also failing to show treatment
effects on hippocampal or total brain
volumes or on amyloid accumulation.
24. Rinne JO, Brooks DJ, Rossor MN, et al.
11C-PiB PET assessment of change in
fibrillar amyloid-beta load in patients
with Alzheimers disease treated with
bapineuzumab: a phase 2, double-blind,
Amyloid-directed monoclonal antibodies for the treatment of Alzheimers disease
Expert Opin. Biol. Ther. (2014) 14(10) 9
E
x
p
e
r
t

O
p
i
n
.

B
i
o
l
.

T
h
e
r
.

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t

Z
u
e
r
i
c
h

o
n

0
7
/
0
6
/
1
4
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
placebo-controlled, ascending-dose study.
Lancet Neurol 2010;9:363-72
25. Blennow K, Zetterberg H, Rinne JO,
et al. AAB-001 201/202 Investigators.
Effect of immunotherapy with
bapineuzumab on cerebrospinal fluid
biomarker levels in patients with mild to
moderate Alzheimer disease. Arch Neurol
2012;69:1002-10
..
Post hoc pooled analysis of two
Phase II trials on bapineuzumab
evaluating cerebrospinal fluid
biomarker levels in mild-to-moderate
Alzheimers disease patients.
26. Sperling RA, Jack CR Jr, Black SE, et al.
Amyloid-related imaging abnormalities in
amyloid-modifying therapeutic trials:
recommendations from the Alzheimers
Association Research Roundtable
Workgroup. Alzheimers Dement
2011;7:367-85
27. Salloway S, Sperling R, Gilman S, et al.
A phase 2 multiple ascending dose trial
of bapineuzumab in mild to moderate
Alzheimer disease. Neurology
2009;73:2061-70
28. Karran E, Hardy J. Antiamyloid therapy
for Alzheimers disease--are we on the
right road? N Engl J Med
2014;370:377-8
29. Maia LF, Kaeser SA, Reichwald J, et al.
Changes in amyloid-b and Tau in the
cerebrospinal fluid of transgenic mice
overexpressing amyloid precursor protein.
Sci Transl Med 2013;5:194re2
30. Fagan AM, Xiong C, Jasielec MS, et al.
Dominantly Inherited Alzheimer
Network. Longitudinal change in CSF
biomarkers in autosomal-dominant
Alzheimers disease. Sci Transl Med
2014;6:226ra30
31. Pfizer and JANSSEN Alzheimer
Immunotherapy Research &
Development, LLC. Study Evaluating
The Safety Of AAB-003 (PF-05236812)
In Subjects With Alzheimers Disease.
ClinicalTrials.gov NCT01193608.
Available from: http://clinicaltrials.gov/
ct2/show/NCT01193608?term=
NCT01193608&rank=1
[Accessed 20 May 2014]
32. Pfizer and JANSSEN Alzheimer
Immunotherapy Research &
Development, LLC. Open Label
Extension Study Evaluating Safety and
Tolerability of AAB-003 (PF-05236812)
in Subject With Mild to Moderate
Alzheimers Disease. ClinicalTrials.gov
NCT01369225. Available from: http://
clinicaltrials.gov/ct2/show/
NCT01369225?term=NCT01369225&
rank=1 [Accessed 20 May 2014]
33. Siemers ER, Friedrich S, Dean RA, et al.
Safety and changes in plasma and
cerebrospinal fluid amyloid-beta after a
single administration of an amyloid-beta
monoclonal antibody in subjects with
Alzheimer disease. Clin Neuropharmacol
2010;33:67-73
34. Farlow M, Arnold SE, van Dyck CH,
et al. Safety and biomarker effects of
solanezumab in patients with Alzheimers
disease. Alzheimers Dement
2012;8:261-71
.
Phase II trial on solanezumab of
52 patients with mild-to-moderate
Alzheimers disease, showing distinct
plasma elevations of b-amyloid (Ab)
and an increase of Ab
1 -- 42
and a
decrease of Ab
1 -- 40
in the
cerebrospinal fluid.
35. Eli Lilly and Co. Continued Safety
Monitoring of Solanezumab in
Alzheimers Disease (EXPEDITION
EXT). ClinicalTrials.gov NCT01127633.
Available from: http://clinicaltrials.gov/
ct2/show/NCT01127633?term=
NCT00905372&rank=2 [Accessed
20 May 2014]
36. Eli Lilly and Co. Progress of Mild
Alzheimers Disease in Participants on
Solanezumab Versus Placebo
(EXPEDITION3). ClinicalTrials.gov
NCT01900665. Available from: http://
clinicaltrials.gov/ct2/show/
NCT01900665?term=NCT01900665&
rank=1 [Accessed 20 May 2014]
37. Moreth J, Mavoungou C,
Schindowski K. Passive anti-amyloid
immunotherapy in Alzheimers disease:
what are the most promising targets?
Immun Ageing 2013;10:18
38. Panza F, Solfrizzi V, Imbimbo BP, et al.
Amyloid-based immunotherapy for
Alzheimers disease in the time of
prevention trials: the way forward.
Expert Rev Clin Immunol
2014;10:405-19
39. Coric V, van Dyck CH, Salloway S,
et al. Safety and tolerability of the
g-secretase inhibitor avagacestat in a
phase 2 study of mild to moderate
Alzheimer disease. Arch Neurol
2012;69:1430-40
40. Doody RS, Raman R, Siemers E, et al.
A phase 2 trial of semagacestat for
treatment of Alzheimers disease. N Engl
J Med 2013;369:341-50
41. Sperling RA, Rentz DM, Johnson KA,
et al. The A4 Study: stopping AD before
symptoms begin? Sci Transl Med
2014;6:228fs13
42. Mills SM, Mallmann J, Santacruz AM,
et al. Preclinical trials in autosomal
dominant AD: implementation of the
DIAN-TU trial. Rev Neurol (Paris)
2013;169:737-43
43. Reiman EM, Langbaum JB, Fleisher AS,
et al. Alzheimers Prevention Initiative:
a plan to accelerate the evaluation of
presymptomatic treatments.
J Alzheimers Dis
2011;26(Suppl 3):321-9
44. Sperling RA, Jack CR Jr, Aisen PS.
Testing the right target and right drug at
the right stage. Sci Transl Med
2011;3:111cm33
45. Solomon A, Mangialasche F, Richard E,
et al. Advances in the prevention of
Alzheimers disease and dementia.
J Intern Med 2014;275:229-50
46. Eli Lilly and Co. with Alzheimers
Disease Cooperative Study (ADCS).
Clinical Trial of Solanezumab for Older
Individuals Who May be at Risk for
Memory Loss (A4). ClinicalTrials.gov
NCT02008357. Available from: http://
clinicaltrials.gov/ct2/show/
NCT02008357?term=Anti-Amyloid
+Treatment+in+Asymptomatic
+AD&rank=1 [Accessed 20 May 2014]
47. Moulder KL, Snider BJ, Mills SL, et al.
Dominantly Inherited Alzheimer
Network: facilitating research and clinical
trials. Alzheimers Res Ther 2013;5:48
48. Washington University School of
Medicine with Eli Lilly and Co.,
Hoffmann-La Roche, Alzheimers
Association, National Institute on Aging
(NIA), and Avid Radiopharmaceuticals.
Dominantly Inherited Alzheimer
Network Trial: An Opportunity to
Prevent Dementia. A Study of Potential
Disease Modifying Treatments in
Individuals at Risk for or With a Type
of Early Onset Alzheimers Disease
Caused by a Genetic Mutation. (DIAN
TU). ClinicalTrials.gov NCT01760005.
Available from: http://clinicaltrials.gov/
ct2/show/NCT01760005?term=
NCT01760005&rank=1 [Accessed
20 May 2014]
49. Bohrmann B, Baumann K, Benz J, et al.
Gantenerumab: a novel human anti-Ab
F. Panza et al.
10 Expert Opin. Biol. Ther. (2014) 14(10)
E
x
p
e
r
t

O
p
i
n
.

B
i
o
l
.

T
h
e
r
.

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t

Z
u
e
r
i
c
h

o
n

0
7
/
0
6
/
1
4
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
antibody demonstrates sustained cerebral
amyloid-b binding and elicits cell-
mediated removal of human
amyloid-beta. J Alzheimers Dis
2012;28:49-69
50. Delrieu J, Ousset PJ, Vellas B.
Gantenerumab for the treatment of
Alzheimers disease. Expert Opin
Biol Ther 2012;12:1077-86
51. Ostrowitzki S, Deptula D, Thurfjell L,
et al. Mechanism of amyloid removal in
patients with Alzheimer disease treated
with gantenerumab. Arch Neurol
2012;69:198-207
. A Phase I clinical trial on
gantenerumab with 16 Alzheimers
disease patients, in which the
antibody-treated patients showed a
dose-dependent decrease of cerebral
amyloid burden assessed with >
1
>
1
C
Pittsburgh compound B (>
1
>
1
C PiB)
positron emission tomography (PET)
amyloid imaging.
52. Hoffmann-La Roche. A Study of
Gantenerumab in Patients With
Prodromal Alzheimers Disease.
ClinicalTrials.gov NCT01224106.
Available from: http://clinicaltrials.gov/
ct2/show/NCT01224106?
term=NCT01224106&rank=1 [Accessed
20 May 2014]
53. Genentech and Banner Alzheimers
Institute. A Study of Crenezumab Versus
Placebo in Preclinical
PSEN1 E280A Mutation Carriers to
Evaluate Efficacy and Safety in the
Treatment of Autosomal-Dominant
Alzheimer Disease, Including a Placebo-
Treated Noncarrier Cohort.
ClinicalTrials.gov NCT01998841.
Available from: http://clinicaltrials.gov/
ct2/show/NCT01224106?term=
NCT01224106&rank=1 [Accessed
20 May 2014]
54. Lemere CA, Lopera F, Kosik KS, et al.
The E280A presenilin 1 Alzheimer
mutation produces increased
Ab42 deposition and severe cerebellar
pathology. Nat Med 1996;2:1146-50
55. Lopera F, Ardilla A, Martinez A, et al.
Clinical features of early-onset Alzheimer
disease in a large kindred with an
E280A presenilin-1 mutation. JAMA
1997;277:793-9
56. Adolfsson O, Pihlgren M, Toni N, et al.
An effector-reduced anti-beta-amyloid
(Ab) antibody with unique Ab binding
properties promotes neuroprotection and
glial engulfment of Abeta. J Neurosci
2012;32:9677-89
.
Phase I trial on crenezumab, showing
no signs of vasogenic edema or
microhemorrhages in Alzheimers
disease patients, even in apolipoprotein
E "4 carriers.
57. Genentech. A Long-Term Safety
Extension Study of Studies ABE4869g
And ABE4955g in Patients With Mild
To Moderate Alzheimers Disease
Treated With Crenezumab.
ClinicalTrials.gov NCT01723826.
Available from: http://clinicaltrials.gov/
ct2/show/NCT01723826?term=
NCT01723826&rank=1
[Accessed 20 May 2014]
58. Caselli RJ, Reiman EM. Characterizing
the preclinical stages of Alzheimers
disease and the prospect of
presymptomatic intervention.
J Alzheimers Dis
2013;33(Suppl 1):S405-16
59. Kozauer N, Katz R. Regulatory
innovation and drug development for
early-stage Alzheimers disease. N Engl
J Med 2013;368:1169-71
60. Lesne S, Koh MT, et al. A specific
amyloid-b protein assembly in the brain
impairs memory. Nature 2006;440:352-7
61. Koffie RM, Meyer-Luehmann M,
Hashimoto T, et al. Oligomeric amyloid
b associates with postsynaptic densities
and correlates with excitatory synapse loss
near senile plaques. Proc Natl Acad
Sci USA 2009;106:4012-17
62. Lee EB, Leng LZ, Zhang B, et al.
Targeting amyloid-b peptide (Ab)
oligomers by passive immunization with
a conformation-selective monoclonal
antibody improves learning and memory
in Abeta precursor protein (APP)
transgenic mice. J Biol Chem
2006;281:4292-9
63. Lambert MP, Velasco PT, Chang L,
et al. Monoclonal antibodies that target
pathological assemblies of Abeta.
J Neurochem 2007;100:23-35
64. Frost JL, Liu B, Kleinschmidt M, et al.
Passive immunization against
pyroglutamate-3 amyloid-beta reduces
plaque burden in Alzheimers-like
transgenic mice: a pilot study.
Neurodegenerative Dis 2012;10:265-70
..
A pilot study that showed that
monoclonal antibodies
anti-pyroglutamate-3 amyloid b (Ab),
a highly pathogenic Ab species,
reduced plaque burden in young and
old Alzheimers disease
transgenic mice.
65. Kim J, Eltorai AE, Jiang H, et al.
Anti-apoE immunotherapy inhibits
amyloid accumulation in a transgenic
mouse model of Abeta amyloidosis.
J Exp Med 2012;209:2149-56
..
Another preclinical study focusing on
passive immunotherapy against other
b-amyloid (Ab)-related targets. In this
study, anti-apolipoprotein E (APOE)
antibodies showed anti-amyloidogenic
effects by binding to APOE in the
plaques and activating microglia-
mediated amyloid clearance in
Alzheimers disease transgenic mice.
66. DeMattos RB, Lu J, Tang Y, et al.
A plaque-specific antibody clears existing
b-amyloid plaques in Alzheimers disease
mice. Neuron 2012;76:908-20
67. Morales-Corraliza J, Schmidt SD,
Mazzella MJ, et al. Immunization
targeting a minor plaque constituent
clears b-amyloid and rescues behavioral
deficits in an Alzheimers disease mouse
model. Neurobiol Aging 2013;34:137-45
68. Weller RO, Subash M, Preston SD,
et al. Perivascular drainage of amyloid-
beta peptides from the brain and its
failure in cerebral amyloid angiopathy
and Alzheimers disease. Brain Pathol
2008;18:253-66
69. Hawkes CA, Hartig W, Kacza J, et al.
Perivascular drainage of solutes is
impaired in the ageing mouse brain and
in the presence of cerebral amyloid
angiopathy. Acta Neuropathol
2011;121:431-43
70. Carare RO, Hawkes CA, Jeffrey M, et al.
Review: cerebral amyloid angiopathy,
prion angiopathy, CADASIL and the
spectrum of protein elimination failure
angiopathies (PEFA) in
neurodegenerative disease with a focus on
therapy. Neuropathol Appl Neurobiol
2013;39:593-611
71. Boche D, Zotova E, Weller RO, et al.
Consequence of Abeta immunization on
the vasculature of human Alzheimers
disease brain. Brain 2008;131:3299-310
72. Wilcock DM, Rojiani A, Rosenthal A,
et al. Passive immunotherapy against
Abeta in aged APP-transgenic mice
reverses cognitive deficits and depletes
parenchymal amyloid deposits in spite of
increased vascular amyloid and
Amyloid-directed monoclonal antibodies for the treatment of Alzheimers disease
Expert Opin. Biol. Ther. (2014) 14(10) 11
E
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p
e
r
t

O
p
i
n
.

B
i
o
l
.

T
h
e
r
.

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t

Z
u
e
r
i
c
h

o
n

0
7
/
0
6
/
1
4
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
microhemorrhage. J Neuroinflammation
2004;1:24
73. Prada CM, Garcia-Alloza M,
Betensky RA, et al. Antibody-mediated
clearance of amyloid-beta peptide from
cerebral amyloid angiopathy revealed by
quantitative in vivo imaging. J Neurosci
2007;27:1973-80
74. Iqbal K, Liu F, Gong CX, et al.
Mechanisms of tau-induced
neurodegeneration. Acta Neuropathol
2009;118:53-69
75. Panza F, Frisardi V, Solfrizzi V, et al.
Immunotherapy for Alzheimers disease:
from anti-b-amyloid to tau-based
immunization strategies. Immunotherapy
2012;4:213-38
76. Krstic D, Knuesel I. Deciphering the
mechanism underlying late-onset
Alzheimer disease. Nat Rev Neurol
2012;9:25-34
77. Lee HP, Zhu X, Casadesus G, et al.
Antioxidant approaches for the treatment
of Alzheimers disease.
Expert Rev Neurother 2010;10:1201-8
78. de la Torre JC. Vascular risk factors:
a ticking time bomb to Alzheimers
disease. Am J Alzheimers Dis
Other Demen 2013;28:551-9
79. Wang YJ. Alzheimer disease: lessons from
immunotherapy for Alzheimer disease.
Nat Rev Neurol 2014;10:188-9
80. Deng J, Hou H, Giunta B, et al.
Autoreactive-Ab antibodies promote APP
beta-secretase processing. J Neurochem
2012;120:732-40
81. Liu YH, Giunta B, Zhou HD, et al.
Immunotherapy for Alzheimer disease:
the challenge of adverse effects.
Nat Rev Neurol 2012;8:465-9
Affiliation
Francesco Panza
1,2
MD PhD,
Vincenzo Solfrizzi
3
MD PhD,
Bruno P Imbimbo
4
PhD &
Giancarlo Logroscino
1,2
MD PhD

Author for correspondence

1
University of Bari Aldo Moro, Department of
Basic Medicine, Neuroscience, and Sense Organs,
Neurodegenerative Disease Unit, Bari, Italy
2
University of Bari Aldo Moro, Department of
Clinical Research in Neurology, Pia Fondazione
Cardinale G. Panico, Tricase, Lecce, Italy
E-mail: geriat.dot@geriatria.uniba.it
3
University of Bari Aldo Moro, Geriatric
Medicine-Memory Unit and Rare Disease
Centre, Bari, Italy
4
Research and Development Department, Chiesi
Farmaceutici, Parma, Italy
F. Panza et al.
12 Expert Opin. Biol. Ther. (2014) 14(10)
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