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revue neurologique 170 (2014) 739–748

Available online at

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www.sciencedirect.com

Biotherapies in neurological diseases

Amyloid beta peptide immunotherapy in


Alzheimer disease
Immunothérapie anti-amyloı¨de dans la maladie d’Alzheimer

J. Delrieu a,*, P.J. Ousset a,b, T. Voisin a,b, B. Vellas a,b


a
Alzheimer’s Disease Clinical Research Centre, Gérontopôle, Toulouse University Hospital, 170,
avenue de Casselardit, 31059 Toulouse cedex 9, France
b
Inserm 1027, Faculté de médecine, 37, allées Jules-Guesde, 31000 Toulouse, France

info article abstract

Article history: Recent advances in the understanding of Alzheimer’s disease pathogenesis have led to the
Received 24 April 2014 development of numerous compounds that might modify the disease process. Amyloid b
Received in revised form peptide represents an important molecular target for intervention in Alzheimer’s disease.
11 September 2014 The main purpose of this work is to review immunotherapy studies in relation to the
Accepted 3 October 2014 Alzheimer’s disease. Several types of amyloid b peptide immunotherapy for Alzheimer’s
Available online 6 November 2014 disease are under investigation, active immunization and passive administration with
monoclonal antibodies directed against amyloid b peptide. Although immunotherapy
Keywords: approaches resulted in clearance of amyloid plaques in patients with Alzheimer’s disease,
Alzheimer’s disease this clearance did not show significant cognitive effect for the moment. Currently, several
Immunotherapy amyloid b peptide immunotherapy approaches are under investigation but also against tau
Vaccine pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate
Monoclonal antibodies that intervention appears to be more effective in early stages of amyloid accumulation in
Biomarkers particular solanezumab with a potential impact at mild Alzheimer’s disease, highlighting
Amyloid b peptide the importance of diagnosing Alzheimer’s disease as early as possible and undertaking
clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET
Mots clés : imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at
Maladie d’Alzheimer baseline, suggesting that they did not have Alzheimer’s disease in the first place. So a new
Immunothérapie third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild
Vaccin Alzheimer’s disease and evidence of amyloid burden has been started. Thus, currently,
Anticorps monoclonaux amyloid intervention is realized at early stage of the Alzheimer’s disease in clinical trials, at
Biomarqueurs prodromal Alzheimer’s disease, or at asymptomatic subjects or at risk to develop Alzhei-
Peptide b amyloı̈de mer’s disease and or at asymptomatic subjects with autosomal dominant mutation.
# 2014 Elsevier Masson SAS. All rights reserved.

* Corresponding author.
E-mail address: delrieu.j@chu-toulouse.fr (J. Delrieu).
http://dx.doi.org/10.1016/j.neurol.2014.10.003
0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.
740 revue neurologique 170 (2014) 739–748

r é s u m é

Les progrès récents dans la compréhension de la maladie d’Alzheimer ont mené à l’élabora-
tion de nombreuses molécules qui pourraient modifier l’histoire naturelle de la maladie. La
voie amyloı̈de représente une cible importante pour les essais thérapeutiques en cours.
L’objectif principal de ce travail est d’examiner les études d’immunothérapie en rapport
avec la maladie d’Alzheimer. Plusieurs types d’immunothérapie anti-amyloı̈de dans la
maladie d’Alzheimer sont à l’étude, une immunisation active et passive avec l’administra-
tion d’anticorps monoclonaux ciblés sur la voie amyloı̈de. Bien que les approches d’immu-
nothérapie ont donné lieu à une clearance des plaques amyloı̈des chez les patients atteints
de la maladie d’Alzheimer, elles n’ont pas encore montré d’effet cognitif significatif pour le
moment. Actuellement, plusieurs approches d’immunothérapie ciblant la voir amyloı̈de
sont à l’étude, mais aussi contre la pathologie tau. Les résultats des études d’immuno-
thérapie dans les essais cliniques indiquent que l’intervention pourrait être plus efficace
dans les stades plus précoces de la maladie, en particulier le solanezumab avec un impact
potentiel sur la maladie de Alzheimer à un stade léger, ceci soulignant l’importance de
diagnostiquer la maladie d’Alzheimer le plus tôt possible. Dans les 2 récents essais de phase
III avec le solanezumab et le bapineuzumab, l’imagerie TEP a révélé que près d’un quart des
patients n’avaient de phénotype amyloı̈de au départ de l’étude, ce qui suggère qu’ils
n’avaient de maladie d’Alzheimer. Ainsi, une nouvelle phase 3 avec le solanezumab appelé
Expédition 3, chez les patients atteints d’une maladie d’Alzheimer à un stade léger et la
preuve de la présence de lésions amyloı̈des cérébrales a récemment débuté. Ainsi, actuel-
lement, l’intervention est réalisé à un stade précoce de la maladie d’Alzheimer dans les
essais cliniques, à un stade prodromal, ou parfois même chez des sujets asymptomatiques
ou à risque de développer la maladie d’Alzheimer et/ou chez des sujets asymptomatiques
avec mutation autosomique dominante.
# 2014 Elsevier Masson SAS. Tous droits réservés.

variable numbers of amyloid-containing microvessels (congo-


1. Introduction philic amyloid angiopathy, CAA).
Currently available evidence strongly supports the position
The main purpose of this work is to review immunotherapy that the initiating event in AD is related to abnormal
studies in relation to the Alzheimer’s disease (AD). To review processing of Ab [2], ultimately leading to formation of Ab
the efficacy and safety of immunotherapy drugs, we used the plaques in the brain. Senile plaques are classified as 2 main
database MEDLINE. We reviewed the English-language, clini- types: diffuse and compact plaques. The major component of
cal trials designed to evaluate the efficacy or/and safety of both types of senile plaques is the amyloid b peptide (Ab). Ab
immunotherapy drugs, from January 1999 through January represents an important molecular target for intervention in
2014. AD, and agents that can prevent its formation and accumula-
The cholinesterase inhibitors and memantine have been tion or stimulate its clearance might ultimately be of
approved to enhance cognition in AD patients. However, the therapeutic benefit. Potential inhibitors of the b and g
effects of these treatments are limited and their clinical secretase enzymes (which are required for the production of
relevance debated [1]. Recent advances in the understanding Ab) are under investigation, but an alternative strategy
of AD pathogenesis have led to the development of numerous involving Ab immunotherapy is attracting much attention.
compounds that might modify the disease process.
1.2. Different approaches of immunotherapy
1.1. Amyloid pathway in drug discovery for Alzheimer’s
disease Several types of immunotherapy for AD are under investiga-
tion [3]. The first, direct immunization with synthetic intact
AD is characterized by a robust neuropathological signature. Ab42 has been evaluated in transgenic mouse models and has
The AD brain is characterized by a decrease in the number of recently provided the first clinical experience of Ab immuno-
neurons in the limbic and association cortices and in certain therapy. This approach stimulates T-cell, B-cell and microglial
subcortical nuclei projecting to them. The most obvious immune responses. A second method of active immunization
neuropathological changes in the AD brain are the amyloid involves the administration of synthetic fragments of Ab
plaques and the neurofibrillary tangles (NFT). These 2 lesions conjugated to a carrier protein avoiding the potential problems
occur in the hippocampus, amygdale association cortices, and associated with mounting a T-cell response directly against
certain subcortical nuclei. They are often accompanied by Ab. The third type of immunotherapy under investigation
revue neurologique 170 (2014) 739–748 741

involves passive administration with monoclonal antibodies both active and passive immunizations reduce tau pathology
directed against Ab. and prevent cognitive decline in transgenic mice [7]. At this
stage addressing the safety of the tau-immunotherapy is
1.3. Mechanisms of action in immunotherapy highly needed, particularly since it has previously shown the
neurotoxic potential of tau-immunotherapy [8].
Several hypothesis [3] concerning mechanisms of action exist:
1.5. Necropsy data in humans

 plaque breakdown: b amyloid plaques are destroyed The authors report a patient with AD without encephalitis
through fragment crystallizable (Fc) mediated phagocytosis who was immunized with AN-1792 [9]. There were no amyloid
by microglial cells. Antibody is able to enter the brain and plaques in the frontal cortex and abundant Ab-immunoreac-
opsonize Ab with resulting Fc receptor-mediated phagocy- tive macrophages, but tangles and amyloid angiopathy were
tosis by microglia. present. The white matter appeared normal and minimal
 peripheral sink: the formation of antigen–antibody comple- lymphocytic infiltration in the leptomeninges was observed.
xes in the periphery sequesters amyloid away from the brain This case illustrates the effects of an Ab-based immunization
and prevents the deposition of new plaques. A further on AD pathogenesis in the absence of overt meningoence-
possibility supported by an increase in serum Ab, most of phalitis and leukoencephalopathy.
which is bound to antibody, suggests that Ab may also be
removed from the brain directly into the blood by modifying 1.6. Biomakers and immunotherapy
the Ab brain–blood equilibrium to enhance clearance of
soluble Ab. Clinical tests are currently used as endpoints in AD trials to
 aggregation inhibitor: the formation of antigen–antibody measure disease progression based on cognitive, functional,
complexes prevents amyloid from accumulating in plaques. or overall decline [10]. Therapeutic modification of the slopes
of clinical outcome measures is a common outcome metric
Ab oligomers are also a possible simultaneous target for used in clinical trials. A consideration in the use of biomarkers
monoclonal antibodies. A potential mechanism of a direct as co-primary outcome measures is the fact that the rates of
disaggregation of plaques by antibody without glial involve- change over time of different biomarkers vary over the course
ment cannot be excluded. of the disease (Table 1).
In phase II AN1792 study, volumetric magnetic resonance
1.4. Preclinical findings imaging (MRI) was performed pre-dose and at month 12 or
early termination [11]. Two hundred eighty-eight patients had
Preclinical studies showed that immunization against Ab can paired scans (mean interval 10.9 months). Antibody respon-
provide protection and reversal of the pathology of AD in ders (n = 45) had greater brain volume decrease (3.12  1.98 vs
animal models. 2.04  1.74%; P = 0.007), greater ventricular enlargement as a
Several research groups have published preclinical evi- percentage of baseline brain volume (1.10  0.75 vs
dence that supports the validity of active immunization 0.48  0.40%; P = 0.001), and a non-significant greater hippo-
strategy, and improvements in cognitive performance have campal volume decrease (3.78  2.63 vs 2.86  3.19%; P = 0.124)
been reported after immunization with Ab42, in addition to a than placebo patients (n = 57). A dissociation between brain
reduction in Ab neuropathology [4]. These findings provide the volume loss and cognitive function was observed in AN1792/
first direct evidence that an intervention that affects the QS-21 antibody responders. The reasons for this remain
presence of Ab in the brain could lead to an improvement in unclear but include the possibility that volume changes were
cognition [5]. One report of immunization with a fragment of due to amyloid removal and associated cerebral fluid shifts. In
the Ab peptide coupled to polylysines has provided prelimi- the small subset of subjects who had cerebrospinal fluid (CSF)
nary evidence that the immunoconjugate approach is also an examinations [12], CSF tau was decreased in antibody
effective way of mounting an immune response that results in responders (n = 11) vs placebo subjects (n = 10; P = 0.001).
reduced AD-like pathology in amyloid precursor protein (APP) In phase II bapineuzumab study [13], exploratory analyses
transgenic mice. These findings reinforce the idea that showed potential treatment differences on cognitive and
immunization with the entire Ab peptide is not necessary functional endpoints but also on biomarkers in study
for efficacy, and are consistent with the observation that ‘‘completers’’ and APOE4 non-carriers. Exploratory MRI
antibodies directed against the amino-terminal and/or central analyses in the modified intent-to-treat population showed
region of the peptide provide protection against amyloid no treatment differences in brain or ventricular volume
pathology. change. APOE4 non-carriers showed 10.7 mL less brain volume
Several research groups have also investigated a Ab passive loss in the bapineuzumab group compared with placebo (95%
immunization strategy, and initial experiments indicate that a CI 3.4, 18.0; P = 0.004). No difference in ventricular volume was
humoral response alone, in the absence of a cellular response noted. APOE4 carriers showed no treatment difference in brain
to Ab, is sufficient to reduce the amyloid burden in the brain volume. However, greater ventricular enlargement was
and to reverse memory deficits [6]. observed in the bapineuzumab group compared with placebo
Clinical development of tau-immunotherapy is not as (2.6 mL; 95% CI 0.2, 5.0; P = 0.037).
advanced, but preclinical data support its development into In phase II ‘‘proof of concept’’ study, the investigators used
clinical trials. In fact, recent studies have demonstrated that 11C-PiB (Carbon-11-labelled Pittsburgh compound B) PET
742
Table 1 – Biomarkers and immunotherapies in clinical trials.
Study Name of the drug Subjects MRI volumetric Plasma Ab CSF Ab40/42 CSF Tau Amyloid-PET
analyses
Gilman S et al, AN1792 Antibody NA NA No effect Ab42 # NA
Neurology 2005 responders
n = 11

Fox NC et al, AN1792 Antibody " brain volume loss NA NA NA NA


Neurology 2005 responders " ventricular
n = 45 enlargement

Salloway et al, Bapineuzumab APOE-e4 # brain volume loss NA NA No effect #

revue neurologique 170 (2014) 739–748


Neurology 2009 non-carriers " ventricular
n = 47 enlargement

Rinne et al, Bapineuzumab n = 20 NA NA NA NA 0.5 mg/kg group: #24%


Lancet 1 mg/kg group: #18%
neurology 2010 2 mg/kg group: #29%

Salloway et al, Bapineuzumab n = 20 NA NA No effect Ab42 # p-tau NA


Neurology 2009 No effect on
total-tau

Salloway et al, Bapineuzumab Sub-groups of Carriers study: no NA NA Carriers study: Carriers study: # SUVR
N Engl J Med 2014 carrier and significant difference # p-tau 0.101; P = 0.004
non-carrier Non-carriers study: no Non-carriers Non-carriers study: no
studies significant difference study: no significant difference
significant
difference

Siemers et al, Solanezumab n = 19 NA " " NA NA


Clin Neuropharm 20 (Ab total) (Ab total)

Doody R et al, Solanezumab Sub-group of NA " Ab40 # Free Ab40 No effect No effect
N Engl J Med 2014 Expedition 1 " Total Ab40
and 2 studies " Total Ab42

Ostrowitzki et al, Gantenerumab n = 16 NA NA NA NA 60-mg group: #15.6%


Arch Neurol 2011 200-mg group: #35.7%

Dodel et al, Gammagard n = 89 NA No significant NA NA NA


Lancet Neurol 2013 difference
MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; NA: not applicable; #: decrease; ": increase; Ab: amyloid b peptide; PET: positron emission tomography; SUVR: standard uptake value
relative.
revue neurologique 170 (2014) 739–748 743

(positrons emission tomography) to investigate the effects of


bapineuzumab on brain amyloid load [14]. Estimated mean 2. Safety findings
11C-PiB retention ratio change from baseline to week 78 was
0.09 (95% CI–0.16 to 0.02; P = 0.014) in the bapineuzumab 2.1. Meningoencephalitis and AN1792
group and 0.15 (95% CI 0.02 to 0.28; P = 0.022) in the placebo
group. Estimated mean difference in 11C-PiB retention ratio Symptoms and laboratory findings consistent with menin-
change from baseline to week 78 between the bapineuzumab goencephalitis (ME) occurred in 18 of 298 (6%) patients treated
group and the placebo group was 0.24 (95% CI –0.39 to –0.09; with AN1792 compared with 0 of 74 on placebo [19]. Sixteen of
P = 0.003). Treatment with bapineuzumab for 78 weeks the 18 had received 2 doses, one had received 1 dose, and one
reduced cortical 11C-PiB retention compared with both had received 3 doses of the study drug before symptoms
baseline and placebo. occurred. The median latency from the first and last injections
The change in CSF biomarkers from baseline to week 52 to symptoms was 75 and 40 days. No case occurred later than 6
was evaluated in a small sub-study (20 bapineuzumab and 15 months after the first immunization. Anti-Ab42 antibody titers
placebo). No differences were observed between bapineuzu- were not correlated with the occurrence or severity of
mab and placebo treated patients for Ab42 or total-tau. symptoms or relapses. Twelve patients recovered to or close
Phospho-tau181 trended toward greater in the bapineuzumab to baseline within weeks, whereas 6 remain with disabling
group [13]. cognitive or neurologic sequelae.
In phase III bapineuzumab studies, between-group diffe- The pathogenesis of the vaccine-induced aseptic ME has
rences were observed with respect to PIB-PET and CSF not been completely resolved. Most evidence available to
phospho-tau concentrations in APOE4 allele carriers but not date points to a critical role of Ab-specific T-cells. This
in non-carriers [15]. includes the fact that there is no consistent correlation
In phase I solanezumab study, plasma and CSF concen- between the anti-AN1792 Ab response and various features of
trations Ab were obtained 21 days after a single dosing [16]. A ME. Only 15 of the 18 affected patients had AN1792-specific
substantial dose-dependent increase in total (bound plus IgG antibodies. In addition, there was no correlation between
unbound) Ab was demonstrated in plasma; CSF total Ab also the severity/time to onset of ME and either the epitope
increased. A dose-dependent change in plasma and CSF Ab specificity or the level of the Ab response. Finally, the vast
was observed. majority of patients who mounted an Ab response did not
In phase III bapineuzumab studies, levels of free Ab40 develop ME. These results suggested that the ME was caused
decreased in the solanezumab groups, with no appreciable by something other than Ab antibodies. A first argument
change in the placebo groups. Levels of total Ab40 increased in supporting a critical involvement of T lymphocytes in the
the solanezumab groups. Levels of total Ab42 also increased in pathogenesis of the encephalitis came from studies demons-
the solanezumab groups, with no appreciable change in the trating that Ab42 contains epitopes capable of activating
placebo groups, whereas levels of free Ab42 did not change human T-cells. They were found within the central domain
significantly. There were no significant changes in CSF levels and the C terminal end of Ab42, the immunodominant ones
of tau or phospho-tau in the solanezumab group or placebo are located at position 16–33. Of note, the N-terminal region
group in either study. Hippocampal volumes decreased as of Ab42 (amino acids 1–15) appeared to be devoid of such
expected during the 80 weeks in the solanezumab group and epitopes. The strongest argument in favor of a T-cell
the placebo group in both studies, but there were no significant pathology of the aseptic ME is derived from post-mortem
treatment-related differences in either study. Whole-brain examination of brains from AD patients who received
volume increased slightly in the solanezumab group and the AN1792 [20]. In contrast to the patient without ME, marked
placebo group in both studies, and the between-group lymphocytic infiltrates were apparent in brains of patients
comparisons were not significant. For the ancillary amyloid suffered from ME. They were most prominent in the vicinity
imaging study using 18F-florbetapir–PET, the composite of amyloid-laden vessels but also found within the cerebral
standardized uptake value ratio combined and normalized cortex and the perivascular spaces. They consisted exclusi-
to the whole cerebellum, did not change significantly in the vely of T-cells, the majority of them were CD4+. The fact that
solanezumab group or the placebo group in either study [17]. the presence of a T-cell infiltrate segregates with the
In phase III solanezumab and bapineuzumab trials, PET occurrence of clinical encephalitis symptoms in these cases
imaging revealed that about a quarter of patients lacked strongly suggests a causal relationship between the ence-
fibrillar amyloid pathology at baseline, suggesting that they phalitis observed in some individuals treated with AN1792/
did not have Alzheimer’s disease in the first place. So a new QS21/PS-80 and the vaccine-induced Ab42-specific, type 1 T-
third phase 3 clinical trial for solanezumab, called Expedition cell response.
3, in patients with mild AD and evidence of amyloid burden Following AN1792, second-generation active immunothe-
has been started. rapies have shown promising results in terms of antibody
In phase II intravenous immunoglobulin study (gamma- response and safety. Phase I CAD106 study suggests that this
gard), median area under curve (AUC) of plasma Ab1–40 was novel active Ab immunotherapy designed to induce N-
not significantly different for intravenous immunoglobulin terminal Ab-specific antibodies without an Ab-specific T-cell
compared with placebo for five of the six intervention groups. response has a favorable safety profile and acceptable anti-
The difference in median AUC of plasma Ab1–40 between the body response in patients with AD. Larger trials with
0.4 g/kg every 2 weeks group and the placebo group was additional dose investigations are needed to confirm the
significant [18] (Table 1). safety and establish the efficacy of CAD106 [21].
744 revue neurologique 170 (2014) 739–748

2.2. Vasogenic cerebral edema and passive reported to reduce amyloid plaques, its effect on CAA is less
immunotherapy clear [24]. There was no apparent effect on CAA following
intracerebral application of Ab-specific antibodies in the study
Vasogenic edema is generated by fluid leakage from the blood by Bacskai and colleagues [6]. In the Wilcock and colleagues
vessels into the brain parenchyma via a damaged blood-brain study, after 3–5 months of treatment, cognitive deficits had
barrier. A working group of academic and industry experts, recovered and amyloid plaques were reduced by 90%
established by the Alzheimer’s Association to help guide the compared to controls [25]. By contrast, the severity of CAA
conduct of clinical trials of amyloid-lowering treatments for had increased 3 to 4 folds and the frequency of CAA-associated
AD, renamed abnormalities corresponding to vasogenic microhemorrhages by 6 to 8 folds. These results on CAA-
edema amyloid-related imaging abnormalities ARIA-E. associated microhemorrhage were in line with an earlier
In the phase II bapineuzumab study, 12 of 124 treated report on passive immunotherapy in old APP23 transgenic
patients developed vasogenic cerebral edema [13]. Half of mice. In this study, a mouse monoclonal IgG1 antibody (Ab1)
these developed clinical symptoms, including headache, recognizing the N-terminal residues 3–6 of human Ab
confusion, dizziness and gait disturbance. Bapineuzumab significantly reduced Ab burden while doubling cerebral
was responsible for this adverse event, as it was observed in microhemorrhages. Of note, in this study, bleeding occurred
none of the placebo treated patients, and it exhibited a clear only after treatment of old (21 months-old) but not of young (6
dose-dependence. Interestingly, it also increased in frequency months-old) mice and without apparent change in either
with increasing APOE-e4 gene dose. Clinical manifestations frequency or severity of CAA. The increased rate of micro-
were generally mild and manageable by withholding or hemorrhage appears to require binding of the antibodies to the
delaying further infusions (although one patient did require amyloid plaques as suggested by Racke and colleagues [26].
treatment with dexamethasone to relieve the edema). They found application of the N-terminally directed antibody
In a retrospective analysis [22], 2 neuroradiologists indepen- (3D6), which is known to bind with high affinity to deposited
dently reviewed 2572 fluid attenuated inversion recovery (FLAIR) amyloid, to exacerbate microhemorrhage. By contrast, an
MRI scans from 262 participants in two phase II studies of antibody directed toward the central domain of Ab but
bapineuzumab and an open-label extension study. A total of 210 incapable of binding to it in its deposited form, neither
patients were included in the risk analyses. Thirty-six patients affected frequency nor severity of CAA-associated microhe-
(17%) developed ARIA-E during treatment with bapineuzumab; morrhages. Further support for the notion that microhemor-
15 of these ARIA-E cases (42%) had not been detected previously. rhage depends on antibody binding to plaques was recently
Thirteen of the 15 patients in whom ARIA were detected in this provided by Schroeter et al. [27]. In this study, incidence and
study received additional treatment infusions while ARIA-E severity of this side effect of passive immunotherapy in AD
were present, without any associated symptoms. Occurrence of mouse models appeared to be directly correlated to the
ARIA-E increased with bapineuzumab dose and presence of antibody dose applied. The investigators were able to show
APOE4 alleles. Adverse events, reported in eight symptomatic that there exists a dose range characterized by a reduction of
patients, included headache, confusion, and neuropsychiatric CAA without exacerbation of microhemorrhage. In a recent
and gastrointestinal symptoms. retrospective analysis [22], incident ARIA-H occurred in 17 of
In phase III bapineuzumab studies, the major safety finding the patients with ARIA-E (47%), compared with seven of 177
was ARIA-E among patients receiving bapineuzumab, which (4%) patients without ARIA-E.
increased with bapineuzumab dose (4.2% in the 0.5-mg/kg In phase III solanezumab studies [17], the incidence of ARIA
bapineuzumab group, 9.4% in the 1-mg/kg bapineuzumab was 4.9% with solanezumab and 5.5% with placebo for
group and 14.2% in the 2-mg/kg bapineuzumab group) and hemorrhage (P = 0.49).
APOE4 allele number and which led to discontinuation of the In conclusion, ARIA consists of a spectrum of imaging
2.0-mg/kg dose [15]. findings with variable clinical correlates, and some patients
In phase II gantenerumab study [23], 2 patients in the high with ARIA-E remain asymptomatic even if treatment is
dose group (homozygous for the ApoE4 allele) showed MRI continued. The increased risk of ARIA among APOE4 carriers,
evidence (using a FLAIR sequence) of ARIA-E in the areas of its association with high monoclonal antibodies (which target
highest plaque removal. As with bapineuzumab, ARIA-E fibrillary forms of amyloid) dose, and its time course in relation
occurred more frequently in people carrying ApoE4 as well as to dosing suggest an association between ARIA and alterations
those on the higher dose (200 mg). These abnormalities in vascular amyloid burden.
resolved after the researchers stopped treatment. Theoreti-
cally, gantenerumab is closer to bapineuzumab than solane-
zumab, as it targets both soluble and fibrillary forms of amyloid. 3. Clinical data
In phase III solanezumab studies [17], the incidence of ARIA
was 0.9% with solanezumab and 0.4% with placebo for edema After the successful completion of the 2 phase I studies [28], a
(P = 0.27). phase IIa trial of AN1792 was initiated to learn more about the
immunotherapy approach [12]. In the phase IIa study, 375
2.3. Microhemorrhages patients were enrolled to receive double-blind treatment with
AN1792 or placebo in a 4:1 ratio. Measures of efficacy included
ARIA include MRI signal abnormalities suggestive of ARIA-E cognitive function, brain volume, biomarker concentration
and microhaemorrhages and haemosiderin deposits (ARIA-H) and day-to-day functioning. Signs and symptoms consistent
[22]. While passive AD immunotherapy was consistently with ME were reported in a small percentage of patients who
revue neurologique 170 (2014) 739–748 745

received AN1792, and all study dosing was halted in January  it seems that solanezumab presents less central nervous
2002 [19]. Of the 300 AN1792 (QS-21)-treated patients, 59 system adverse events than bapineuzumab.
(19.7%) developed the predetermined antibody response.
Double-blind assessments were maintained for 12 months. In fact, in phase I [16], II and III studies, there was no
No significant differences were found between antibody clinical, CSF, or MRI evidence of ME or vasogenic edema.
responder and placebo groups [12] for Alzheimer’s Disease Analyses of data from 2 phase III solanezumab trials did not
Assessment Scale-Cognitive subscale (ADAS–Cog), Disability show efficacy of this monoclonal antibody. Nonetheless,
Assessment for Dementia (DAD), Clinical Dementia Rating further studies of solanezumab, in patients with mild AD
(CDR), Mini-mental state examination (MMSE), or Clinical (ClinicalTrials.gov Identifier: NCT01900665), in asymptomatic
Global Impression of Change (CGIC), but analyses of the z- persons with biomarker evidence of brain amyloid accumula-
score composite across the Neuro-psychological Test Battery tion (A4 study, ClinicalTrials.gov Identifier: NCT02008357), or
(NTB) revealed differences favoring antibody responders in individuals at risk for or with a type of early onset AD caused
(0.03  0.37 vs 0.20  0.45; P = 0.020). Although immunization by a genetic mutation (DIAN-TU001, ClinicalTrials.gov Identi-
with Ab42 resulted in clearance of amyloid plaques in patients fier: NCT01760005), are necessary for a thorough test of this
with AD, this clearance did not prevent progressive neurode- particular anti-amyloid approach.
generation [29]. Other monoclonal antibodies against Ab reportedly exhibit
In the phase II study of bapineuzumab, 234 patients were properties distinct from bapineuzumab. PF-04360365 targets
enrolled, randomly assigned to bapineuzumab or placebo in 4 the free carboxy-terminus of Ab1–40, specifically Ab33–40.
dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 GSK933776A (which targets the N-terminus of Ab like
infusions, 13 weeks apart, with final assessments at week 78. bapineuzumab) and gantenerumab are respectively in phase
No significant differences were found in the primary efficacy I and III. To the casual observer, gantenerumab may seem to be
analysis (ADAS-Cog and DAD). Exploratory analyses showed just another antibody that aims to clear Ab. In truth, not all of
potential treatment differences on cognitive and functional these antibodies are created equal:
endpoints in study ‘‘completers’’ and APOE4 non-carriers. In
the completer population, treatment differences were obser-  gantenerumab is the first human antibody. The adminis-
ved on the ADAS-Cog, NTB, and DAD but not on the CDR-SB, tration of the treatment must be repeated. Thus, it is
and the MMSE showed only a trend [13]. necessary to obtain antibodies with lower immunogenicity.
In phase III bapineuzumab studies, there were no signifi- The production of fully human antibodies could be a
cant between-group differences in the primary outcomes solution;
(ADAS-Cog and DAD). At week 78, the between-group  gantenerumab grabs both central and N-terminal portions
differences in the change from baseline in the ADAS-cog11 of Ab;
and DAD scores (bapineuzumab group minus placebo group)  currently, there are 3 phase III ongoing studies with
were 0.2 (P = 0.80) and 1.2 (P = 0.34), respectively, in the gantenerumab, for mild AD (ClinicalTrials.gov Identifier:
carrier study; the corresponding differences in the non-carrier NCT02051608), for prodromal AD (ClinicalTrials.gov Identi-
study were 0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg/kg fier: NCT01224106) and for early onset AD caused by a genetic
dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with mutation (ClinicalTrials.gov Identifier: NCT01760005).
the 1.0-mg/kg dose [15].
In phase III solanezumab studies [17], solanezumab failed to MABT5102A (crenezumab) binds to Ab monomers, oligo-
improve cognition (ADAS-Cog) or functional ability (ADCS- mers, and fibrils with equally high affinity. Participants in
ADL). However, in patients with mild AD, based on indepen- crenezumab phase II trial are carriers of a presenilin 1
dent analyses by the ADCS, the modeled between-group mutation, PSEN1 E280A, which is autosomal dominant and
difference in the change in the ADAS-cog14 score from baseline has complete penetrance (ClinicalTrials.gov Identifier:
to week 80 was 1.7 points (95% CI, 3.5 to 0.1; P = 0.06). NCT01998841). Anti-Ab antibodies occur naturally in pooled
Solanezumab could be a potential therapy for patients with preparations of intravenous immunoglobulin (IVIg or IGIV),
mild AD. So, Lilly plans to conduct an additional Phase III study which is already food and drug administration approved for
of solanezumab (Expedition 3 trial) in patients with mild AD. the treatment of a variety of other neurological conditions.
Preliminary work showed that IVIg treatment may be
efficacious in the treatment of AD [30], and advantages to
4. Future perspectives and directions this approach include that IVIg already has a long clinical track
record, it is generally safe and well tolerated, and it
4.1. Drugs in development circumvents the high research and manufacturing costs
associated with monoclonal antibodies [31]. There is one trial
Solanezumab is a monoclonal antibody raised against Ab13–28. currently underway for IVIg in AD (Table 2). Development of
It differs from bapineuzumab in several ways: gammagard is currently stopped [18].
Avoiding both the strong Th1 effects of QS-21 adjuvant and
 it recognizes a distinct epitope in the central portion of the the T-cell epitopes at the C-terminus of Ab, CAD106 consists of
peptide; a short N-terminal fragment (sequence predicted not to
 whereas bapineuzumab binds amyloid plaques more stron- activate T-cell responses to Ab) of Ab attached to a virus-
gly than soluble Ab, solanezumab selectively binds to like particle (presents repetitively the antigen Ab1–6 to elicit a
soluble Ab with little to no affinity for the fibrillar form; strong B-cell response and stimulates T-cells), with no
746 revue neurologique 170 (2014) 739–748

Table 2 – Passive Ab immunotherapies in development.


Drug name Phase Pharmacology Type Sponsor Primary outcomes
in ongoing trials

Epitope Isotype
Bapineuzumab Stopped 1–5 IgG1 Humanized Janssen/Elan/ Cognitive and
(AAB-001, ELN115727) Free N-terminus Pfizer Functional

Solanezumab III 13–28 (central IgG1 Humanized Eli Lilly ADAS-Cog, ADCS-ADL
(LY2062430) portion) in Expedition 3
CSF Ab in DIAN-TU001

Ponezumab Stopped 33–40 IgG2 Humanized Pfizer Safety/tolerability


(PF-04360365) Free C-terminus Pharmacokinetics

Gantenerumab III N-terminus and IgG1 Fully human Hoffman- La ADAS-Cog, ADCS-ADL
central portion Roche in mild AD
Amount of fibrillar
amyloid deposition in
DIAN-TU001

Crenezumab II Oligomeric and IgG4 Humanized Genentech ADAS-Cog


MABT5102A protofibrillar forms, CDR-SOB
(aa 13–14 appears
relevant)

GSK933776A I N-terminus NP NP GlaxoSmithKline Safety/tolerability

SAR228810 I Prefibrillar Ab NP Humanized Sanofi-Aventis Safety/tolerability


aggregates Pharmacokinetics

BAN2401 II Toxic amyloid beta IgG1 Humanized Eisai Derived Composite


protofibrils Clinical Score

NewGam 10% IVIG II Bind central and NP NP Sutter Health Change in ventricular
C-terminus as well volumetric as
as pathogenic measured by MRI
Gammagard Stopped conformations of Ab NP NP Baxter ADAS-Cog
IGIV, 10% (focus on dimers) Healthcare ADCS-ADL
Corporation
NP: not published; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative Study-
Activities of Daily Living; CDR-SOB: Clinical Dementia Rating scale Sum of Boxes; aa: amino acid.

additional adjuvant. This agent is currently in Phase II these so-called ‘‘affitope’’ peptides, AD01 and AD02, were
trials. Using a novel approach, Affiris is testing short, 6- administered with aluminum hydroxide as adjuvant in
amino peptides that mimic the free N-terminus of Ab and Phase I trials. Other vaccines are currently in development
cause cross-reactivity against the native peptide. Two of (Table 3).

Table 3 – Active immunotherapies.


Drug name Phase Drugs used and binding Sponsor Primary outcomes
characteristics in ongoing trials
CAD106 II B-cell epitope peptide, Ab1–6, Novartis Safety and tolerability
coupled to carrier protein
(bacteriophage coat protein)

ACC001 II B-cell epitope peptide, Ab1–6, Pfizer Cerebral amyloid burden


coupled to carrier protein, Qs21 as
adjuvant

AFFITOPE I Peptide mimicking the B-cell Affiris Safety and tolerability


AD02 epitope peptide, Ab1–6, with no
sequence similarities

UB 311 NP Targeting the N-terminal amino United Biomedical Immunogenicity


acids (1–14) of the amyloid beta
peptide

V950 I Multivalent Ab vaccine Merck Safety and tolerability

AADvac1 I Directed against pathologically Axon Safety and tolerability


modified Alzheimer tau protein Neuroscience SE
revue neurologique 170 (2014) 739–748 747

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