Amyloid beta peptide immunotherapy in Alzheimer disease.

NEUROL-1376; No. of Pages 10 revue neurologique xxx (2014) xxx–xxx

Available online at

ScienceDirect www.sciencedirect.com

Biotherapies in neurological diseases

Amyloid beta peptide immunotherapy in Alzheimer disease Immunothe´rapie 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, Ge´rontopoˆle, Toulouse University Hospital, 170, avenue de Casselardit, 31059 Toulouse cedex 9, France b Inserm 1027, Faculte´ de me´decine, 37, alleés 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 xxx

disease are under investigation, active immunization and passive administration with

Keywords:

approaches resulted in clearance of amyloid plaques in patients with Alzheimer’s disease,

monoclonal antibodies directed against amyloid b peptide. Although immunotherapy 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 cle´s :

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

Immunothe´rapie

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 amyloı¨de

mer’s disease and or at asymptomatic subjects with autosomal dominant mutation. # 2014 Elsevier Masson SAS. All rights reserved.

* Corresponding author. E-mail address: [email protected] (J. Delrieu). http://dx.doi.org/10.1016/j.neurol.2014.10.003 0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Delrieu J, et al. Amyloid beta peptide immunotherapy in Alzheimer disease. Revue neurologique (2014), http:// dx.doi.org/10.1016/j.neurol.2014.10.003

NEUROL-1376; No. of Pages 10

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revue neurologique xxx (2014) xxx–xxx

r e´ s u m e´ Les progre`s rećents dans la compre´hension de la maladie d’Alzheimer ont mene´ a` l’e´laboration de nombreuses molećules qui pourraient modifier l’histoire naturelle de la maladie. La voie amyloı¨de repre´sente une cible importante pour les essais the´rapeutiques en cours. L’objectif principal de ce travail est d’examiner les e´tudes d’immunothe´rapie en rapport avec la maladie d’Alzheimer. Plusieurs types d’immunothe´rapie anti-amyloı¨de dans la maladie d’Alzheimer sont a` l’e´tude, une immunisation active et passive avec l’administration d’anticorps monoclonaux cible´s sur la voie amyloı¨de. Bien que les approches d’immunothe´rapie ont donne´ lieu a` une clearance des plaques amyloı¨des chez les patients atteints de la maladie d’Alzheimer, elles n’ont pas encore montre´ d’effet cognitif significatif pour le moment. Actuellement, plusieurs approches d’immunothe´rapie ciblant la voir amyloı¨de sont a` l’e´tude, mais aussi contre la pathologie tau. Les re´sultats des e´tudes d’immunothe´rapie dans les essais cliniques indiquent que l’intervention pourrait eˆtre plus efficace dans les stades plus prećoces de la maladie, en particulier le solanezumab avec un impact potentiel sur la maladie de Alzheimer a` un stade le´ger, ceci soulignant l’importance de diagnostiquer la maladie d’Alzheimer le plus toˆt possible. Dans les 2 rećents essais de phase III avec le solanezumab et le bapineuzumab, l’imagerie TEP a re´ve´le´ que pre`s d’un quart des patients n’avaient de pheńotype amyloı¨de au de´part de l’e´tude, ce qui sugge`re qu’ils n’avaient de maladie d’Alzheimer. Ainsi, une nouvelle phase 3 avec le solanezumab appele´ Expe´dition 3, chez les patients atteints d’une maladie d’Alzheimer a` un stade le´ger et la preuve de la pre´sence de le´sions amyloı¨des ce´re´brales a rećemment de´bute´. Ainsi, actuellement, l’intervention est reálise´ a` un stade prećoce de la maladie d’Alzheimer dans les essais cliniques, a` un stade prodromal, ou parfois meˆme chez des sujets asymptomatiques ou a` risque de de´velopper la maladie d’Alzheimer et/ou chez des sujets asymptomatiques avec mutation autosomique dominante. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.

1.

Introduction

The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer’s disease (AD). To review the efficacy and safety of immunotherapy drugs, we used the database MEDLINE. We reviewed the English-language, clinical trials designed to evaluate the efficacy or/and safety of immunotherapy drugs, from January 1999 through January 2014. The cholinesterase inhibitors and memantine have been approved to enhance cognition in AD patients. However, the effects of these treatments are limited and their clinical relevance debated [1]. Recent advances in the understanding of AD pathogenesis have led to the development of numerous compounds that might modify the disease process.

variable numbers of amyloid-containing microvessels (congophilic amyloid angiopathy, CAA). Currently available evidence strongly supports the position that the initiating event in AD is related to abnormal processing of Ab [2], ultimately leading to formation of Ab plaques in the brain. Senile plaques are classified as 2 main types: diffuse and compact plaques. The major component of both types of senile plaques is the amyloid b peptide (Ab). Ab represents an important molecular target for intervention in AD, and agents that can prevent its formation and accumulation or stimulate its clearance might ultimately be of therapeutic benefit. Potential inhibitors of the b and g secretase enzymes (which are required for the production of Ab) are under investigation, but an alternative strategy involving Ab immunotherapy is attracting much attention.

1.2. 1.1. Amyloid pathway in drug discovery for Alzheimer’s disease AD is characterized by a robust neuropathological signature. The AD brain is characterized by a decrease in the number of neurons in the limbic and association cortices and in certain subcortical nuclei projecting to them. The most obvious neuropathological changes in the AD brain are the amyloid plaques and the neurofibrillary tangles (NFT). These 2 lesions occur in the hippocampus, amygdale association cortices, and certain subcortical nuclei. They are often accompanied by

Different approaches of immunotherapy

Several types of immunotherapy for AD are under investigation [3]. The first, direct immunization with synthetic intact Ab42 has been evaluated in transgenic mouse models and has recently provided the first clinical experience of Ab immunotherapy. This approach stimulates T-cell, B-cell and microglial immune responses. A second method of active immunization involves the administration of synthetic fragments of Ab conjugated to a carrier protein avoiding the potential problems associated with mounting a T-cell response directly against Ab. The third type of immunotherapy under investigation



involves passive administration with monoclonal antibodies directed against Ab.

1.3.

Mechanisms of action in immunotherapy

3

both active and passive immunizations reduce tau pathology and prevent cognitive decline in transgenic mice [7]. At this stage addressing the safety of the tau-immunotherapy is 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. plaque breakdown: b amyloid plaques are destroyed through fragment crystallizable (Fc) mediated phagocytosis by microglial cells. Antibody is able to enter the brain and opsonize Ab with resulting Fc receptor-mediated phagocytosis by microglia. peripheral sink: the formation of antigen–antibody complexes in the periphery sequesters amyloid away from the brain and prevents the deposition of new plaques. A further possibility supported by an increase in serum Ab, most of which is bound to antibody, suggests that Ab may also be removed from the brain directly into the blood by modifying the Ab brain–blood equilibrium to enhance clearance of soluble Ab. aggregation inhibitor: the formation of antigen–antibody complexes prevents amyloid from accumulating in plaques. Ab oligomers are also a possible simultaneous target for monoclonal antibodies. A potential mechanism of a direct disaggregation of plaques by antibody without glial involvement cannot be excluded.

1.4.

Preclinical findings

Preclinical studies showed that immunization against Ab can provide protection and reversal of the pathology of AD in animal models. Several research groups have published preclinical evidence that supports the validity of active immunization strategy, and improvements in cognitive performance have been reported after immunization with Ab42, in addition to a reduction in Ab neuropathology [4]. These findings provide the first direct evidence that an intervention that affects the presence of Ab in the brain could lead to an improvement in cognition [5]. One report of immunization with a fragment of the Ab peptide coupled to polylysines has provided preliminary evidence that the immunoconjugate approach is also an effective way of mounting an immune response that results in reduced AD-like pathology in amyloid precursor protein (APP) transgenic mice. These findings reinforce the idea that immunization with the entire Ab peptide is not necessary for efficacy, and are consistent with the observation that antibodies directed against the amino-terminal and/or central region of the peptide provide protection against amyloid pathology. Several research groups have also investigated a Ab passive immunization strategy, and initial experiments indicate that a humoral response alone, in the absence of a cellular response to Ab, is sufficient to reduce the amyloid burden in the brain and to reverse memory deficits [6]. Clinical development of tau-immunotherapy is not as advanced, but preclinical data support its development into clinical trials. In fact, recent studies have demonstrated that

Necropsy data in humans

The authors report a patient with AD without encephalitis who was immunized with AN-1792 [9]. There were no amyloid plaques in the frontal cortex and abundant Ab-immunoreactive macrophages, but tangles and amyloid angiopathy were present. The white matter appeared normal and minimal lymphocytic infiltration in the leptomeninges was observed. This case illustrates the effects of an Ab-based immunization on AD pathogenesis in the absence of overt meningoencephalitis and leukoencephalopathy.

1.6.

Biomakers and immunotherapy

Clinical tests are currently used as endpoints in AD trials to measure disease progression based on cognitive, functional, or overall decline [10]. Therapeutic modification of the slopes of clinical outcome measures is a common outcome metric used in clinical trials. A consideration in the use of biomarkers as co-primary outcome measures is the fact that the rates of change over time of different biomarkers vary over the course of the disease (Table 1). In phase II AN1792 study, volumetric magnetic resonance imaging (MRI) was performed pre-dose and at month 12 or early termination [11]. Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 1.98 vs 2.04 1.74%; P = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 0.75 vs 0.48 0.40%; P = 0.001), and a non-significant greater hippocampal volume decrease (3.78 2.63 vs 2.86 3.19%; P = 0.124) than placebo patients (n = 57). A dissociation between brain volume loss and cognitive function was observed in AN1792/ QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts. In the small subset of subjects who had cerebrospinal fluid (CSF) examinations [12], CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; P = 0.001). In phase II bapineuzumab study [13], exploratory analyses showed potential treatment differences on cognitive and functional endpoints but also on biomarkers in study ‘‘completers’’ and APOE4 non-carriers. Exploratory MRI analyses in the modified intent-to-treat population showed no treatment differences in brain or ventricular volume change. APOE4 non-carriers showed 10.7 mL less brain volume loss in the bapineuzumab group compared with placebo (95% CI 3.4, 18.0; P = 0.004). No difference in ventricular volume was noted. APOE4 carriers showed no treatment difference in brain volume. However, greater ventricular enlargement was observed in the bapineuzumab group compared with placebo (2.6 mL; 95% CI 0.2, 5.0; P = 0.037). In phase II ‘‘proof of concept’’ study, the investigators used 11C-PiB (Carbon-11-labelled Pittsburgh compound B) PET


Name of the drug

Subjects

MRI volumetric analyses

Plasma Ab

CSF Ab40/42

CSF Tau

Amyloid-PET

Gilman S et al, Neurology 2005

AN1792

Antibody responders n = 11

NA

NA

No effect Ab42

#

NA

Fox NC et al, Neurology 2005

AN1792

Antibody responders n = 45

" brain volume loss " ventricular enlargement

NA

NA

NA

NA

Salloway et al, Neurology 2009

Bapineuzumab

APOE-e4 non-carriers n = 47

# brain volume loss " ventricular enlargement

NA

NA

No effect

#

Rinne et al, Lancet neurology 2010

Bapineuzumab

n = 20

NA

NA

NA

NA

0.5 mg/kg group: #24% 1 mg/kg group: #18% 2 mg/kg group: #29%

Salloway et al, Neurology 2009

Bapineuzumab

n = 20

NA

NA

No effect Ab42

# p-tau No effect on total-tau

NA

Salloway et al, N Engl J Med 2014

Bapineuzumab

Sub-groups of carrier and non-carrier studies

Carriers study: no significant difference Non-carriers study: no significant difference

NA

NA

Carriers study: # p-tau Non-carriers study: no significant difference

Carriers study: # SUVR 0.101; P = 0.004 Non-carriers study: no significant difference

Siemers et al, Clin Neuropharm 20

Solanezumab

n = 19

NA

" (Ab total)

" (Ab total)

NA

NA

Doody R et al, N Engl J Med 2014

Solanezumab

Sub-group of Expedition 1 and 2 studies

NA

" Ab40

# Free Ab40 " Total Ab40 " Total Ab42

No effect

No effect

Ostrowitzki et al, Arch Neurol 2011

Gantenerumab

n = 16

NA

NA

NA

NA

60-mg group: #15.6% 200-mg group: #35.7%

Dodel et al, Lancet Neurol 2013

Gammagard

n = 89

NA

No significant difference

NA

NA

NA

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.


Study


4


Table 1 – Biomarkers and immunotherapies in clinical trials.


(positrons emission tomography) to investigate the effects of bapineuzumab on brain amyloid load [14]. Estimated mean 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 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 change from baseline to week 78 between the bapineuzumab group and the placebo group was 0.24 (95% CI –0.39 to –0.09; P = 0.003). Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. The change in CSF biomarkers from baseline to week 52 was evaluated in a small sub-study (20 bapineuzumab and 15 placebo). No differences were observed between bapineuzumab and placebo treated patients for Ab42 or total-tau. Phospho-tau181 trended toward greater in the bapineuzumab group [13]. In phase III bapineuzumab studies, between-group differences were observed with respect to PIB-PET and CSF phospho-tau concentrations in APOE4 allele carriers but not in non-carriers [15]. In phase I solanezumab study, plasma and CSF concentrations Ab were obtained 21 days after a single dosing [16]. A substantial dose-dependent increase in total (bound plus unbound) Ab was demonstrated in plasma; CSF total Ab also increased. A dose-dependent change in plasma and CSF Ab was observed. In phase III bapineuzumab studies, levels of free Ab40 decreased in the solanezumab groups, with no appreciable change in the placebo groups. Levels of total Ab40 increased in the solanezumab groups. Levels of total Ab42 also increased in the solanezumab groups, with no appreciable change in the placebo groups, whereas levels of free Ab42 did not change significantly. There were no significant changes in CSF levels of tau or phospho-tau in the solanezumab group or placebo group in either study. Hippocampal volumes decreased as expected during the 80 weeks in the solanezumab group and the placebo group in both studies, but there were no significant treatment-related differences in either study. Whole-brain volume increased slightly in the solanezumab group and the placebo group in both studies, and the between-group comparisons were not significant. For the ancillary amyloid imaging study using 18F-florbetapir–PET, the composite standardized uptake value ratio combined and normalized to the whole cerebellum, did not change significantly in the solanezumab group or the placebo group in either study [17]. In phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer’s disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild AD and evidence of amyloid burden has been started. In phase II intravenous immunoglobulin study (gammagard), median area under curve (AUC) of plasma Ab1–40 was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups. The difference in median AUC of plasma Ab1–40 between the 0.4 g/kg every 2 weeks group and the placebo group was significant [18] (Table 1).

2.

Safety findings

2.1.

Meningoencephalitis and AN1792

5

Symptoms and laboratory findings consistent with meningoencephalitis (ME) occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo [19]. Sixteen of the 18 had received 2 doses, one had received 1 dose, and one had received 3 doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Ab42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas 6 remain with disabling cognitive or neurologic sequelae. The pathogenesis of the vaccine-induced aseptic ME has not been completely resolved. Most evidence available to date points to a critical role of Ab-specific T-cells. This includes the fact that there is no consistent correlation between the anti-AN1792 Ab response and various features of ME. Only 15 of the 18 affected patients had AN1792-specific IgG antibodies. In addition, there was no correlation between the severity/time to onset of ME and either the epitope specificity or the level of the Ab response. Finally, the vast majority of patients who mounted an Ab response did not develop ME. These results suggested that the ME was caused by something other than Ab antibodies. A first argument supporting a critical involvement of T lymphocytes in the pathogenesis of the encephalitis came from studies demonstrating that Ab42 contains epitopes capable of activating human T-cells. They were found within the central domain and the C terminal end of Ab42, the immunodominant ones are located at position 16–33. Of note, the N-terminal region of Ab42 (amino acids 1–15) appeared to be devoid of such epitopes. The strongest argument in favor of a T-cell pathology of the aseptic ME is derived from post-mortem examination of brains from AD patients who received AN1792 [20]. In contrast to the patient without ME, marked lymphocytic infiltrates were apparent in brains of patients suffered from ME. They were most prominent in the vicinity of amyloid-laden vessels but also found within the cerebral cortex and the perivascular spaces. They consisted exclusively of T-cells, the majority of them were CD4+. The fact that the presence of a T-cell infiltrate segregates with the occurrence of clinical encephalitis symptoms in these cases strongly suggests a causal relationship between the encephalitis observed in some individuals treated with AN1792/ QS21/PS-80 and the vaccine-induced Ab42-specific, type 1 Tcell response. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Phase I CAD106 study suggests that this novel active Ab immunotherapy designed to induce Nterminal Ab-specific antibodies without an Ab-specific T-cell response has a favorable safety profile and acceptable antibody response in patients with AD. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106 [21].



6


2.2. Vasogenic cerebral edema and passive immunotherapy Vasogenic edema is generated by fluid leakage from the blood vessels into the brain parenchyma via a damaged blood-brain barrier. A working group of academic and industry experts, established by the Alzheimer’s Association to help guide the conduct of clinical trials of amyloid-lowering treatments for AD, renamed abnormalities corresponding to vasogenic edema amyloid-related imaging abnormalities ARIA-E. In the phase II bapineuzumab study, 12 of 124 treated patients developed vasogenic cerebral edema [13]. Half of these developed clinical symptoms, including headache, confusion, dizziness and gait disturbance. Bapineuzumab was responsible for this adverse event, as it was observed in none of the placebo treated patients, and it exhibited a clear dose-dependence. Interestingly, it also increased in frequency with increasing APOE-e4 gene dose. Clinical manifestations were generally mild and manageable by withholding or delaying further infusions (although one patient did require treatment with dexamethasone to relieve the edema). In a retrospective analysis [22], 2 neuroradiologists independently reviewed 2572 fluid attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase II studies of bapineuzumab and an open-label extension study. A total of 210 patients were included in the risk analyses. Thirty-six patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. Thirteen of the 15 patients in whom ARIA were detected in this study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose and presence of APOE4 alleles. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. In phase III bapineuzumab studies, the major safety finding was ARIA-E among patients receiving bapineuzumab, which increased with bapineuzumab dose (4.2% in the 0.5-mg/kg bapineuzumab group, 9.4% in the 1-mg/kg bapineuzumab group and 14.2% in the 2-mg/kg bapineuzumab group) and APOE4 allele number and which led to discontinuation of the 2.0-mg/kg dose [15]. In phase II gantenerumab study [23], 2 patients in the high dose group (homozygous for the ApoE4 allele) showed MRI evidence (using a FLAIR sequence) of ARIA-E in the areas of highest plaque removal. As with bapineuzumab, ARIA-E occurred more frequently in people carrying ApoE4 as well as those on the higher dose (200 mg). These abnormalities resolved after the researchers stopped treatment. Theoretically, gantenerumab is closer to bapineuzumab than solanezumab, as it targets both soluble and fibrillary forms of amyloid. In phase III solanezumab studies [17], the incidence of ARIA was 0.9% with solanezumab and 0.4% with placebo for edema (P = 0.27).

2.3.

Microhemorrhages

ARIA include MRI signal abnormalities suggestive of ARIA-E and microhaemorrhages and haemosiderin deposits (ARIA-H) [22]. While passive AD immunotherapy was consistently

reported to reduce amyloid plaques, its effect on CAA is less clear [24]. There was no apparent effect on CAA following intracerebral application of Ab-specific antibodies in the study by Bacskai and colleagues [6]. In the Wilcock and colleagues study, after 3–5 months of treatment, cognitive deficits had recovered and amyloid plaques were reduced by 90% compared to controls [25]. By contrast, the severity of CAA had increased 3 to 4 folds and the frequency of CAA-associated microhemorrhages by 6 to 8 folds. These results on CAAassociated microhemorrhage were in line with an earlier report on passive immunotherapy in old APP23 transgenic mice. In this study, a mouse monoclonal IgG1 antibody (Ab1) recognizing the N-terminal residues 3–6 of human Ab significantly reduced Ab burden while doubling cerebral microhemorrhages. Of note, in this study, bleeding occurred only after treatment of old (21 months-old) but not of young (6 months-old) mice and without apparent change in either frequency or severity of CAA. The increased rate of microhemorrhage appears to require binding of the antibodies to the amyloid plaques as suggested by Racke and colleagues [26]. They found application of the N-terminally directed antibody (3D6), which is known to bind with high affinity to deposited amyloid, to exacerbate microhemorrhage. By contrast, an antibody directed toward the central domain of Ab but incapable of binding to it in its deposited form, neither affected frequency nor severity of CAA-associated microhemorrhages. Further support for the notion that microhemorrhage depends on antibody binding to plaques was recently provided by Schroeter et al. [27]. In this study, incidence and severity of this side effect of passive immunotherapy in AD mouse models appeared to be directly correlated to the antibody dose applied. The investigators were able to show that there exists a dose range characterized by a reduction of CAA without exacerbation of microhemorrhage. In a recent retrospective analysis [22], incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. In phase III solanezumab studies [17], the incidence of ARIA was 4.9% with solanezumab and 5.5% with placebo for hemorrhage (P = 0.49). In conclusion, ARIA consists of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE4 carriers, its association with high monoclonal antibodies (which target fibrillary forms of amyloid) dose, and its time course in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden.

3.

Clinical data

After the successful completion of the 2 phase I studies [28], a phase IIa trial of AN1792 was initiated to learn more about the immunotherapy approach [12]. In the phase IIa study, 375 patients were enrolled to receive double-blind treatment with AN1792 or placebo in a 4:1 ratio. Measures of efficacy included cognitive function, brain volume, biomarker concentration and day-to-day functioning. Signs and symptoms consistent with ME were reported in a small percentage of patients who



received AN1792, and all study dosing was halted in January 2002 [19]. Of the 300 AN1792 (QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups [12] for Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS–Cog), Disability Assessment for Dementia (DAD), Clinical Dementia Rating (CDR), Mini-mental state examination (MMSE), or Clinical Global Impression of Change (CGIC), but analyses of the zscore composite across the Neuro-psychological Test Battery (NTB) revealed differences favoring antibody responders (0.03 0.37 vs 0.20 0.45; P = 0.020). Although immunization with Ab42 resulted in clearance of amyloid plaques in patients with AD, this clearance did not prevent progressive neurodegeneration [29]. In the phase II study of bapineuzumab, 234 patients were enrolled, randomly assigned to bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. No significant differences were found in the primary efficacy analysis (ADAS-Cog and DAD). Exploratory analyses showed potential treatment differences on cognitive and functional endpoints in study ‘‘completers’’ and APOE4 non-carriers. In the completer population, treatment differences were observed on the ADAS-Cog, NTB, and DAD but not on the CDR-SB, and the MMSE showed only a trend [13]. In phase III bapineuzumab studies, there were no significant between-group differences in the primary outcomes (ADAS-Cog and DAD). At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were 0.2 (P = 0.80) and 1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the non-carrier study were 0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg/kg dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg/kg dose [15]. In phase III solanezumab studies [17], solanezumab failed to improve cognition (ADAS-Cog) or functional ability (ADCSADL). However, in patients with mild AD, based on independent analyses by the ADCS, the modeled between-group difference in the change in the ADAS-cog14 score from baseline to week 80 was 1.7 points (95% CI, 3.5 to 0.1; P = 0.06). Solanezumab could be a potential therapy for patients with mild AD. So, Lilly plans to conduct an additional Phase III study of solanezumab (Expedition 3 trial) in patients with mild AD.

4.

Future perspectives and directions

4.1.

Drugs in development

Solanezumab is a monoclonal antibody raised against Ab13–28. It differs from bapineuzumab in several ways: it recognizes a distinct epitope in the central portion of the peptide; whereas bapineuzumab binds amyloid plaques more strongly than soluble Ab, solanezumab selectively binds to soluble Ab with little to no affinity for the fibrillar form;

7

it seems that solanezumab presents less central nervous system adverse events than bapineuzumab. In fact, in phase I [16], II and III studies, there was no clinical, CSF, or MRI evidence of ME or vasogenic edema. Analyses of data from 2 phase III solanezumab trials did not show efficacy of this monoclonal antibody. Nonetheless, further studies of solanezumab, in patients with mild AD (ClinicalTrials.gov Identifier: NCT01900665), in asymptomatic persons with biomarker evidence of brain amyloid accumulation (A4 study, ClinicalTrials.gov Identifier: NCT02008357), or in individuals at risk for or with a type of early onset AD caused by a genetic mutation (DIAN-TU001, ClinicalTrials.gov Identifier: NCT01760005), are necessary for a thorough test of this particular anti-amyloid approach. Other monoclonal antibodies against Ab reportedly exhibit properties distinct from bapineuzumab. PF-04360365 targets the free carboxy-terminus of Ab1–40, specifically Ab33–40. GSK933776A (which targets the N-terminus of Ab like bapineuzumab) and gantenerumab are respectively in phase I and III. To the casual observer, gantenerumab may seem to be just another antibody that aims to clear Ab. In truth, not all of these antibodies are created equal: gantenerumab is the first human antibody. The administration of the treatment must be repeated. Thus, it is necessary to obtain antibodies with lower immunogenicity. The production of fully human antibodies could be a solution; gantenerumab grabs both central and N-terminal portions of Ab; currently, there are 3 phase III ongoing studies with gantenerumab, for mild AD (ClinicalTrials.gov Identifier: NCT02051608), for prodromal AD (ClinicalTrials.gov Identifier: NCT01224106) and for early onset AD caused by a genetic mutation (ClinicalTrials.gov Identifier: NCT01760005). MABT5102A (crenezumab) binds to Ab monomers, oligomers, and fibrils with equally high affinity. Participants in crenezumab phase II trial are carriers of a presenilin 1 mutation, PSEN1 E280A, which is autosomal dominant and has complete penetrance (ClinicalTrials.gov Identifier: NCT01998841). Anti-Ab antibodies occur naturally in pooled preparations of intravenous immunoglobulin (IVIg or IGIV), which is already food and drug administration approved for 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 this approach include that IVIg already has a long clinical track record, it is generally safe and well tolerated, and it circumvents the high research and manufacturing costs associated with monoclonal antibodies [31]. There is one trial currently underway for IVIg in AD (Table 2). Development of gammagard is currently stopped [18]. Avoiding both the strong Th1 effects of QS-21 adjuvant and the T-cell epitopes at the C-terminus of Ab, CAD106 consists of a short N-terminal fragment (sequence predicted not to activate T-cell responses to Ab) of Ab attached to a viruslike particle (presents repetitively the antigen Ab1–6 to elicit a strong B-cell response and stimulates T-cells), with no



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Table 2 – Passive Ab immunotherapies in development. Drug name

Phase

Pharmacology

Type

Sponsor

Primary outcomes in ongoing trials

Epitope

Isotype

Bapineuzumab (AAB-001, ELN115727)

Stopped

1–5 Free N-terminus

IgG1

Humanized

Janssen/Elan/ Pfizer

Cognitive and Functional

Solanezumab (LY2062430)

III

13–28 (central portion)

IgG1

Humanized

Eli Lilly

ADAS-Cog, ADCS-ADL in Expedition 3 CSF Ab in DIAN-TU001

Ponezumab (PF-04360365)

Stopped

33–40 Free C-terminus

IgG2

Humanized

Pfizer

Safety/tolerability Pharmacokinetics

Gantenerumab

III

N-terminus and central portion

IgG1

Fully human

Hoffman- La Roche

ADAS-Cog, ADCS-ADL in mild AD Amount of fibrillar amyloid deposition in DIAN-TU001

Crenezumab MABT5102A

II

Oligomeric and protofibrillar forms, (aa 13–14 appears relevant)

IgG4

Humanized

Genentech

ADAS-Cog CDR-SOB

GSK933776A

I

N-terminus

NP

NP

GlaxoSmithKline

Safety/tolerability

SAR228810

I

Prefibrillar Ab aggregates

NP

Humanized

Sanofi-Aventis

Safety/tolerability Pharmacokinetics

BAN2401

II

Toxic amyloid beta protofibrils

IgG1

Humanized

Eisai

Derived Composite Clinical Score

NewGam 10% IVIG

II

NP

NP

Sutter Health

Gammagard IGIV, 10%

Stopped

Bind central and C-terminus as well as pathogenic conformations of Ab (focus on dimers)

NP

NP

Baxter Healthcare Corporation

Change in ventricular volumetric as measured by MRI ADAS-Cog ADCS-ADL

NP: not published; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative StudyActivities of Daily Living; CDR-SOB: Clinical Dementia Rating scale Sum of Boxes; aa: amino acid.

additional adjuvant. This agent is currently in Phase II trials. Using a novel approach, Affiris is testing short, 6amino peptides that mimic the free N-terminus of Ab and cause cross-reactivity against the native peptide. Two of

these so-called ‘‘affitope’’ peptides, AD01 and AD02, were administered with aluminum hydroxide as adjuvant in Phase I trials. Other vaccines are currently in development (Table 3).

Table 3 – Active immunotherapies. Drug name

Phase

Drugs used and binding characteristics

Sponsor

Primary outcomes in ongoing trials

CAD106

II

B-cell epitope peptide, Ab1–6, coupled to carrier protein (bacteriophage coat protein)

Novartis

Safety and tolerability

ACC001

II

B-cell epitope peptide, Ab1–6, coupled to carrier protein, Qs21 as adjuvant

Pfizer

Cerebral amyloid burden

AFFITOPE AD02

I

Peptide mimicking the B-cell epitope peptide, Ab1–6, with no sequence similarities

Affiris


UB 311

NP

Targeting the N-terminal amino acids (1–14) of the amyloid beta peptide

United Biomedical

Immunogenicity

V950

I

Multivalent Ab vaccine

Merck


AADvac1

I

Directed against pathologically modified Alzheimer tau protein

Axon Neuroscience SE




4.2. Targeting pathological tau protein by immunotherapy Another important target in AD is the NFT, composed primarily of hyperphosphorylated-tau proteins. Ab immunotherapy results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. In tangle mouse models, immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of NFT [32]. Passive immunization with tau antibodies can decrease tau pathology and functional impairments [33]. Indeed, these results must be confirmed in human studies. AADvac1 is the only vaccine in clinical development (Table 3).

5.

Conclusion

As well as its clinical potential, this immunological approach will provide a framework for testing the amyloid hypothesis. The idea that the results of immunization against an abnormal proteinaceous build-up in the brain of an animal model could translate into a treatment and potentially prevent AD was initially received with sincere optimism. Active immunization schedules are being developed to minimize T-lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. Thus, currently, amyloid intervention is realized at early stage of the AD in clinical trials, at prodromal AD, at asymptomatic subjects at risk to develop AD and at asymptomatic subjects with autosomal dominant mutation. This new immunotherapy approach (i.e. to treat early) requires: early efficient prodromal AD biomarkers; to develop different primary outcomes, biomarkers or new composite cognitive markers. The first author is involved in SAR228810 phase I trial. JD is involved in the writing of the manuscript’s first draft and in the review of the subsequent drafts. JD, PJO, TV and BV took part in the execution of the project and in the review of the manuscript.

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Disclosure of interest The authors declare that they have no conflict of interest concerning this article.

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