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Immunotherapy against amyloid pathology in Alzheimer's disease
JNS-12538; No of Pages 5 Journal of the Neurological Sciences xxx (2013) xxx–xxx
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Immunotherapy against amyloid pathology in Alzheimer's disease Daniela Galimberti ⁎, Laura Ghezzi, Elio Scarpini Neurology Unit, Dept. of Pathophysiology and Transplantation, “Dino Ferrari” Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy
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Article history: Received 29 September 2012 Received in revised form 9 November 2012 Accepted 10 December 2012 Available online xxxx Keywords: Alzheimer's disease Amyloid Disease-modifying drugs Vaccination Passive immunization
a b s t r a c t The first drugs developed for Alzheimer's disease (AD), anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed “disease modifying” drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms, including the deposition of extracellular amyloid beta (Aβ) plaques and of intracellular neurofibrillary tangles. The most innovative approach is represented by the vaccination and passive immunization against Aβ peptide. In this article, current knowledge about concluded and ongoing clinical trials with both vaccination with different antigens and passive immunization will be reviewed and discussed. © 2012 Elsevier B.V. All rights reserved.
1. Introduction 1.1. Pathogenesis of Alzheimer's disease Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with a prevalence of 5% after 65 years of age, increasing to about 30% in people aged 85 years or older. It is characterized clinically by progressive cognitive impairment, including impaired judgment, decision-making and orientation, often accompanied, in later stages, by psychobehavioral disturbances as well as language impairment. Mutations in genes encoding for amyloid precursors protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) account for about 5% of cases, characterized by an early onset (before 65 years of age). So far, 33 different mutations, causing amino acid changes in putative sites for the cleavage of the protein, have been described in the APP gene in 90 families, together with 185 mutations in PSEN1(in 405 families) and 13 in PSEN2in 22 families (http://www. molgen.vib-ua.be). The two major neuropathology hallmarks of AD are extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The production of Aβ, which represents a crucial step in AD pathogenesis, is the result of cleavage of APP, which is over-expressed in AD [1]. Aβ forms highly insoluble and proteolysis resistant fibrils known as senile plaques (SP). NFTs are composed of the tau protein. In healthy subjects, tau is a component of microtubules, which represent ⁎ Corresponding author at: via F. Sforza, 35, 20122, Milan, Italy. Tel.: +39 2 55033847; fax: +39 2 55036580. E-mail address: [email protected] (D. Galimberti).
the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilize growing axons, which are necessary for the development and growth of neurites [1]. In AD, tau protein is abnormally hyperphosphorylated and forms insoluble fibrils, originating deposits within the cell. A number of additional pathogenic mechanisms, possibly overlapping with Aβ plaque and NFT formation, have been described, including inflammation [2] oxidative damage [3], iron deregulation [4], cholesterol metabolism [5]. 2. Symptomatic treatments Acetylcholine levels were demonstrated to be reduced in AD [6]. Based on this observation, the first drugs developed for AD were aimed to increase the levels of such neurotransmitter by inhibiting cholinesterase activity, and were named anticholinesterase inhibitors (AchEI). At present, four AchEI are approved for the treatment of mild to moderate AD: tacrine (First Horizon Pharmaceuticals), donepezil (Pfizer), rivastigmine (Novartis), and galantamine (Janssen) [7,8]. Donepezil is now approved also for severe AD. Although tacrine was the first drug approved for AD in 1993, it is rarely used due to hepatotoxicity. A meta-analysis of thirteen randomized, double blind, placebo controlled trials with donepezil, rivastigmine and galantamine were considered by the Cochrane Dementia and Cognitive Improvement Group's Specialized Register. Conclusions were that the three AChEI are efficacious for mild to moderate AD, although it is not possible to identify patients who will respond to treatment prior to treatment.
0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2012.12.013
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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There is no evidence that treatment with an AChEI is not cost effective. In addition, despite the slight variations in the mode of action of the three AChEI, there is no evidence of any differences among them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than 3 months is used. Titration with donepezil is more straightforward and the lower dose may be worthy of consideration [9]. Recently, it was demonstrated that continued treatment with donepezil is associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months in patients with moderate or severe AD [10]. Rivastigmine is currently available also as a transdermal patch (Exelon® patch, Rivastach® patch, Prometax® patch). Previous evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with AD, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favorable tolerability profile as compared with oral AchEI (see [11] for review). A further symptomatic therapeutic option available for moderate to severe AD is memantine. This drug is an un-competitive, moderateaffinity, NMDA antagonist believed to protect neurons from excitotoxicity. A recent meta-analysis on the efficacy of AChEIs and memantine indicates that these treatments can result in statistically significant but clinically marginal improvement [12]. Regarding tolerability, AChEIs are associated with cholinomimetic effects. Nausea (2–8%) and vomiting (1–5%) were reported across all AChEI trials as the most common reasons for trial discontinuation. Dizziness, anorexia, and diarrhea were also commonly experienced; however, improved tolerability has been reached with transdermal administration of rivastigmine. The most frequently reported adverse events in memantine trials were dizziness, headache, and confusion [13]. 3. Modulation of amyloid deposition through vaccination On the basis of recent additional findings on AD pathogenesis, novel treatments under development aim to interfere with pathogenic steps previously mentioned, in an attempt to block the course of the disease in early phases (even preclinical). For this reason they are currently termed “disease modifying” drugs. As it is thought that the amyloid deposition is the very first pathogenic event in AD pathogenesis, that in turn activates a cascade of additional pathogenic mechanisms, the majority of new approaches under development aim to avoid Aβ peptide deposition or to remove already deposited amyloid. In this framework, the most studied and promising approach is immunotherapy. 3.1. The amyloid hypothesis The APP plays a central role in AD pathogenesis and in AD research, as it is the precursor of Aβ, which is the heart of the amyloid cascade hypothesis of AD. The human APP gene was first identified in 1987 by several laboratories independently [14–16]. The two APP homologs, APLP1 and APLP2, were discovered several years later. APP is a type I membrane protein. Two predicted cleavages, one in the extracellular domain (β-secretase cleavage) and another in the transmembrane region (γ-secretase cleavage) are necessary to release Aβ from the precursor protein. Remarkably, APP lies in chromosome 21, and this provided an immediate connection to the invariant development of AD pathology in trisomy 21 (Down's syndrome). The first mutations demonstrated to be causative of inherited forms of familial AD were identified in the APP gene, providing evidence that APP plays a central role in AD
pathogenesis. Notably, only APP but not its homologs APLP1 and APLP2, contains sequences encoding the Aβ domain. Full-length APP undergoes sequential proteolytic processing. It is first cleaved by α-secretase (non-amyloidogenic pathway) or β-secretase (amyloidogenic pathway) within the luminal domain, resulting in the shedding of nearly the entire ectodomain and generation of βor β–C-terminal fragments (CTFs). The major neuronal β-secretase, named BACE1 (β-site APP cleaving enzyme), is a transmembrane aspartyl protease which cleaves APP within the ectodomain, generating the N-terminus of Aβ [17]. Several zinc metalloproteinase, and the aspartyl protease BACE2, can cleave APP at the β-secretase site [18] localized within the Aβ domain, thus hampering the generation of intact Aβ. The second proteolytic event in APP processing involves intramembranous cleavage of α- and β-CTFs by γ-secretase, which liberates a 3 kDa protein, named p3, and Aβ peptide, into the extracellular milieu. The minimal components of γ-secretase include presenilin PS1 or PS2, nicastrin, APH-1 and PEN-2 [19]. Biochemical evidence is consistent with PS1 (or PS2) as the catalytic subunit of the γ-secretase, whereas APH-1 and PEN-2 stabilize the γ-secretase complex, and nicastrin mediates the recruitment of APP CTFs to the catalytic site of the γ-secretase. Major sites of γ-secretase cleavage correspond to positions 40 and 42, leading to the formation of the Aβ[1–40] and Aβ[1–42] peptides. Amyloidogenic processing is the favored pathway of APP metabolism in neurons, due to the greater abundance of BACE1, whereas non-amyloidogenic pathway predominates in other cell types. It seems that none of the above mentioned secretases have unique substrate specificity towards APP. Besides APP, a number of other transmembrane proteins undergo ectodomain shedding by enzymes with α-secretase activity. Regarding BACE1, its low affinity for APP led to the hypothesis that APP is not its sole physiological substrate. Similarly, PS1 and PS2 play a crucial role in intramembranous γ-secretase cleavage of several type I membrane proteins other than APP, including Notch1 receptors and its ligands [20]. A number of functional domains have been mapped to the extraand intracellular region of APP, including metal (copper and zinc) binding, extracellular matrix components (heparin, collagen and laminin), and neurotrophic and adhesion domains. Thus far, a thropic role for APP has been suggested, as it stimulates neurite outgrowth in a variety of experimental settings. The N-terminal heparin-binding domain of APP also stimulates neurite outgrowth and promotes synaptogenesis [21]. APP was initially proposed to act as a cell surface receptor. Nevertheless, the evidence supporting this hypothesis has been unconvincing. In 2004, a candidate ligand had been proposed. In was in fact reported that F-spondin, a neuronal secreted signaling glycoprotein that may function in neuronal development and repair, binds to the extracellular domain of APP as well as of APLP1 and APLP2 [22]. This binding reduces β-secretase cleavage of APP, suggesting therefore that F-spondin binding may regulate APP processing. 3.2. Vaccination In 1999 Schenk et al. [23] demonstrated that immunization with Aβ as an antigen attenuated AD-like pathology in transgenic mice over-expressing the APP gene, by removing amyloid from the central nervous system. This transgenic mouse model of AD progressively develops several neuropathological features of the disease in an age-related and brain-region-dependent manner. Immunization of young animals with Aβ prevented the development of plaque formation, neuritic dystrophy and astroglyosis, whereas in older animals, vaccination reduced extent and progression of AD-like pathologies. Given these extremely promising preclinical results, a phase I controlled study was started, in a cohort of 80 patients with mild to moderate AD. Results demonstrated that this vaccine induced an amyloid
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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antibody response in more than half the cases. Right after, a multicenter, randomized, placebo-controlled, phase II double-blind clinical trial using active immunization with Aβ42 plus adjuvant was started in 2001 in a cohort of 300 patients, using the preaggregated Aβ peptide AN1792. However, following reports of aseptic meningo-encephalitis in 6% of treated patients, the trial was halted after 2–3 injections. Of the 300 patients treated, 60% developed antibody response. The final results of the trial were published in 2005 [24]. Double-blind assessment was maintained for 12 months, demonstrating no significant differences in cognition between antibody responders and placebo group for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), Disability Assessment for Dementia (DAS), Clinical Dementia Rating (CDR), MMSE and Clinical Global Impression of Change (CGIC). In a small subset of patients, cerebrospinal fluid (CSF) tau levels were decreased in antibody responders although Aβ levels remained unchanged. Long-term follow-up of treated patients and further analysis of autopsy data modified and moderated the negative impact of the first results, encouraging additional clinical attempts. Subsequent observations on AN1792 vaccinated patients or transgenic models and on brain tissue derived from mice and humans using a new tissue amyloid immunoreactivity (TAPIR) method suggested that antibodies against Aβ-related epitopes are capable of slowing the progression of neuropathology in AD. Hock and Nitsch [25] followed for four years 30 patients who received a prime and booster immunization over the first year after vaccination, providing further support to continue investigation of antibody treatment in AD. In 2008, a paper was published describing the relation between Aβ42 immune response, degree of plaque removal and long-term clinical outcomes [26]. In June 2003, 80 patients (or their caregivers), who had entered the phase I and II of the AN1792 trial, gave their consent for long-term clinical follow-up (maximum: 6 years) and post-mortem neuropathological examination. In autopsy-examined brain from patients who received immunization, mean Aβ load was lower than in the placebo group. Despite this observation, however, no evidence of improved survival or an improvement in time to severe dementia was observed in such patients. Therefore, plaque removal is likely not enough to halt progressive neurodegeneration in AD, prompting some intriguing challenges to the amyloid hypothesis. Although severe adverse events occurred in the first AN1792 trial and cognitive results were unclear, immunization was not abandoned. Based on previous data obtained on autopsy and neuropathological data [27,28], it was thought that the use of the full length amyloid peptide in AN1792 led to a vigorous T-cell autoimmune response that caused the meningeal inflammation. This could be due to molecular mimicry between T-cell epitopes and the C-terminal region of the molecule [29]. Therefore, subsequent efforts focused on designing second-generation amyloid vaccines that would favor a humoral rather than a cellular immune response. The first second-generation vaccine tested in patients with AD is CAD106 (Novartis), a vaccine that presents multiple copies of Aβ1-6 peptide derived from the N-terminal B cell epitope of Aβ, that avoids T cell activation, coupled to the Qβ virus-like particle. In animals, CAD106 induced Aβ-antibody titers without activating Aβ-reactive T-cells. Administration of CAD106 to APP transgenic mice showed a reduction of amyloid accumulation in the brain. A phase I, doubleblind, placebo-controlled, 52-week study was carried out in two centers in Sweden. Fifty-eight patients with mild to moderate AD, aged 50–80 years, were entered into one of two cohorts according to time of study entry, and then randomly allocated to receive either CAD 106 or placebo (ratio 4:1; the first cohort, consisting of 31 patients, received CAD106 50 μg or placebo; the second, consisting of 27 patients, received CAD106 150 μg or placebo). Each patient received three subcutaneous injections. Primary objectives were to assess safety and tolerability of CAD106 and to identify Aβ-antibody
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response (patients with Aβ-IgG serum titers > 16 units at least once during the study were considered responders). Almost all patients (56/58) reported adverse events. The most common side effect in cohort 1 was nasopharyngitis, whereas in cohort 2 it was injection site erythema. No cases of clinical or subclinical cases of meningoencephalitis were observed. 67% of CAD106-treated patients in cohort I and 82% in cohort 2 developed Aβ antibody response. However, also one placebo-treated patient out of 12 had Aβ-IgG concentrations that qualified them as responder. In conclusion, results of these trials suggest that CAD106 has a favorable safety profile and acceptable antibody response in patients with AD [30]. Additional vaccines under clinical testing include: – ACI-24 (AC immune) is an Aβ1-15 peptide to which on both ends two lysines are attached. The antigen is embedded in a liposome membrane. The drug restored memory defects of transgenic mice and is currently evaluated in a phase I/II clinical trial in Denmark, Finland and Sweden (Thomson Reuters Pharma). – Affitope AD-02 (Affiris, Vienna AT and licensee GlaxoSmithKline Biologicals) is a six amino acid peptide vaccine targeting the N-terminus of amyloid-β . The antibody response is focused exclusively on amyloid-β and did not show crossreactivity to APP. A European phase II clinical trial in 420 patients is ongoing (Thomson Reuters Pharma). – Affitope-AD-03 (Affiris and licensee GlaxoSmithKline Biologicals) entered a phase I clinical trial in 2010, and the study was completed in November 2011 (Thomson Reuters Pharma). - ACC-001 (vanutide cridificar; Pfizer). Two phase II studies have been developed in patients with mild to moderate AD: one in Japan (completed) and one ongoing in USA. – UB-311 (United Biomedical) is an intramuscularly administered vaccine targeting N-terminal amino acids 1–14 of Aβ in phase I clinical trials in Taiwan in patients with mild to moderate AD (Thomson Reuters Pharma). – V-950 (Merck) is an N-terminal Aβ peptide conjugated to an aluminum-containing adjuvant. A phase II, double-blind, randomized, placebo-controlled, dose escalating study to evaluate the safety, tolerability, and immunogenicity of V-950 formulated on aluminum-containing adjuvant with or without ISCOMATRIX™ adjuvant in patients with AD has been completed (http:// clinicaltrials.gov), but results have not been published yet. 4. Passive immunization 4.1. Humanized antibodies An alternative solution to avoid an undesirable T-cell induced inflammation that can be a source of side effects is to use passive immunization. This is achieved by passively infusing anti-Aβ antibodies into patients, eliciting an immune response without requiring a pro-inflammatory T-cell reaction. The first antibody tested is the humanized monoclonal anti-Aβ antibody Bapineuzumab (Wyeth and Elan), tested initially in a phase II trial in 200 patients with mild to moderate AD. The 18-month, multi-dose, one-to-one randomization trial was conducted at about 30 sites in the US. It was designed to assess safety, tolerability and standard efficacy endpoints (ADAS-Cog, DAS) of multiple ascending doses of Bapineuzumab in patients. Prior to the completion of the phase II study, a phase III trial was initiated. The results of these trials did not show overall efficacy but a small subset of patients, i.e., the ApoE non-carriers who received the second-lowest of the four doses six times, responded truly well by 78 weeks. Subsequent trials in non-carriers were negative and 2 trials in APOe 4 carriers were initiated but then discontinued due to lack of effect. Solanezumab (LY2062430; Ely Lilly) is a humanized monoclonal antibody that binds to the central region of β-amyloid. A phase 2, randomized, double-blind, placebo-controlled clinical trial was carried
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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out to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab in patients with mild-to-moderate AD. Fifty-two patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and CSF examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the ADAS-cognitive portion was administered. Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ(1–40) and Aβ(1–42) in plasma increased in a dose-dependent manner. Antibody treatment increased total Aβ(1–40) and Aβ(1–42) in CSF. The ADAS-Cog was unchanged after the 12-week antibody administration. This study showed that antibody administration is well tolerated with doses up to 400 mg weekly. The increase in unbound CSF Aβ(1–42) suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ(1–42) from amyloid plaques [31]. Two large phase II trials (EXPEDITION1 and EXPEDITION2) were conducted. More than 2000 patients have been recruited and randomized to receive 400 mg of solanezumab versus placebo every 4 weeks for 80 weeks. Follow up with an open-label extension of the phase III has been set up in order to determine the long-term safety of solanezumab (www.clinicaltrials. gov). The results of EXPEDITION 1 showed a significant reduction in cognitive decline of 42% in mild AD (P b 0.008) but EXPEDITION 2 showed a only a non-significant 20% reduction in cognitive decline (P = 0.120). There was no significant functional improvement in either trial but there was a 17% reduction in functional decline (P = 0.057) for the phase III. Additional antibodies, that vary in terms of the Aβ epitopes they target, and their affinity to other amyloid species and stages, such as soluble oligomers and protofibrils, are in clinical development, including: – R1450 (gantenerumab, Hoffman-LaRoche). After phase I completion, a phase II clinical trial was initiated in Canada (n = 360) in 2011. Prodromal AD patients receive 105 or 225 mg, administered by s.c. injection every 4 weeks for 104 weeks. Endpoints include effects on cognition and functioning, safety and pharmacokinetics. In 2012, the trial was expanded to a phase II/III trial, and the total population enrolled include 770 participants. – MABT5102A (crenezumab, Genentech). After phase I completion, a phase II clinical trial (n = 372) was initiated in 2011. The first Alzheimer's Prevention Initiative (API) will study crenezumab in 300people from a large family in Columbia with a rare genetic mutation that typically triggers AD symptoms around age of 45 (collaboration among: National Institutes of Health, Banner's Alzheimer's Institute, and Genentech). – PF-04360365 (Pfizer, phase II completed). – GSK933776A (GlaxoSmithKline, phase I completed). – NI-101 (Biogen Idec, phase I clinical trial in patients with mild to moderate AD ongoing). – PF-05236812 (Janssen Alzheimer Immunotherapy and Pfizer, phase I trial ongoing). – RN6G (Rinat Neuroscience Corp., New York, now Pfizer, phase I completed). – SAR-228810 (Sanofi, phase I ongoing). – BAN-2401 (Eisai, phase I trial in 80 patients with mild to moderate AD ongoing).
healthy blood donors. In light of these observations, a phase I trial has been carried out in the US. Eight AD patients were treated with IVIg (Gammagard S/D Immune Globulin Intravenous Human), donated by Baxter Healthcare Corporation. Seven patients completed the study. After 6 months, cognitive function stopped declining in all seven patients and improved in six of them (http://www.alzforum.org). In a phase II trial in 24 patients, the 8 subjects taking placebo worsened, whereas the 16 treated patients improved moderately on both cognitive and quality-of-life measures over the first 6 months [32,33]. A phase III clinical trial in AD patients enrolling 390 patients is ongoing. The first report of long-term (three-year) stabilization of Alzheimer's disease symptoms with IVIG (Gammagard, Baxter), including no decline on measures of cognition, memory, daily functioning and mood, was reported in July 2012 at the Alzheimer's Association International Conference in Vancouver. Octagam (Octapharma, Lachen, Switzerland) is a 10% liquid intravenous immunoglobulin launched for the treatment of primary immunodeficiency. A phase II clinical trial in 58 patients with AD had been started in the USA.
5. Concluding remarks From data presented in this review, a few points should be considered for planning future clinical trials. First of all, mechanisms at the basis of the pathogenesis of AD need to be deeply investigated before developing novel claimed disease-modifying compounds. Despite promising premises related to the so-called “amyloid hypothesis”, as well as to other pathogenic mechanisms, large phase III trials with vaccines or passive immunization failed to demonstrate any effect on cognition. An important lesson comes from the neuropathological analysis of brains from patients who received immunization, which demonstrated that, although mean Aβ load was lower than in the placebo group, there was no evidence of improved survival or improvement in time to severe dementia. Therefore, plaque removal seems to be not sufficient to halt progressive neurodegeneration in AD. In light of these considerations, it is of crucial importance to better understand the relationship between tau, Aβ and other factors for developing novel potentially disease-modifying drugs. The second point to be taken into account is that treatments for AD could be effective only in certain phases of the disease. A few disease-modifying compounds showed some benefits in mild, but not moderate AD. Therefore, therapeutic trials should be carried out as early as possible during the course of the disease, implying the need to identify more accurate tools for early diagnosis. In this regard, new research diagnostic criteria have been proposed in 2007 [34], introducing the use of CSF analysis, structural and functional imaging and genetics, together with classical neuropsychological testing, for early and specific diagnosis. Large-scale international controlled multicenter trials are engaged in phase III development of the core feasible imaging and CSF biomarkers candidates in AD. If the validation of these new criteria will be achieved, they should be considered in the setting of future clinical trials to identify more homogeneous study groups. Last, indicators useful as surrogate outcome measures (surrogate biomarkers) should be identified in order to have: 1) substitutes for clinical endpoints (at present, represented mainly by neuropsychological testing) 2) tools able to predict clinical benefit, or the opposite (identify “responders”) 3) demonstrate whether there are diseasemodifying properties. So far, none among biomarkers proposed for early diagnosis has been validated as a surrogate marker for monitoring treatments.
4.2. Intravenous immunoglobulins
Conflict of interest
Natural anti-amyloid antibodies have been found in human Intravenous Immunoglobulins (IVIg) obtained from the pooled plasma of
This review represents an update of a previously published article [35]. Authors have no financial conflict of interest.
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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Immunotherapy against amyloid pathology in Alzheimer's disease Daniela Galimberti ⁎, Laura Ghezzi, Elio Scarpini Neurology Unit, Dept. of Pathophysiology and Transplantation, “Dino Ferrari” Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy
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Article history: Received 29 September 2012 Received in revised form 9 November 2012 Accepted 10 December 2012 Available online xxxx Keywords: Alzheimer's disease Amyloid Disease-modifying drugs Vaccination Passive immunization
a b s t r a c t The first drugs developed for Alzheimer's disease (AD), anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed “disease modifying” drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms, including the deposition of extracellular amyloid beta (Aβ) plaques and of intracellular neurofibrillary tangles. The most innovative approach is represented by the vaccination and passive immunization against Aβ peptide. In this article, current knowledge about concluded and ongoing clinical trials with both vaccination with different antigens and passive immunization will be reviewed and discussed. © 2012 Elsevier B.V. All rights reserved.
1. Introduction 1.1. Pathogenesis of Alzheimer's disease Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with a prevalence of 5% after 65 years of age, increasing to about 30% in people aged 85 years or older. It is characterized clinically by progressive cognitive impairment, including impaired judgment, decision-making and orientation, often accompanied, in later stages, by psychobehavioral disturbances as well as language impairment. Mutations in genes encoding for amyloid precursors protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) account for about 5% of cases, characterized by an early onset (before 65 years of age). So far, 33 different mutations, causing amino acid changes in putative sites for the cleavage of the protein, have been described in the APP gene in 90 families, together with 185 mutations in PSEN1(in 405 families) and 13 in PSEN2in 22 families (http://www. molgen.vib-ua.be). The two major neuropathology hallmarks of AD are extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The production of Aβ, which represents a crucial step in AD pathogenesis, is the result of cleavage of APP, which is over-expressed in AD [1]. Aβ forms highly insoluble and proteolysis resistant fibrils known as senile plaques (SP). NFTs are composed of the tau protein. In healthy subjects, tau is a component of microtubules, which represent ⁎ Corresponding author at: via F. Sforza, 35, 20122, Milan, Italy. Tel.: +39 2 55033847; fax: +39 2 55036580. E-mail address: [email protected] (D. Galimberti).
the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilize growing axons, which are necessary for the development and growth of neurites [1]. In AD, tau protein is abnormally hyperphosphorylated and forms insoluble fibrils, originating deposits within the cell. A number of additional pathogenic mechanisms, possibly overlapping with Aβ plaque and NFT formation, have been described, including inflammation [2] oxidative damage [3], iron deregulation [4], cholesterol metabolism [5]. 2. Symptomatic treatments Acetylcholine levels were demonstrated to be reduced in AD [6]. Based on this observation, the first drugs developed for AD were aimed to increase the levels of such neurotransmitter by inhibiting cholinesterase activity, and were named anticholinesterase inhibitors (AchEI). At present, four AchEI are approved for the treatment of mild to moderate AD: tacrine (First Horizon Pharmaceuticals), donepezil (Pfizer), rivastigmine (Novartis), and galantamine (Janssen) [7,8]. Donepezil is now approved also for severe AD. Although tacrine was the first drug approved for AD in 1993, it is rarely used due to hepatotoxicity. A meta-analysis of thirteen randomized, double blind, placebo controlled trials with donepezil, rivastigmine and galantamine were considered by the Cochrane Dementia and Cognitive Improvement Group's Specialized Register. Conclusions were that the three AChEI are efficacious for mild to moderate AD, although it is not possible to identify patients who will respond to treatment prior to treatment.
0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2012.12.013
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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There is no evidence that treatment with an AChEI is not cost effective. In addition, despite the slight variations in the mode of action of the three AChEI, there is no evidence of any differences among them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than 3 months is used. Titration with donepezil is more straightforward and the lower dose may be worthy of consideration [9]. Recently, it was demonstrated that continued treatment with donepezil is associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months in patients with moderate or severe AD [10]. Rivastigmine is currently available also as a transdermal patch (Exelon® patch, Rivastach® patch, Prometax® patch). Previous evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with AD, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favorable tolerability profile as compared with oral AchEI (see [11] for review). A further symptomatic therapeutic option available for moderate to severe AD is memantine. This drug is an un-competitive, moderateaffinity, NMDA antagonist believed to protect neurons from excitotoxicity. A recent meta-analysis on the efficacy of AChEIs and memantine indicates that these treatments can result in statistically significant but clinically marginal improvement [12]. Regarding tolerability, AChEIs are associated with cholinomimetic effects. Nausea (2–8%) and vomiting (1–5%) were reported across all AChEI trials as the most common reasons for trial discontinuation. Dizziness, anorexia, and diarrhea were also commonly experienced; however, improved tolerability has been reached with transdermal administration of rivastigmine. The most frequently reported adverse events in memantine trials were dizziness, headache, and confusion [13]. 3. Modulation of amyloid deposition through vaccination On the basis of recent additional findings on AD pathogenesis, novel treatments under development aim to interfere with pathogenic steps previously mentioned, in an attempt to block the course of the disease in early phases (even preclinical). For this reason they are currently termed “disease modifying” drugs. As it is thought that the amyloid deposition is the very first pathogenic event in AD pathogenesis, that in turn activates a cascade of additional pathogenic mechanisms, the majority of new approaches under development aim to avoid Aβ peptide deposition or to remove already deposited amyloid. In this framework, the most studied and promising approach is immunotherapy. 3.1. The amyloid hypothesis The APP plays a central role in AD pathogenesis and in AD research, as it is the precursor of Aβ, which is the heart of the amyloid cascade hypothesis of AD. The human APP gene was first identified in 1987 by several laboratories independently [14–16]. The two APP homologs, APLP1 and APLP2, were discovered several years later. APP is a type I membrane protein. Two predicted cleavages, one in the extracellular domain (β-secretase cleavage) and another in the transmembrane region (γ-secretase cleavage) are necessary to release Aβ from the precursor protein. Remarkably, APP lies in chromosome 21, and this provided an immediate connection to the invariant development of AD pathology in trisomy 21 (Down's syndrome). The first mutations demonstrated to be causative of inherited forms of familial AD were identified in the APP gene, providing evidence that APP plays a central role in AD
pathogenesis. Notably, only APP but not its homologs APLP1 and APLP2, contains sequences encoding the Aβ domain. Full-length APP undergoes sequential proteolytic processing. It is first cleaved by α-secretase (non-amyloidogenic pathway) or β-secretase (amyloidogenic pathway) within the luminal domain, resulting in the shedding of nearly the entire ectodomain and generation of βor β–C-terminal fragments (CTFs). The major neuronal β-secretase, named BACE1 (β-site APP cleaving enzyme), is a transmembrane aspartyl protease which cleaves APP within the ectodomain, generating the N-terminus of Aβ [17]. Several zinc metalloproteinase, and the aspartyl protease BACE2, can cleave APP at the β-secretase site [18] localized within the Aβ domain, thus hampering the generation of intact Aβ. The second proteolytic event in APP processing involves intramembranous cleavage of α- and β-CTFs by γ-secretase, which liberates a 3 kDa protein, named p3, and Aβ peptide, into the extracellular milieu. The minimal components of γ-secretase include presenilin PS1 or PS2, nicastrin, APH-1 and PEN-2 [19]. Biochemical evidence is consistent with PS1 (or PS2) as the catalytic subunit of the γ-secretase, whereas APH-1 and PEN-2 stabilize the γ-secretase complex, and nicastrin mediates the recruitment of APP CTFs to the catalytic site of the γ-secretase. Major sites of γ-secretase cleavage correspond to positions 40 and 42, leading to the formation of the Aβ[1–40] and Aβ[1–42] peptides. Amyloidogenic processing is the favored pathway of APP metabolism in neurons, due to the greater abundance of BACE1, whereas non-amyloidogenic pathway predominates in other cell types. It seems that none of the above mentioned secretases have unique substrate specificity towards APP. Besides APP, a number of other transmembrane proteins undergo ectodomain shedding by enzymes with α-secretase activity. Regarding BACE1, its low affinity for APP led to the hypothesis that APP is not its sole physiological substrate. Similarly, PS1 and PS2 play a crucial role in intramembranous γ-secretase cleavage of several type I membrane proteins other than APP, including Notch1 receptors and its ligands [20]. A number of functional domains have been mapped to the extraand intracellular region of APP, including metal (copper and zinc) binding, extracellular matrix components (heparin, collagen and laminin), and neurotrophic and adhesion domains. Thus far, a thropic role for APP has been suggested, as it stimulates neurite outgrowth in a variety of experimental settings. The N-terminal heparin-binding domain of APP also stimulates neurite outgrowth and promotes synaptogenesis [21]. APP was initially proposed to act as a cell surface receptor. Nevertheless, the evidence supporting this hypothesis has been unconvincing. In 2004, a candidate ligand had been proposed. In was in fact reported that F-spondin, a neuronal secreted signaling glycoprotein that may function in neuronal development and repair, binds to the extracellular domain of APP as well as of APLP1 and APLP2 [22]. This binding reduces β-secretase cleavage of APP, suggesting therefore that F-spondin binding may regulate APP processing. 3.2. Vaccination In 1999 Schenk et al. [23] demonstrated that immunization with Aβ as an antigen attenuated AD-like pathology in transgenic mice over-expressing the APP gene, by removing amyloid from the central nervous system. This transgenic mouse model of AD progressively develops several neuropathological features of the disease in an age-related and brain-region-dependent manner. Immunization of young animals with Aβ prevented the development of plaque formation, neuritic dystrophy and astroglyosis, whereas in older animals, vaccination reduced extent and progression of AD-like pathologies. Given these extremely promising preclinical results, a phase I controlled study was started, in a cohort of 80 patients with mild to moderate AD. Results demonstrated that this vaccine induced an amyloid
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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antibody response in more than half the cases. Right after, a multicenter, randomized, placebo-controlled, phase II double-blind clinical trial using active immunization with Aβ42 plus adjuvant was started in 2001 in a cohort of 300 patients, using the preaggregated Aβ peptide AN1792. However, following reports of aseptic meningo-encephalitis in 6% of treated patients, the trial was halted after 2–3 injections. Of the 300 patients treated, 60% developed antibody response. The final results of the trial were published in 2005 [24]. Double-blind assessment was maintained for 12 months, demonstrating no significant differences in cognition between antibody responders and placebo group for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), Disability Assessment for Dementia (DAS), Clinical Dementia Rating (CDR), MMSE and Clinical Global Impression of Change (CGIC). In a small subset of patients, cerebrospinal fluid (CSF) tau levels were decreased in antibody responders although Aβ levels remained unchanged. Long-term follow-up of treated patients and further analysis of autopsy data modified and moderated the negative impact of the first results, encouraging additional clinical attempts. Subsequent observations on AN1792 vaccinated patients or transgenic models and on brain tissue derived from mice and humans using a new tissue amyloid immunoreactivity (TAPIR) method suggested that antibodies against Aβ-related epitopes are capable of slowing the progression of neuropathology in AD. Hock and Nitsch [25] followed for four years 30 patients who received a prime and booster immunization over the first year after vaccination, providing further support to continue investigation of antibody treatment in AD. In 2008, a paper was published describing the relation between Aβ42 immune response, degree of plaque removal and long-term clinical outcomes [26]. In June 2003, 80 patients (or their caregivers), who had entered the phase I and II of the AN1792 trial, gave their consent for long-term clinical follow-up (maximum: 6 years) and post-mortem neuropathological examination. In autopsy-examined brain from patients who received immunization, mean Aβ load was lower than in the placebo group. Despite this observation, however, no evidence of improved survival or an improvement in time to severe dementia was observed in such patients. Therefore, plaque removal is likely not enough to halt progressive neurodegeneration in AD, prompting some intriguing challenges to the amyloid hypothesis. Although severe adverse events occurred in the first AN1792 trial and cognitive results were unclear, immunization was not abandoned. Based on previous data obtained on autopsy and neuropathological data [27,28], it was thought that the use of the full length amyloid peptide in AN1792 led to a vigorous T-cell autoimmune response that caused the meningeal inflammation. This could be due to molecular mimicry between T-cell epitopes and the C-terminal region of the molecule [29]. Therefore, subsequent efforts focused on designing second-generation amyloid vaccines that would favor a humoral rather than a cellular immune response. The first second-generation vaccine tested in patients with AD is CAD106 (Novartis), a vaccine that presents multiple copies of Aβ1-6 peptide derived from the N-terminal B cell epitope of Aβ, that avoids T cell activation, coupled to the Qβ virus-like particle. In animals, CAD106 induced Aβ-antibody titers without activating Aβ-reactive T-cells. Administration of CAD106 to APP transgenic mice showed a reduction of amyloid accumulation in the brain. A phase I, doubleblind, placebo-controlled, 52-week study was carried out in two centers in Sweden. Fifty-eight patients with mild to moderate AD, aged 50–80 years, were entered into one of two cohorts according to time of study entry, and then randomly allocated to receive either CAD 106 or placebo (ratio 4:1; the first cohort, consisting of 31 patients, received CAD106 50 μg or placebo; the second, consisting of 27 patients, received CAD106 150 μg or placebo). Each patient received three subcutaneous injections. Primary objectives were to assess safety and tolerability of CAD106 and to identify Aβ-antibody
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response (patients with Aβ-IgG serum titers > 16 units at least once during the study were considered responders). Almost all patients (56/58) reported adverse events. The most common side effect in cohort 1 was nasopharyngitis, whereas in cohort 2 it was injection site erythema. No cases of clinical or subclinical cases of meningoencephalitis were observed. 67% of CAD106-treated patients in cohort I and 82% in cohort 2 developed Aβ antibody response. However, also one placebo-treated patient out of 12 had Aβ-IgG concentrations that qualified them as responder. In conclusion, results of these trials suggest that CAD106 has a favorable safety profile and acceptable antibody response in patients with AD [30]. Additional vaccines under clinical testing include: – ACI-24 (AC immune) is an Aβ1-15 peptide to which on both ends two lysines are attached. The antigen is embedded in a liposome membrane. The drug restored memory defects of transgenic mice and is currently evaluated in a phase I/II clinical trial in Denmark, Finland and Sweden (Thomson Reuters Pharma). – Affitope AD-02 (Affiris, Vienna AT and licensee GlaxoSmithKline Biologicals) is a six amino acid peptide vaccine targeting the N-terminus of amyloid-β . The antibody response is focused exclusively on amyloid-β and did not show crossreactivity to APP. A European phase II clinical trial in 420 patients is ongoing (Thomson Reuters Pharma). – Affitope-AD-03 (Affiris and licensee GlaxoSmithKline Biologicals) entered a phase I clinical trial in 2010, and the study was completed in November 2011 (Thomson Reuters Pharma). - ACC-001 (vanutide cridificar; Pfizer). Two phase II studies have been developed in patients with mild to moderate AD: one in Japan (completed) and one ongoing in USA. – UB-311 (United Biomedical) is an intramuscularly administered vaccine targeting N-terminal amino acids 1–14 of Aβ in phase I clinical trials in Taiwan in patients with mild to moderate AD (Thomson Reuters Pharma). – V-950 (Merck) is an N-terminal Aβ peptide conjugated to an aluminum-containing adjuvant. A phase II, double-blind, randomized, placebo-controlled, dose escalating study to evaluate the safety, tolerability, and immunogenicity of V-950 formulated on aluminum-containing adjuvant with or without ISCOMATRIX™ adjuvant in patients with AD has been completed (http:// clinicaltrials.gov), but results have not been published yet. 4. Passive immunization 4.1. Humanized antibodies An alternative solution to avoid an undesirable T-cell induced inflammation that can be a source of side effects is to use passive immunization. This is achieved by passively infusing anti-Aβ antibodies into patients, eliciting an immune response without requiring a pro-inflammatory T-cell reaction. The first antibody tested is the humanized monoclonal anti-Aβ antibody Bapineuzumab (Wyeth and Elan), tested initially in a phase II trial in 200 patients with mild to moderate AD. The 18-month, multi-dose, one-to-one randomization trial was conducted at about 30 sites in the US. It was designed to assess safety, tolerability and standard efficacy endpoints (ADAS-Cog, DAS) of multiple ascending doses of Bapineuzumab in patients. Prior to the completion of the phase II study, a phase III trial was initiated. The results of these trials did not show overall efficacy but a small subset of patients, i.e., the ApoE non-carriers who received the second-lowest of the four doses six times, responded truly well by 78 weeks. Subsequent trials in non-carriers were negative and 2 trials in APOe 4 carriers were initiated but then discontinued due to lack of effect. Solanezumab (LY2062430; Ely Lilly) is a humanized monoclonal antibody that binds to the central region of β-amyloid. A phase 2, randomized, double-blind, placebo-controlled clinical trial was carried
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
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out to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab in patients with mild-to-moderate AD. Fifty-two patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and CSF examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the ADAS-cognitive portion was administered. Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ(1–40) and Aβ(1–42) in plasma increased in a dose-dependent manner. Antibody treatment increased total Aβ(1–40) and Aβ(1–42) in CSF. The ADAS-Cog was unchanged after the 12-week antibody administration. This study showed that antibody administration is well tolerated with doses up to 400 mg weekly. The increase in unbound CSF Aβ(1–42) suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ(1–42) from amyloid plaques [31]. Two large phase II trials (EXPEDITION1 and EXPEDITION2) were conducted. More than 2000 patients have been recruited and randomized to receive 400 mg of solanezumab versus placebo every 4 weeks for 80 weeks. Follow up with an open-label extension of the phase III has been set up in order to determine the long-term safety of solanezumab (www.clinicaltrials. gov). The results of EXPEDITION 1 showed a significant reduction in cognitive decline of 42% in mild AD (P b 0.008) but EXPEDITION 2 showed a only a non-significant 20% reduction in cognitive decline (P = 0.120). There was no significant functional improvement in either trial but there was a 17% reduction in functional decline (P = 0.057) for the phase III. Additional antibodies, that vary in terms of the Aβ epitopes they target, and their affinity to other amyloid species and stages, such as soluble oligomers and protofibrils, are in clinical development, including: – R1450 (gantenerumab, Hoffman-LaRoche). After phase I completion, a phase II clinical trial was initiated in Canada (n = 360) in 2011. Prodromal AD patients receive 105 or 225 mg, administered by s.c. injection every 4 weeks for 104 weeks. Endpoints include effects on cognition and functioning, safety and pharmacokinetics. In 2012, the trial was expanded to a phase II/III trial, and the total population enrolled include 770 participants. – MABT5102A (crenezumab, Genentech). After phase I completion, a phase II clinical trial (n = 372) was initiated in 2011. The first Alzheimer's Prevention Initiative (API) will study crenezumab in 300people from a large family in Columbia with a rare genetic mutation that typically triggers AD symptoms around age of 45 (collaboration among: National Institutes of Health, Banner's Alzheimer's Institute, and Genentech). – PF-04360365 (Pfizer, phase II completed). – GSK933776A (GlaxoSmithKline, phase I completed). – NI-101 (Biogen Idec, phase I clinical trial in patients with mild to moderate AD ongoing). – PF-05236812 (Janssen Alzheimer Immunotherapy and Pfizer, phase I trial ongoing). – RN6G (Rinat Neuroscience Corp., New York, now Pfizer, phase I completed). – SAR-228810 (Sanofi, phase I ongoing). – BAN-2401 (Eisai, phase I trial in 80 patients with mild to moderate AD ongoing).
healthy blood donors. In light of these observations, a phase I trial has been carried out in the US. Eight AD patients were treated with IVIg (Gammagard S/D Immune Globulin Intravenous Human), donated by Baxter Healthcare Corporation. Seven patients completed the study. After 6 months, cognitive function stopped declining in all seven patients and improved in six of them (http://www.alzforum.org). In a phase II trial in 24 patients, the 8 subjects taking placebo worsened, whereas the 16 treated patients improved moderately on both cognitive and quality-of-life measures over the first 6 months [32,33]. A phase III clinical trial in AD patients enrolling 390 patients is ongoing. The first report of long-term (three-year) stabilization of Alzheimer's disease symptoms with IVIG (Gammagard, Baxter), including no decline on measures of cognition, memory, daily functioning and mood, was reported in July 2012 at the Alzheimer's Association International Conference in Vancouver. Octagam (Octapharma, Lachen, Switzerland) is a 10% liquid intravenous immunoglobulin launched for the treatment of primary immunodeficiency. A phase II clinical trial in 58 patients with AD had been started in the USA.
5. Concluding remarks From data presented in this review, a few points should be considered for planning future clinical trials. First of all, mechanisms at the basis of the pathogenesis of AD need to be deeply investigated before developing novel claimed disease-modifying compounds. Despite promising premises related to the so-called “amyloid hypothesis”, as well as to other pathogenic mechanisms, large phase III trials with vaccines or passive immunization failed to demonstrate any effect on cognition. An important lesson comes from the neuropathological analysis of brains from patients who received immunization, which demonstrated that, although mean Aβ load was lower than in the placebo group, there was no evidence of improved survival or improvement in time to severe dementia. Therefore, plaque removal seems to be not sufficient to halt progressive neurodegeneration in AD. In light of these considerations, it is of crucial importance to better understand the relationship between tau, Aβ and other factors for developing novel potentially disease-modifying drugs. The second point to be taken into account is that treatments for AD could be effective only in certain phases of the disease. A few disease-modifying compounds showed some benefits in mild, but not moderate AD. Therefore, therapeutic trials should be carried out as early as possible during the course of the disease, implying the need to identify more accurate tools for early diagnosis. In this regard, new research diagnostic criteria have been proposed in 2007 [34], introducing the use of CSF analysis, structural and functional imaging and genetics, together with classical neuropsychological testing, for early and specific diagnosis. Large-scale international controlled multicenter trials are engaged in phase III development of the core feasible imaging and CSF biomarkers candidates in AD. If the validation of these new criteria will be achieved, they should be considered in the setting of future clinical trials to identify more homogeneous study groups. Last, indicators useful as surrogate outcome measures (surrogate biomarkers) should be identified in order to have: 1) substitutes for clinical endpoints (at present, represented mainly by neuropsychological testing) 2) tools able to predict clinical benefit, or the opposite (identify “responders”) 3) demonstrate whether there are diseasemodifying properties. So far, none among biomarkers proposed for early diagnosis has been validated as a surrogate marker for monitoring treatments.
4.2. Intravenous immunoglobulins
Conflict of interest
Natural anti-amyloid antibodies have been found in human Intravenous Immunoglobulins (IVIg) obtained from the pooled plasma of
This review represents an update of a previously published article [35]. Authors have no financial conflict of interest.
Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013
D. Galimberti et al. / Journal of the Neurological Sciences xxx (2013) xxx–xxx
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Please cite this article as: Galimberti D, et al, Immunotherapy against amyloid pathology in Alzheimer's disease, J Neurol Sci (2013), http:// dx.doi.org/10.1016/j.jns.2012.12.013