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Profile of Gantenerumab and Its Potential in the Treatment of Alzheimer’S Disease

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Profile of Gantenerumab and Its Potential in the Treatment of Alzheimer’S Disease Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease Dijana Novakovic1 Abstract: Alzheimer’s disease, which is characterized by gradual cognitive decline associated Marco Feligioni2 with deterioration of daily living activities and behavioral disturbances throughout the course Sergio Scaccianoce1 of the disease, is estimated to affect 27 million people around the world. It is expected that Alessandra Caruso1 the illness will affect about 63 million people by 2030, and 114 million by 2050, worldwide. Sonia Piccinin2 Current Alzheimer’s disease medications may ease symptoms for a time but are not capable of Chiara Schepisi1,2 slowing down disease progression. Indeed, all currently available therapies, such as cholinest- erase inhibitors (donepezil, galantamine, rivastigmine), are primarily considered symptomatic Francesco Errico3 therapies, although recent data also suggest possible disease-modifying effects. Gantenerumab Nicola B Mercuri4 is an investigational fully human anti-amyloid beta monoclonal antibody with a high capacity Ferdinando Nicoletti1,5 For personal use only. to bind and remove beta-amyloid plaques in the brain. This compound, currently undergoing 1,4 Robert Nisticò Phase II and III clinical trials represents a promising agent with a disease-modifying potential 1Department of Physiology and in Alzheimer’s disease. Here, we present an overview of gantenerumab ranging from preclinical Pharmacology, Sapienza University studies to human clinical trials. of Rome, Rome, Italy; 2European Brain Research Institute, Rome, Italy; Keywords: Alzheimer’s disease, gantenerumab, monoclonal antibody, amyloid-β, clinical 3Ceinge Biotecnologie Avanzate, trials Naples, Italy; 4Laboratory of Experimental Neurology, Istituto di Ricerca e Cura a Carattere Scientifico, Santa Lucia Foundation, Rome, Italy; Introduction 5Istituto di Ricerca e Cura a Carattere Alzheimer’s disease (AD) is the most common form of dementia. It is estimated that Scientifico, Neuromed, Pozzilli, Italy AD affects 27 million people around the world, with the number of diagnosed cases expected to rise dramatically in the near future.1 AD is characterized by deficits in memory, language, executive functions, and other intellectual abilities that are serious Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 21-Nov-2018 enough to interfere with daily life. From a neuropathological point of view, the AD brain shows marked atrophy in the brain and the formation of two pathological lesions: extracellular amyloid plaques composed largely of amyloid-beta peptide (Aβ) and neu- rofibrillary tangles (NFTs), which are intracellular aggregates of hyperphosphorylated tau proteins.2 In recent years, however, growing evidence has supported the idea that disruption of connectivity within neural circuits, loss of synapses, and deteriorated synaptic function precedes the death of neurons. At this time, the US Food and Drug Administration and the European Medicines Agency have approved four drugs to treat the cognitive symptoms of AD; three are acetylcholinesterase inhibitors (rivastigmine, Correspondence: Robert Nisticò galantamine, and donepezil) and the other (memantine) is an uncompetitive antagonist Department of Physiology and at glutamatergic N-methyl-D-aspartate receptors. Because reduction in the activity of Pharmacology, Sapienza University of Rome, P Aldo Moro 5, Rome 00185, Italy the cholinergic neurons is a well-known feature of AD, acetylcholinesterase inhibitors Tel +39 065 0170 3122 may improve some cognitive aspects in patients with AD. However, prolonged use of Fax +39 066 0513 244 Email [email protected] these drugs has also proven effective in slowing down or halting disease progression. submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2013:7 1359–1364 1359 Dovepress © 2013 Novakovic et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/DDDT.S53401 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Novakovic et al Dovepress In fact, several evidences from preclinical studies indicate Active versus passive that these compounds might rescue neuronal damage and immunotherapy death from beta-amyloid (Aβ)-induced toxicity, thus inter- The therapeutic potential of clearing Aβ deposition by trig- 3 fering with AD pathogenesis. The exact mechanisms by gering a humoral immune response to fibrillar Aβ42 or pas- which these effects are achieved remain to be elucidated, sively administering anti-Aβ antibodies has been the most although several reports suggest neuroprotective,4,5 anti- extensively validated anti-Aβ approach in preclinical studies. inflammatory,6–8 and antioxidant roles.9,10 Nevertheless, AD Either active or passive Aβ immunotherapy was developed to still remains an unmet medical need for which therapies diminish the load of Aβ by promoting its removal.19 Active await new discoveries. immunization (vaccination) with either Aβ42 (the prevalent form of Aβ in the amyloid plaques of AD) or other synthetic Targeting Aβ production fragments has been successfully evaluated in transgenic and removal mouse models of AD and is generally based on the stimula- At this time, the amyloid cascade hypothesis is the most tion of T-cell, B-cell, and microglial immune responses. The important theory of AD, postulating that accumulation results of the trials, initially promising, have been partially of Aβ into plaques is the causative pathological event.11 dashed by the appearance of meningoencephalitis in some On the basis of this hypothesis, interventions that reduce patients.20 Another type of immunotherapy under investiga- Aβ load in the brain would be likely to attenuate both the tion implicates passive administration with monoclonal or neuropathological changes and functional deficits character- polyclonal antibodies directed against Aβ. This approach cir- izing AD. Indeed, several different Aβ-lowering strategies cumvents the need for the patient to mount an immunological have been developed during past years. Among these, Aβ response to the Aβ peptide. Although both active and passive fibrillogenesis represents a major target for therapeutic administration of anti-Aβ antibodies seem to be effective in intervention in AD and related human β-amyloidosis.12 reducing AD-like pathology in preclinical models of AD, the Certain small-molecule inhibitors of synthetic Aβ fibril- mechanism by which they accomplish this effect, whether For personal use only. logenesis inhibit formation of cell-derived, secreted oli- by stimulating microglial activity, preventing its aggregation gomers of Aβ and prevent the impairment of long-term or promoting its disaggregation, or a combination of these, potentiation (LTP) induced by Aβ.13,14 Importantly, this still remains elusive. protective effect was achieved only under conditions in Of all Aβ immunotherapies, the furthest advanced in which the inhibitors prevented new oligomer formation.15 clinical development are the passive monoclonal antibod- In fact, to be effective, inhibitors of fibrillogenesis need ies bapineuzumab21 and solanezumab.22 Bapineuzumab is a to be used at the initial stages of oligomerization, thus humanized monoclonal antibody against the N-terminus of avoiding a paradoxical enhanced neurotoxicity that may Aβ (Aβ1–5), whereas solanezumab is a humanized monoclonal derive from active prefibrillar assemblies such as low-n antibody designed to bind the central portion of Aβ (Aβ12–28). oligomers released after inhibition of fibril formation. For Of note, bapineuzumab, despite lowering key biomarkers of these reasons, a promising strategy consisted of preventing AD such as amyloid brain plaque and phosphorylated tau Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 21-Nov-2018 the formation of Aβ by enhancing α-secretase activity or protein in cerebrospinal fluid, failed to produce significant inhibiting either β-secretase or γ-secretase activity. Among cognitive improvements in two major clinical trials.23 In addi- these, either γ-secretase inhibitors or modulators represented tion, the Phase III results for solanezumab were only mildly the therapeutic approach with the highest expectations. encouraging (Eli Lilly and Co, Indianapolis, IN, USA; Expe- However, recent clinical trials of γ-secretase inhibitors and dition studies 1 and 2), so the development of this compound γ-secretase modulators, including semagacestat, avagaces- for the treatment of AD-related dementia will continue with a tat, and R-flurbiprofen, have been discontinued for lack of confirmatory clinical trial to be launched later in 2013 (see the efficacy and/or adverse effects, the mechanisms of which December 12, 2012, press release on the Lilly website).24 still remain unclear.16 An alternative approach consisted of Other
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