E Giacobini

Université de Genève, Carouge, GE, Switzerland

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Publications (194)584.38 Total impact

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    ABSTRACT: The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
    Journal of Internal Medicine 03/2014; 275(3). · 6.46 Impact Factor
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    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alz-heimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increas-ing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanisti-cally-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The cross-fertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clini-cal utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy". The 10th International Hong Kong/Springfield Pan-Asian Symposium on Advances in Alzheimer Therapy, held in Kowloon, Hong Kong, on February 28, 29 and March 1, 2008, for the first time integrated across East and West more than 1200 basic and clinical research scientists/physicians to impart the latest information to unravel the origin and patho-genesis of Alzheimer's disease (AD) and to both discuss and highlight improvements towards its diagnosis and potential treatment by established as well as novel strategies. This unique biennial symposium series continues to provide a priceless mechanism to bring under the same roof a dichot-omy of scientific interests and expertise to specifically focus them on AD and related dementias and to disseminate the most current knowledge on recent advances in its potential therapy. AD is now recognized as an incurable, degenerative and terminal disease that is global – afflicting an estimated 26.6 million people worldwide in 2006, with the number growing in an unabated and frightening manner.
  • dressNature Reviews Drug Discovery 12/2013; · 33.08 Impact Factor
  • Ezio Giacobini, Gabriel Gold
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    ABSTRACT: Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis-which places amyloid plaques at the heart of AD pathogenesis-does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD.
    Nature Reviews Neurology 11/2013; · 15.52 Impact Factor
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    ABSTRACT: An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer’s disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.
    Alzheimer's & Dementia. 07/2013; 9(4):438–444.
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    ABSTRACT: To gather preliminary evidence in Alzheimer's disease (AD) for the efficacy of phenserine, a non-competitive acetylcholinesterase inhibitor that has independent modulatory effects on amyloid-β generation, a 12-week comparison of patients receiving phenserine (10 and 15 mg BID) or placebo was conducted under double-blind conditions. Patients who completed 12 weeks of the double-blind before others were continued in the double-blind to determine longer-term treatment effects. At 12 weeks, mean ADAS-cog (AD assessment scale-cognitive) changes from baseline were -2.5 and -1.9 for high-dose phenserine (n=83) and placebo (n=81) groups, respectively, a non-statistically significant improvement for the high-dose phenserine group relative to placebo. CIBIC+ (clinician's interview based impression of change + caregiver's input) values for the high-dose and placebo groups were similar at 12 weeks. For patients who received more than 12 weeks of therapy, the ADAS-cog changes were -3.18 and -0.66 for the high-dose phenserine (n=52) and placebo (n=63) groups, respectively, a difference achieving statistical significance (p=0.0286). After 12 weeks, CIBIC+ values were 3.59 and 3.95 for the high-dose (n=54) and placebo (n=66) groups respectively (p=0.0568). These results from this short-term study are consistent with phenserine potentially benefiting mild to moderate Alzheimer's disease symptomatically but do not address possible amyloid metabolic mediated effects on disease processes in AD.
    Journal of Alzheimer's disease: JAD 10/2010; 22(4):1201-8. · 4.17 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy".
    Current Alzheimer research 05/2009; 6(2):83-5. · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically- based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on “Advances in Alzheimer therapy”.
    Current Alzheimer Research 03/2009; 6(2):83-85. · 3.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although significant accomplishments have been made in research to understand, diagnose and treat Alz-heimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increas-ing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanisti-cally-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The cross-fertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clini-cal utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy". The 10th International Hong Kong/Springfield Pan-Asian Symposium on Advances in Alzheimer Therapy, held in Kowloon, Hong Kong, on February 28, 29 and March 1, 2008, for the first time integrated across East and West more than 1200 basic and clinical research scientists/physicians to impart the latest information to unravel the origin and patho-genesis of Alzheimer's disease (AD) and to both discuss and highlight improvements towards its diagnosis and potential treatment by established as well as novel strategies. This unique biennial symposium series continues to provide a priceless mechanism to bring under the same roof a dichot-omy of scientific interests and expertise to specifically focus them on AD and related dementias and to disseminate the most current knowledge on recent advances in its potential therapy. AD is now recognized as an incurable, degenerative and terminal disease that is global – afflicting an estimated 26.6 million people worldwide in 2006, with the number growing in an unabated and frightening manner.
  • Source
    Robert E Becker, Nigel H Greig, Ezio Giacobini
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    ABSTRACT: Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.
    Journal of Alzheimer's disease: JAD 12/2008; 15(2):303-25. · 4.17 Impact Factor
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    Ezio Giacobini, Robert E Becker
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    ABSTRACT: Following the introduction of cholinesterase inhibitors in 1986 and a 20-yr long period of successful clinical application in mild, moderate and severe patients, the treatment of AD has turned to modify the course of pathological processes thought to comprise the disease. Several active and passive vaccines are presently under investigation for efficacy, reducing amyloid-beta in the brain of patients with mild-moderately advanced disease. Three large international immunization trials are in progress in US and Europe on mild-moderate AD patients. Among these, the most advanced trial in time is the humanized antibody trial. In addition, drugs aiming to reduce tau phosphorylation (GSK3 inhibitors) are about to enter clinical phases of development. Due to intrinsic difficulties, the developments of gamma-and beta-secretase inhibitors have not yet reached clinical stages. Only one anti-amyloid-aggregation, an aminoglycan compound, and one anti-APO-E approach with rosiglitazone are currently in clinical testing. Stem-cell therapy and gene-replacing therapy remain experimental and far from clinical application. Based on experimental evidence that NGF (nerve growth factor) treatment could provide prolonged protection of the central cholinergic system, i.c.v. infusion of NGF, with genetically modified fibroblasts or gene therapy are under current investigation. NGF treatment could probably double the clinical effect of ChEIs in time. Given the level of scientific and clinical activity it is reasonable to expect that within the next five to ten years a new therapy for AD will, by blocking disease progression, both produce long term stabilization of at least 5 years in patients with AD and prevent or delay emergence in persons at risk for AD.
    Journal of Alzheimer's disease: JAD 09/2007; 12(1):37-52. · 4.17 Impact Factor
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    ABSTRACT: Full text available
    Current Alzheimer Research 08/2007; 4(4):336-339. · 3.68 Impact Factor
  • Source
    Lon S. Schneider, Ezio Giacobini
    CNS Drug Reviews 06/2006; 5(1):13 - 26. · 4.92 Impact Factor
  • Article: P3-459
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2006; 2(3).
  • Nigel H Greig, Debomoy K Lahiri, Ezio Giacobini
    Current Alzheimer Research 08/2005; 2(3):275-9. · 3.68 Impact Factor
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    ABSTRACT: An epidemiology closely linked with the increase in life span. In most countries, the prevalence of dementia varies between 6 and 8% for individuals aged 65 years or more. It then dramatically increases with each subsequent decade, reaching around 30% of the population aged over 85. The costs associated with dementia are correlated with the increase in age and are of increasing concern for politicians, healthcare professionals and family members of demented patients. Current estimations are approximate, but dementia appears to be the most costly disease for society after the age of 65 years in France, the Netherlands, Sweden, or the United States. Detailed cost analyses have distinguished the direct medical,direct non-medical and intangible costs. The most important contribution in costs for society is the long-term care by health care professionals (institutionalization corresponding to 2/3 of the total costs for society!), but the care provided by the helpers and the families is even greater, even though difficult to quantify. The current question is to know whether present and future medical treatments will be able to reduce the tremendous financial costs of this chronic disease.
    La Presse Médicale 02/2005; 34(1):35-41. · 0.87 Impact Factor
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    ABSTRACT: •An epidemiology closely linked with the increase in life span In most countries, the prevalence of dementia varies between 6 and 8% for individuals aged 65 years or more. It then dramatically increases with each subsequent decade, reaching around 30% of the population aged over 85.•The costs associated with dementia are correlated with the increase in age and are of increasing concern for politicians, health care professionals and family members of demented patients. Current estimations are approximate, but dementia appears to be the most costly disease for society after the age of 65 years in France, the Netherlands, Sweden, or the United States.•Detailed cost analyses have distinguished the direct medical, direct non-medical and intangible costs.•The most important contribution in costs for society is the long-term care by health care professionals (institutionalization corresponding to 2/3 of the total costs for society !), but the care provided by the helpers and the families is even greater, even though difficult to quantify.•The current question is to know whether present and future medical treatments will be able to reduce the tremendous financial costs of this chronic disease.
    Presse Medicale. 01/2005; 34(1):35-41.
  • Ezio Giacobini
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    ABSTRACT: An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in Alzheimer disease (AD) patients. While AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15 fold from 5 to 75nM concentrations with little cholinergic side effects in the animal. Based on these data and on clinical data showing a relation between CSF BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolyzing brain acetylcholine. Based on the changes of ChE activity in the brain of AD patients, a rational indication of selective BuChEI (or of mixed double function inhibitors) is the treatment of advanced cases. A second novel aspect of ChEI therapy is the emerging of new indications which include various forms of dementia such as dementia with Lewy Bodies, Down Syndrome, vascular dementia and Parkinson Dementia. Clinical results demonstrate examples of versatility of cholinergic enhancement.
    Pharmacological Research 11/2004; 50(4):433-40. · 4.35 Impact Factor
  • Robert E. Becker M.D, Ezio Giacobini
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    ABSTRACT: Up to 20% or more of individuals who will be 80 years of age will develop senile dementia of the Alzheimer type (SDAT). In SDAT patients cholinergic neurons in the basal forebrain undergo profound damage, which is reflected in decreased acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity, and choline uptake in cortical terminals. Physostigmine has been widely used to increase brain acetylcholine concentration by inhibiting acetylcholinesterase. The pharmacokinetics of physostigmine and its effects on acetylcholine concentration are not well studied. Our studies of physostigmine pharmacokinetics in dogs, rats, and humans suggest that a “slow-release formulation” may be necessary to achieve increases in acetylcholine concentrations that will have therapeutic effects in SDAT. To investigate one potential “slow release formulation” of physostigmine we have studied direct injection into the lateral ventricles of the brain.
    Drug Development Research 10/2004; 14(3‐4):235 - 246. · 0.87 Impact Factor
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    ABSTRACT: This is the first study of a multiple-dose trial of metrifonate (Met), a long-acting cholinesterase (ChE) inhibitor, conducted over a prolonged period of time in humans. We have administered Met to 20 patients who met NINCDS-ADRDA criteria for probable Alzheimer disease (AD). Patients were given, under open conditions, single oral doses of Met. 2.5, 5, 7.5, and 15 mg/kg/wk. A statistically significant improvement in the Alzheimer Disease Assessment Scale (ADAS) scores was observed with the 5 mg/kg/wk dose. Maximal improvement on the ADAS was associated with a mean 55.9% (± 12.6% standard deviation) activity level of red blood cell (RBC) acetylcholinesterase (AChE). Over 80% inhibition of plasma and RBC ChE was achieved with only minor side effects. Cholinesterate inhibition in the CSF of two patients was 37% and 47.5% 24 hr after a second dose of 5 mg/kg/wk of Met separated by 7 days from the first dose.Twenty-seven minor side effects were reported: none on 2.5 mg, 5 on 5 mg, 9 on 7.5 mg, and 13 on the 15 mg dose. None of the side effects was clinically significant or drug related or required termination of treatment of dosage adjustment. We conclude that Met is a useful pharmacological probe of cholinergic function in the central nervous system and that double-blind evaluation of Met in AD is warranted.
    Drug Development Research 10/2004; 19(4):425 - 434. · 0.87 Impact Factor

Publication Stats

3k Citations
584.38 Total Impact Points

Institutions

  • 1997–2014
    • Université de Genève
      • • Division of Geriatrics
      • • Faculty of Medicine
      Carouge, GE, Switzerland
  • 1967–2010
    • Karolinska Institutet
      • Institutionen för neurobiologi, vårdvetenskap och samhälle - NVS
      Solna, Stockholm, Sweden
  • 2008
    • National Institute on Aging
      • Drug Design and Development Section
      Baltimore, Maryland, United States
  • 2005
    • Hôpitaux Universitaires de Genève
      Genève, Geneva, Switzerland
  • 1984–2004
    • Southern Illinois University School of Medicine
      • • Department of Pharmacology
      • • Department of Psychiatry
      Springfield, IL, United States
    • University of Illinois Springfield
      Спрингфилд, Florida, United States
    • Southern Illinois University Edwardsville
      Illinois, United States
    • University of Saskatchewan
      Saskatoon, Saskatchewan, Canada
  • 1991
    • Tokyo University of Science
      Edo, Tōkyō, Japan
  • 1973–1983
    • University of Connecticut
      Storrs, Connecticut, United States
  • 1978
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1971
    • University of Minnesota Twin Cities
      Minneapolis, Minnesota, United States
  • 1970
    • Università degli Studi di Torino
      Torino, Piedmont, Italy