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Taking the Next Steps in the Treatment of Alzheimer's Disease: Disease-Modifying Agents

  • Stephen Salloway

Extract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the United States and the number of AD patients is increasing at an alarming rate. There is no cure for AD and the currently available treatments are symptomatic, providing only limited effects on disease pathophysiology and progression. An overwhelming need exists for therapies that can slow or halt this debilitating disease process. Disease modification in AD has been defined from patient-focused, regulatory, and neurobiological perspectives. The latter two of these perspectives rely largely on an interruption of the disease process and a clear demonstration of this interruption. As defined by Cummings, a disease-modifying treatment is a “pharmacologic treatment that retards the underlying process of AD by intervening in the neurobiological processes that constitute the pathology and pathophysiology of the disease and lead to cell death or dysfunction.” By this definition, the burden of confirmatory study is placed on any new treatment for which the claim of “disease modification” is to be made (Slide 1).

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1.Sampaio, C. Alzheimer disease: disease modifying trials; where are we? Where do we need to go? A reflective paper. J Nutr Health Aging. 2006;10(2):113115.
2.Mani, RB. The evaluation of disease modifying therapies in Alzheimer's disease: a regulatory viewpoint. Stat Med. 2004;23(2):305314.
3.Cummings, JL. Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials. Alzheimers Dement. 2006;2(4):263271.
4.Games, D, Adams, D, Alessandrini, R, et, al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature. 1995;373(6514):523527.
5.Holcomb, L.Gordon, MN, McGowan, E, et al.Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 1998;4(1):97100.
6.Lewis, PA, Piper, S, Baker, M, et al.Expression of BRI–amyloid β peptide fusion proteins: a novel method for specific high-level expression of amyloid β peptides. Biochim Biophys Acta. 2001;1537(1):5862.
7.Lewis, J, McGowan, E, Rockwood, J, et al.Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 2000;25(4):402405.
8.Oddo, S, Caccamo, A, Shepherd, JD, et al.Triple-transgenic model of Alzheimer's disease with plaques and tangles: intraceliular Aβ and synaptic dysfunction. Neuron. 2003;39(3):409421.
9.Golde, TE. The Aβ hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 2005;15(1):8487.
10.Cummings, JL, Cole, G. Alzheimer disease. JAMA. 2002;287(18):23352338.
11.Zhu, CW, Scarmeas, N, Torgan, R, et al.Longitudinal study of effects of patient characteristics on direct costs in Alzheimer disease. Neurology. 2006;67(6):9981005.
12.Zhu, CW, Scarmeas, N, Torgan, R, et al.Clinical features associated with costs in early AD: baseline data from the Predictors Study. Neurology. 2006;66(7):10211028.
13.Brookmeyer, R, Gray, S, Kawas, C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88(9):13371342.
14.Pollack, SJ, Lewis, H. Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease. Curr Opin Investig Drugs. 2005;6(1):3547.
15.Wong, GT, Manfra, D, Poulet, FM, et al.Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279(13):1287612882.
16.Morihara, T, Chu, T, Ubeda, O, Beech, W, Cole, GM. Selective inhibition of Aβ42 production by NSAID R-enantiomers. J Neurochem. 2002;83(4):10091012.
17.Wilcock, GK, Black, SE, Haworth, J, et al.Efficacy and safety of MPC-7869 (R-flurbiprofen), a selective Aβ42-lowering agent, in Alzheimer's disease (AD): results of a 12-month phase 2 trial and 1-year follow-on study. Alzheimers Dement. 2006;2(3 suppl 1):S81S82.
18.Aisen, PS, Saumier, D, Briand, R, et al.A Phase II study targeting amyloid-β with 3APS in mild-to-moderate Alzheimer disease. Neurology. 2006;67(10):17571763.
19.Neurochem announces results from tramiprosate (ALZHEMED™) North American Phase III clinical trial. Laval, Quebec: Neurochem Inc.: August 26, 2007.
20.Transition Therapeutics announces completion of Phase I clinical studies with Alzheimer's disease drug candidate ELND-005/AZD-103. Toronto, Ontario: Transition Therapeutics Inc.; August 30, 2007.
21.Boche, D, Nicoll, JA, Weller, RO. Immunotherapy for Alzheimer's disease and other dementias. Curr Opin Neurol. 2005;18(6):720725.
22.Schenk, D, Barbour, R, Dunn, W, et al.Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400(6740):173177.
23.Bayer, AJ, Bullock, R, Jones, RW, et al.Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD. Neurology. 2005;64(1):94101.
24.Hock, C, Konietzko, U, Streffer, JR, et al.Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003;38(4):547554.
25.Nicoll, JAR, Wilkinson, D, Holmes, C, Steart, P, Markham, H, Weller, RO. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat Med. 2003;9(4):448452.
26.Solomon, B. Intravenous immunoglobulin and Alzheimer's disease immunotherapy. Curr Opin Mol Ther. 2007;9(1):7985.
27.Dodel, RC, Du, Y, Depboylu, C, et al.Intravenous immunoglobulins containing antibodies against β-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004;75(10):14721474.
28.Pfizer and TransTech Pharma enter into agreement for the development and commercialization of RAGE modulators. New York, NY: Pfizer Inc.; September 18, 2006.
29.Geroldi, D, Falcone, C, Emanuele, E. Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target. Curr Med Chem. 2006;13(17):19711978.
30.Lee, VM, Trojanowski, JQ. Neurodegenerative tauopathies: human disease and transgenic mouse models. Neuron. 1999;24(3):507510.
31.Cole, G. A transgenic triple scores a home run. Nat Med. 2006;12(7):762763.
32.Haroutunia, V, Davies, P, Vianna, C, Buxbaum, JD, Purohit, DP. Tau protein abnormalities associated with the progression of Alzheimer disease type dementia. Neurobiol Aging. 2007;28(1):17.
33.Hrnkova, M, Zilka, N, Minichova, Z, Koson, P, Novak, M. Neurodegeneration caused by expression of human truncated tau leads to progressive neurobehavioural impairment in transgenic rats. Brain Res. 2007;1130(1):206213.
34.Roberson, ED, Scearce-Levie, K, Palop, JJ, et al.Reducing endogenous tau ameliorates amyloid β–induced deficits in an Alzheimer's disease mouse model. Science. 2007;316(5825):750754.
35.DeKosky, ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J Am Geriatr Soc. 2003;51(5 suppl dementia):S314S320.
36.Arnaud, L, Robakis, NK, Figueiredo-Pereira, ME. It may take inflammation, phosphorylation and ubiquitination to “tangle” in Alzheimer's disease. Neurodegener Dis. 2006;3(6”:313319.
37.Jick, H, Zornberg, GL, Jick, SS, Seshadri, S, Drachman, DA. Statins and the risk of dementia. Lancet. 2000;356(9242):16271631.
38.Fillit, HM. The role of hormone replacement therapy in the prevention of Alzheimer disease. Arch Intern Med. 2002;162(17):19341942.
39.Morris, MC, Evans, DA, Bienias, JL, et al.Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002;287(24):32303237.
40.Oken, BS, Storzbach, DM, Kaye, JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol. 1998;55(11):14091415.
41.Frank, B, Gupta, S. A review of antioxidants and Alzheimer's disease. Ann Clin Psychiatry. 2005;17(4):269286.
42. in t' Veld, BA, Ruitenberg, A, Hofman, A, et al.Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001;345(21):15151521.
43.Nordberg, A, Hellström-Lindahl, E, Lee, M, et al.Chronic nicotine treatment reduces β-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw). J Neurochem. 2002;81(3):655658.
44.Dickson, DW. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J Clin Invest. 2004;114(1):2327.
45.Lad, SP, Neet, KE, Mufson, EJ. Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease. Curr Drug Targets CNS Neurol Disord. 2003;2(5):315334.
46.Tuszynski, MH, Thal, L, Pay, M, et al.A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11(5):551555.
47.Pradines, A, Magazin, M, Schiltz, P, Le Fur, G, Caput, D, Ferrara, P. Evidence for nerve growth factor-potentiating activities of the nonpeptidic compound SR 57746A in PC12 cells. J Neurochem. 1995;64(5):19541964.
48.Fournier, J, Boutot, G, Keane, PE, Maffrand, JP, Le Fur, G, Soubrié, P. The non-peptide neuroprotective agent SR 57746A interacts with neurotrophin-3 to induce differentiation in the PC12 cell-line. J Pharm Pharmacol. 1998;50(3):323327.
49.Labie, C, Lafon, C, Marmouget, C, et al.Effect of the neuroprotective compound SR57746A on nerve growth factor synthesis in cultured astrocytes from neonatal rat cortex. Br J Pharmacol. 1999;127(1):139144.
50.Fournier, J, Steinberg, R, Gauthier, T, et al.Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates. Neuroscience. 1993;55(3):629641.
51.Lemaire, L, Fournier, J, Ponthus, C, et al.Magnetic resonance imaging of the neuroprotective effect of xaliproden in rats. Invest Radiol. 2002;37(6):321327.
52.Terranova, JP, Kan, JP, Storme, JJ, Perreaut, P, Le Fur, G, Soubrié, P. Administration of amyloid β-peptides in the rat medial septum causes memory deficits: reversal by SR 57746A, a non-peptide neurotrophic compound. Neurosci Lett. 1996;213(2):7982.
53.18-Month Study of the Efficacy of Xaliproden (SR57746A) in Patients With Mild-to-Moderate Dementia of the Alzheimer's Type. Available at: http://clinicaltrials.gov/ct/show/NCT00103649. Accessed February 22, 2008.
54.A promising R&D portfolio, well positioned to deliver future growth. Paris, France: sanofi-aventis: September 17, 2007. Available at: http://en.sanofi-aventis.com/press/ppc_18851.asp#3. Accessed February 22, 2008.
55.Dubois, B, Feldman, HH, Jacova, C, et al.Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734746.

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