Therapieentwicklungen bei der Alzheimer-Krankheit

Zusammenfassung

Die Entwicklung neuer Therapien zur Behandlung der Alzheimer-Krankheit ist ein Fokus der weltweiten Arzneimittelforschung. Es wird an potenteren Therapien zur symptomatischen Behandlung, insbesondere zur Behandlung von Verhaltensstörungen, aber auch an Medikamenten, die in die Pathophysiologie der Erkrankung eingreifen, geforscht, mit dem Ziel, das Voranschreiten der Alzheimer-Krankheit aufzuhalten oder zumindest zu verlangsamen. Dazu verlagert sich der Schwerpunkt der Identifikation von Menschen mit Alzheimer-Krankheit in Stadien der Prä-Demenz wie das der leichten kognitiven Störung (Mild Cognitive Impairment, MCI oder nahezu gleichbedeutend beginnende Alzheimer-Demenz: prodromal AD) oder gar in asymptomatische Stadien. Bisher ermutigendste Ergebnisse liegen für den Ansatz der passiven Immunisierung mittels monoklonaler Antikörper gegen Aβ42 vor. Bisher gelang es nicht, mit mehreren abgeschlossenen zulassungsrelevanten Studien statistisch signifikante Unterschiede auf den primären Zielparametern zu demonstrieren. Der Antikörper gegen Amyloid Aducanumab erhielt, basierend auf der Reduktion von Amyloid, eine vorläufige Zulassung mit Auflagen in den USA; das Zulassungsverfahren für Europa ist noch im Gange. Die gegenwärtigen pharmakologischen Ansätze zur Behandlung der Alzheimer-Krankheit bieten einen begrenzten symptomatischen Nutzen. Bisher ist noch keine verlaufsverzögernde Behandlung gegen die Alzheimer-Krankheit in Deutschland auf dem Markt. Daher ist zu empfehlen, Patienten, insbesondere in prä-dementiellen Stadien oder im Stadium der beginnenden Alzheimer-Demenz, eine Teilnahme an klinischen Studien zu empfehlen, um die Entwicklung von neuen und besser wirksamen Medikamenten zur Behandlung der Alzheimer-Krankheit, die dann vielen Patienten zu Gute kommen können, zu beschleunigen.

Abstract

The development of new therapies to treat Alzheimer’s disease is a focus of global drug discovery. Research is being conducted into more potent therapies for symptomatic treatment, particularly for behavioral disturbances, but also into drugs that intervene in the pathophysiology of the disease, with the aim of halting or at least slowing the progression of the disease. To this end, the focus of identifying people with Alzheimer’s disease is shifting to stages of pre-dementia such as that of Mild Cognitive Impairment (MCI), almost synonymous with prodromal AD, or even to asymptomatic stages. Currently, passive immunization using monoclonal antibodies against Aβ42 has shown the most encouraging results. However, it has not been possible to demonstrate statistically significant differences on the primary target parameters in multiple completed pivotal trials. The anti-amyloid antibody aducanumab received conditional preliminary approval in the U.S. based on amyloid reduction; approval for its use in Europe is an ongoing process. Current pharmacological treatments of Alzheimer’s disease offer limited symptomatic benefit. No drugs to delay progression of the disease is yet on the market in Germany. Therefore, it is recommended that patients, especially those in pre-dementia stages or at the onset of Alzheimer’s disease, be encouraged to participate in clinical trials in order to help develop new drugs that are more effective in the treatment of this disease and that can then benefit many more patients in the future.

Schlüsselwörter

Alzheimer-Krankheit - Alzheimer-Demenz - Therapien - Studien - Klinische Prüfungen

Key words

Alzheimer’s disease - Alzheimer’s dementia - therapy - studies - clinical trials

Publication History

Received: 09 January 2022

Accepted after revision: 07 March 2022

Article published online:
19 May 2022

• Literature

• 1 Grimmer T. Medikamente zur Behandlung der Alzheimer Krankheit in der Entwicklung. In: Jessen F, editor. Handbuch Alzheimer-Krankheit Grundlagen – Diagnostik – Therapie – Versorgung – Prävention. De Gruyter 2018; 451-463
• 2 Herrmann N, Ruthirakuhan M, Gallagher D. et al. Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer’s Disease. Am J Geriatr Psychiatry 2019; 27: 1161-1173
• 3 Cummings JL, Lyketsos CG, Peskind ER. et al. Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA 2015; 314: 1242-1254
• 4 Herring WJ, Ceesay P, Snyder E. et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer’s disease dementia and insomnia: a randomized trial. Alzheimers Dement 2020; 16: 541-551
• 5 Lozano AM, Fosdick L, Chakravarty MM. et al. A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer’s Disease. J Alzheimers Dis 2016; 54: 777-787
• 6 Grimmer T, Perneczky R, Kurz A. Current immune therapy for Alzheimer’s disease. Nervenarzt 2008; 79: 832-835
• 7 Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 2006; 6: 404-416
• 8 Janus C, Pearson J, McLaurin JA. et al. Aß peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. nature 2000; 408: 979-982
• 9 Morgan D, Diamond DM, Gottschall PE. et al. Abeta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. nature 2000; 408: 982-985
• 10 Schenk D, Barbour R, Dunn W. et al. Immunization with amyloid-ß attenuates Alzheimer-disease-like pathology in the PDAPP mouse. nature 1999; 400: 173-177
• 11 Bard F, Cannon C, Barbour R. et al. Peripherally administered antibodies against amyloid ß-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000; 6: 916-919
• 12 Bayer AJ, Bullock R, Jones RW. et al. Evaluation of the safety and immunogenicity of synthetic Aß42 (AN1792) in patients with AD. Neurology 2005; 64: 94-101
• 13 Gilman S, Koller M, Black RS. et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64: 1553-1562
• 14 Orgogozo JM, Gilman S, Dartigues JF. et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61: 46-54
• 15 Ferrer I, Boada RM, Sanchez Guerra ML. et al. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 2004; 14: 11-20
• 16 Nicoll JA, Wilkinson D, Holmes C. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003; 9: 448-452
• 17 Spinney L. Update on Elan vaccine for Alzheimer’s disease. Lancet Neurol 2004; 3: 5
• 18 Boche D, Nicoll JA. The Role of the Immune System in Clearence of Aß from the Brain. Brain Pathol 2008; 18: 267-278
• 19 Holmes C, Boche D, Wilkinson D. et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372: 216-223
• 20 Salloway S, Sperling R, Gilman S. et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73: 2061-2070
• 21 Salloway S, Sperling R, Fox NC. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322-333
• 22 Doody RS, Thomas RG, Farlow M. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 311-321
• 23 Goos JD, Henneman WJ, Sluimer JD. et al. Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population. Neurology 2010; 74: 1954-1960
• 24 Sperling R, Salloway S, Brooks DJ. et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012; 11: 241-249
• 25 Rinne JO, Brooks DJ, Rossor MN. et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 2010; 9: 363-372
• 26 Ostrowitzki S, Deptula D, Thurfjell L. et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69: 198-207
• 27 Farlow M, Arnold SE, van Dyck CH. et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 2012; 8: 261-271
• 28 Sevigny J, Chiao P, Bussiere T. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. nature 2016; 537: 50-56
• 29 Swanson CJ, Zhang Y, Dhadda S. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther 2021; 13: 80
• 30 Adolfsson O, Pihlgren M, Toni N. et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 2012; 32: 9677-9689
• 31 Salloway S, Farlow M, McDade E. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med 2021; 27: 1187-1196
• 32 Logovinsky V, Satlin A, Lai R. et al. Safety and tolerability of BAN2401--a clinical study in Alzheimer’s disease with a protofibril selective Abeta antibody. Alzheimers Res Ther 2016; 8: 14
• 33 Siemers ER, Sundell KL, Carlson C. et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement 2016; 12: 110-120
• 34 Hori Y, Takeda S, Cho H. et al. A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid beta in the brain in a transgenic model of Alzheimer disease. J Biol Chem 2015; 290: 1966-1978
• 35 Costa MJF, de Araujo IDT, da Rocha AL. et al. Relationship of Porphyromonas gingivalis and Alzheimer’s disease: a systematic review of pre-clinical studies. Clin Oral Investig 2021; 25: 797-806
• 36 Zhang P, Kishimoto Y, Grammatikakis I. et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 2019; 22: 719-728
• 37 Wang T, Kuang W, Chen W. et al. A phase II randomized trial of sodium oligomannate in Alzheimer’s dementia. Alzheimers Res Ther 2020; 12: 110
• 38 Xiao S, Chan P, Wang T. et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia. Alzheimers Res Ther 2021; 13: 62
• 39 Morawski M, Schilling S, Kreuzberger M. et al. Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-beta load and cognitive decline in Alzheimer’s disease. J Alzheimers Dis 2014; 39: 385-400
• 40 Frost JL, Le KX, Cynis H. et al. Pyroglutamate-3 amyloid-beta deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol 2013; 183: 369-381
• 41 Scheltens P, Hallikainen M, Grimmer T. et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther 2018; 10: 107
• 42 Del Ser T, Steinwachs KC, Gertz HJ. et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis 2013; 33: 205-215
• 43 Lovestone S, Boada M, Dubois B. et al. A phase II trial of tideglusib in Alzheimer’s disease. J Alzheimers Dis 2015; 45: 75-88
• 44 Kontsekova E, Zilka N, Kovacech B. et al. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 2014; 6: 44
• 45 Novak P, Kovacech B, Katina S. et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat Aging 2021; 1: 521-534
• 46 Livingston G, Huntley J, Sommerlad A. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 2020; 396: 413-446
• 47 De Felice FG, Vieira MN, Bomfim TR. et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A 2009; 106: 1971-1976
• 48 Craft S, Raman R, Chow TW. et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol 2020; 77: 1099-1109
• 49 Boada M, Lopez OL, Olazaran J. et al. A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease: Primary results of the AMBAR Study. Alzheimers Dement 2020; 16: 1412-1425