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Targeting Amyloid with Tramiprosate in Patients with Mild-to-Moderate Alzheimer Disease

Published online by Cambridge University Press:  04 December 2007

P.S. Aisen ,
R. Briand ,
D. Saumier ,
J. Laurin ,
A. Duong  and
D. Garceau
P.S. Aisen
Affiliation:
Department of Neurology, Georgetown University Medical Center, Washington DC, USA; Email: [email protected]
R. Briand
Affiliation:
Neurochem Inc., Laval, Quebec, Canada; Email: [email protected]
D. Saumier
Affiliation:
Neurochem Inc., Laval, Quebec, Canada; Email: [email protected]
J. Laurin
Affiliation:
Neurochem Inc., Laval, Quebec, Canada; Email: [email protected]
A. Duong
Affiliation:
Neurochem Inc., Laval, Quebec, Canada; Email: [email protected]
D. Garceau
Affiliation:
Neurochem Inc., Laval, Quebec, Canada; Email: [email protected]
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Extract

ABSTRACT

Background: Tramiprosate (3-amino-1-propanesulfonic acid, 3APS, ALZHEMED™) is an investigational product candidate that is believed to reduce amyloid deposition in the brain by binding to soluble Aβ, thereby slowing or halting the progression of Alzheimer Disease (AD). Design and Methods: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of tramiprosate in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or tramiprosate 50, 100, or 150 mg BID for 3 months. At the end of the double-blind study, 42 of these patients entered an open-label extension study in which they received tramiprosate 150 mg BID for an additional 17 months. Assessments included plasma and CSF tramiprosate concentrations, CSF Aβ42 concentrations, and psychometric tests (Alzheimer's Disease Assessment Scale – cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating Scale – Sum of Boxes). Results: Tramiprosate had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild-to-moderate in severity. Overall, six tramiprosate-treated patients discontinued because of side effects (all causalities) and there were no drug-related serious adverse events. Tramiprosate crossed the blood–brain barrier and dose-dependently reduced CSF Aβ42 levels after 3 months of treatment. There were no psychometric score differences between treatment groups after 3 months of double-blind treatment. However, psychometric score changes over the 17-month open-label extension study are consistent with a slowing of cognitive and clinical decline, particularly in mild subjects. Interpretation: Long-term administration of tramiprosate is safe and tolerated in patients with mild-to-moderate AD. The short-term reduction of CSF Aβ42 levels and the long-term open-label cognitive and clinical assessments are consistent with disease-modification.

Keywords

Alzheimer's Diseaseamyloid betabiomarkerclinical trialcognitionCSFdisease modification.
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 111 - 125
Copyright
© 2008 Cambridge University Press

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Footnotes

Trial data adapted and Figure 2 reproduced with permission from Aisen et al. (2007). A phase II study targeting amyloid-B with 3APS in mild-to-moderate Alzheimer disease. Neurology, 67, 1757–1763.

References

American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorder (4th ed.), Text Revision. Washington, DC: American Psychiatric Association.
Azzi, M., Morissette, C., Fallon, L., Martin, R., Galarneau, A., Sebastiani, G., et al. (2007). Involvement of both GABA-dependent and -independent pathways in tramiprosate neuroprotective effects against amyloid-beta toxicity 8th International Conference AD/PD, 14–18 March, Salzburg, Austria.
Barten, D.M., Guss, V.L., Corsa, J.A., Loo, A., Hansel, S.B., Zheng, M., et al. (2005). Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. Journal of Pharmacology and Experimental Therapeutics, 312 (2), 635–643.Google Scholar
Best, J.D., Jay, M.T., Otu, F., Ma, J., Nadin, A., Ellis, S., et al. (2005). Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]. Journal of Pharmacology and Experimental Therapeutics, 313 (2), 902–908.Google Scholar
Canevari, L., Abramov, A.Y., & Duchen, M.R. (2004). Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochemical Research, 29 (3), 637–650.Google Scholar
Christensen, D.D. (2007). Changing the course of Alzheimer's disease: anti-amyloid disease-modifying treatments on the horizon. Primary Care Companion Journal of Clinical Psychiatry, 9 (1), 32–41.Google Scholar
Citron, M. (2004). Strategies for disease modification in Alzheimer's disease. Nature Reviews Neuroscience, 5 (9), 677–685.Google Scholar
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A.Y., Seubert, P., et al. (1992). Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature, 360 (6405), 672–674.Google Scholar
Dodart, J.C., Bales, K.R., Gannon, K.S., Greene, S.J., DeMattos, R.B., Mathis, C., et al. (2002). Immunization reverses memory deficits without reducing brain abeta burden in Alzheimer's disease model. Nature Neuroscience, 5 (5), 452–457.Google Scholar
Dodel, R.C., Du, Y., Depboylu, C., Hampel, H., Frolich, L., Haag, A., et al. (2004). Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. Journal of Neurology Neurosurgery and Psychiatry, 75 (10), 1472–1474.Google Scholar
Folstein, M.F., Folstein, S.E., & McHugh, P.R. (1975). “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12 (3), 189–198.Google Scholar
Gandy, S. (2005). The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. Journal of Clinical Investigation, 115 (5), 1121–1129.Google Scholar
Gervais, F., Paquette, J., Morissette, C., Krzywkowski, P., Yu, M., Azzi, M., et al. (2007). Targeting soluble abeta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiology of Aging, 28 (4), 537–547.Google Scholar
Giaccone, G., Tagliavini, F., Linoli, G., Bouras, C., Frigerio, L., Frangione, B., et al. (1989). Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neuroscience Letters, 97 (1–2), 232–238.Google Scholar
Gilman, S., Koller, M., Black, R.S., Jenkins, L., Griffith, S.G., Fox, N.C., et al. (2005). Clinical effects of abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64 (9), 1553–1562.Google Scholar
Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature, 349 (6311), 704–706.Google Scholar
Krzywkowski, P., Sebastiani, G., Williams, S., Delorme, D., & Greenberg, B.G. (2007). Tramiprosate prevents amyloid beta-induced inhibition of long-term potentiation in rat hippocampal slices 8th International Conference AD/PD, 14–18 March, Salzburg, Austria.
Lemere, C.A., Beierschmitt, A., Iglesias, M., Spooner, E.T., Bloom, J.K., Leverone, J.F., et al. (2004). Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. American Journal of Pathology, 165 (1), 283–297.Google Scholar
Levy-Lahad, E., Wijsman, E.M., Nemens, E., Anderson, L., Goddard, K.A., Weber, J.L., et al. (1995). A familial Alzheimer's disease locus on chromosome 1. Science, 269 (5226), 970–973.Google Scholar
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E.M. (1984). Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology, 34 (7), 939–944.Google Scholar
Mohs, R.C., & Cohen, L. (1988). Alzheimer's disease assessment scale (ADAS). Psychopharmacology Bulletin, 24 (4), 627–628.Google Scholar
Morris, J.C. (1993). The clinical dementia rating (CDR): current version and scoring rules. Neurology, 43 (11), 2412–2414.Google Scholar
Naslund, J., Haroutunian, V., Mohs, R., Davis, K.L., Davies, P., Greengard, P., et al. (2000). Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline (In Process Citation). JAMA, 283 (12), 1571–1577.Google Scholar
Ritchie, C.W., Bush, A.I., Mackinnon, A., Macfarlane, S., Mastwyk, M., MacGregor, L., et al. (2003). Metal-Protein attenuation with iodochlorhydroxyquin (clioquinol) targeting A{beta} amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Archives of Neurology, 60 (12), 1685–1691.Google Scholar
Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, K., et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 375, 754–760.Google Scholar
Solomon, B. (2007). Beta-amyloid-based immunotherapy as a treatment of Alzheimers disease. Drugs Today (Barc), 43 (5), 333–342.Google Scholar
Tanzi, R.E., Moir, R.D., & Wagner, S.L. (2004). Clearance of Alzheimer's abeta peptide; the many roads to perdition. Neuron, 43 (5), 605–608.Google Scholar
Thal, L.J., Kantarci, K., Reiman, E.M., Klunk, W.E., Weiner, M.W., Zetterberg, H., et al. (2006). The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Disease and Associated Disorders, 20 (1), 6–15.Google Scholar