Escalating Doses of Memantine in Down Syndrome (MEDS-123)

Summary

Down syndrome (DS) is typically caused by an extra chromosome 21 in the cell nucleus (trisomy 21, or T21). T21 is both the most common cause of genetically defined intellectual disability and the earliest documented cause of Alzheimer's disease (AD)-type pathology. Currently, all presymptomatic individuals with DS are classified as having 'Stage 0' DS-associated AD (DSAD). DSAD pathology evolves inexorably, with virtually all individuals with DS developing AD pathology by age 40, and approximately 50% meeting clinical dementia diagnosis criteria at 55 years of age. This study will test the hypothesis that the FDA-approved AD drug memantine, at higher-than-standard doses, may be effective as a cognitive enhancer in adolescents and young adults with DS. The primary goal of this phase 1b clinical trial will be the assessment of the safety and tolerability of three memantine doses in persons with DS. In addition, we will assess the effect of this drug on cognitive test scores and plasma biomarkers of AD in the study participants. Finally, we will also investigate steady-state plasma levels of memantine and the time course of memantine plasma levels after a single dose in the study participants (pharmacokinetics, or PK). The data generated through this phase 1b study will provide the essential safety, PK, and preliminary efficacy signals required to advance a phase 2 trial evaluating high-dose memantine as a first-in-class therapeutic strategy in DS.

Timeline

Start

2026-06

Primary completion

2028-05

Completion

2028-05

Publications

• Background Costa AC. The glutamatergic hypothesis for Down syndrome: the potential use of N-methyl-D-aspartate receptor antagonists to enhance cognition and decelerate neurodegeneration. CNS Neurol Disord Drug Targets. 2014 Feb;13(1):16-25. doi: 10.2174/18715273113126660183.
• Background Costa AC, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology. 2008 Jun;33(7):1624-32. doi: 10.1038/sj.npp.1301535. Epub 2007 Aug 15.
• Background Scott-McKean JJ, Costa AC. Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine. Learn Mem. 2011 Nov 18;18(12):774-8. doi: 10.1101/lm.024182.111. Print 2011 Dec.
• Background Scott-McKean JJ, Roque AL, Surewicz K, Johnson MW, Surewicz WK, Costa ACS. Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome. Neural Plast. 2018 Apr 10;2018:9235796. doi: 10.1155/2018/9235796. eCollection 2018.
• Background Rueda N, Llorens-Martin M, Florez J, Valdizan E, Banerjee P, Trejo JL, Martinez-Cue C. Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J Alzheimers Dis. 2010;21(1):277-90. doi: 10.3233/JAD-2010-100240.
• Background Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC. Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome. Behav Brain Res. 2011 Aug 10;221(2):610-22. doi: 10.1016/j.bbr.2010.03.036. Epub 2010 Apr 2.
• Background Mann DM, Yates PO, Marcyniuk B. Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes. Neuropathol Appl Neurobiol. 1984 May-Jun;10(3):185-207. doi: 10.1111/j.1365-2990.1984.tb00351.x.
• Background Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev. 2007;13(3):237-46. doi: 10.1002/mrdd.20163.
• Background Sinai A, Mokrysz C, Bernal J, Bohnen I, Bonell S, Courtenay K, Dodd K, Gazizova D, Hassiotis A, Hillier R, McBrien J, McCarthy J, Mukherji K, Naeem A, Perez-Achiaga N, Rantell K, Sharma V, Thomas D, Walker Z, Whitham S, Strydom A. Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. J Alzheimers Dis. 2018;61(2):717-728. doi: 10.3233/JAD-170624.
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• Background Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA, Goldson EJ, Costa AC. Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry. 2012 Jul 17;2(7):e141. doi: 10.1038/tp.2012.66.
• Background Victorino DB, Bederman IR, Costa ACS. Pharmacokinetic Properties of Memantine after a Single Intraperitoneal Administration and Multiple Oral Doses in Euploid Mice and in the Ts65Dn Mouse Model of Down's Syndrome. Basic Clin Pharmacol Toxicol. 2017 Nov;121(5):382-389. doi: 10.1111/bcpt.12816. Epub 2017 Jul 10.
• Background Costa ACS, Brandao AC, Boada R, Barrionuevo VL, Taylor HG, Roth E, Stasko MR, Johnson MW, Assir FF, Roberto MP, Salmona P, Abreu-Silveira G, Bederman I, Prendergast E, Huls A, Abrishamcar S, Mustacchi Z, Scheidemantel T, Roizen NJ, Ruedrich S. Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2022 Jan;21(1):31-41. doi: 10.1016/S1474-4422(21)00369-0.
• Background Costa ACS, Brandao AC, Leiva V, Taylor HG, Johnson MW, Salmona P, Abreu-Silveira G, Scheidemantel T, Roizen NJ, Ruedrich S, Boada R. Baseline Neuropsychological Characteristics of Adolescents and Young Adults with Down Syndrome Who Participated in Two Clinical Trials of the Drug Memantine. Brain Sci. 2025 Oct 29;15(11):1164. doi: 10.3390/brainsci15111164.
• Background Jack CR Jr, Andrews SJ, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC. Revised criteria for the diagnosis and staging of Alzheimer's disease. Nat Med. 2024 Aug;30(8):2121-2124. doi: 10.1038/s41591-024-02988-7.
• Background McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, Maayan N, Ware J, Debarros J. Memantine for dementia. Cochrane Database Syst Rev. 2019 Mar 20;3(3):CD003154. doi: 10.1002/14651858.CD003154.pub6.
• Background Ahmad-Sabry MH, Shareghi G. EFFECTS OF MEMANTINE ON PAIN IN PATIENTS WITH COMPLEX REGIONAL PAIN SYNDROME--A RETROSPECTIVE STUDY. Middle East J Anaesthesiol. 2015 Feb;23(1):51-4.
• Background Sinis N, Birbaumer N, Gustin S, Schwarz A, Bredanger S, Becker ST, Unertl K, Schaller HE, Haerle M. Memantine treatment of complex regional pain syndrome: a preliminary report of six cases. Clin J Pain. 2007 Mar-Apr;23(3):237-43. doi: 10.1097/AJP.0b013e31802f67a7.
• Background Strupp M, Kremmyda O, Brandt T. Pharmacotherapy of vestibular disorders and nystagmus. Semin Neurol. 2013 Jul;33(3):286-96. doi: 10.1055/s-0033-1354594. Epub 2013 Sep 21.
• Background Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu LM, Tyrer S, Francis PT, Johnson T, Bullock R, Ballard C; MEADOWS trial researchers. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Feb 11;379(9815):528-36. doi: 10.1016/S0140-6736(11)61676-0. Epub 2012 Jan 10.
• Background Hithersay R, Startin CM, Hamburg S, Mok KY, Hardy J, Fisher EMC, Tybulewicz VLJ, Nizetic D, Strydom A. Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years. JAMA Neurol. 2019 Feb 1;76(2):152-160. doi: 10.1001/jamaneurol.2018.3616.
• Background Carr J, Collins S. 50 years with Down syndrome: A longitudinal study. J Appl Res Intellect Disabil. 2018 Sep;31(5):743-750. doi: 10.1111/jar.12438. Epub 2018 Mar 2.
• Background Maekawa Y, Hasegawa S, Ishizuka T, Shiosakai K, Ishizuka H. Pharmacokinetics and Bioequivalence of Memantine Tablet and a New Dry Syrup Formulation in Healthy Japanese Males: Two Single-Dose Crossover Studies. Adv Ther. 2019 Oct;36(10):2930-2940. doi: 10.1007/s12325-019-01044-y. Epub 2019 Aug 9.

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