Insulin-Sensitizing Anti-Inflammatory Small Molecule for Investigative Treatment of Dementia

Summary

This study seeks to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of Alzheimer's disease and inflammatory and metabolic parameters that can be measure in the central nervous system (CNS) with advanced neuroimaging techniques in patients treated with NE3107 (17a-ethynyl-androst-5-3b,7b,17b-triol).

Timeline

Start

2022-01-19

Primary completion

2022-07-20

Completion

2022-08-20

Publications

• Background Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007 Jan 24;27(4):796-807. doi: 10.1523/JNEUROSCI.3501-06.2007.
• Background Connolly S. Economics of dementia: A review of methods. Dementia (London). 2020 Jul;19(5):1426-1440. doi: 10.1177/1471301218800639. Epub 2018 Sep 19.
• Background Khan, T.K. (2016) Chapter 1 - introduction to Alzheimer's disease biomarkers. Biomarkers in Alzheimer's Disease, pp. 3-23. doi:10.1016/B978-0-12-804832-0.00001-8
• Background Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021 Apr;46:101102. doi: 10.1016/j.molmet.2020.101102. Epub 2020 Oct 14.
• Background Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L, Detre JA, Wolk DA, Arnold SE. Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study. Alzheimer Dis Assoc Disord. 2017 Apr-Jun;31(2):107-113. doi: 10.1097/WAD.0000000000000202.
• Background Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018 Sep 6;4:575-590. doi: 10.1016/j.trci.2018.06.014. eCollection 2018.
• Background Chen MJ, Ramesha S, Weinstock LD, Gao T, Ping L, Xiao H, Dammer EB, Duong DD, Levey AI, Lah JJ, Seyfried NT, Wood LB, Rangaraju S. Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease. J Neurosci Res. 2021 Jun;99(6):1704-1721. doi: 10.1002/jnr.24829. Epub 2021 Mar 17.
• Background Rorbach-Dolata A, Piwowar A. Neurometabolic Evidence Supporting the Hypothesis of Increased Incidence of Type 3 Diabetes Mellitus in the 21st Century. Biomed Res Int. 2019 Jul 21;2019:1435276. doi: 10.1155/2019/1435276. eCollection 2019.
• Background Chow HM, Shi M, Cheng A, Gao Y, Chen G, Song X, So RWL, Zhang J, Herrup K. Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Nat Neurosci. 2019 Nov;22(11):1806-1819. doi: 10.1038/s41593-019-0505-1. Epub 2019 Oct 21.
• Background Reading CL, Ahlem CN, Murphy MF. NM101 Phase III study of NE3107 in Alzheimer's disease: rationale, design and therapeutic modulation of neuroinflammation and insulin resistance. Neurodegener Dis Manag. 2021 Aug;11(4):289-298. doi: 10.2217/nmt-2021-0022. Epub 2021 Jul 12.
• Background Maioli F, Coveri M, Pagni P, Chiandetti C, Marchetti C, Ciarrocchi R, Ruggero C, Nativio V, Onesti A, D'Anastasio C, Pedone V. Conversion of mild cognitive impairment to dementia in elderly subjects: a preliminary study in a memory and cognitive disorder unit. Arch Gerontol Geriatr. 2007;44 Suppl 1:233-41. doi: 10.1016/j.archger.2007.01.032.
• Background McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.
• Background Amieva H, Letenneur L, Dartigues JF, Rouch-Leroyer I, Sourgen C, D'Alchee-Biree F, Dib M, Barberger-Gateau P, Orgogozo JM, Fabrigoule C. Annual rate and predictors of conversion to dementia in subjects presenting mild cognitive impairment criteria defined according to a population-based study. Dement Geriatr Cogn Disord. 2004;18(1):87-93. doi: 10.1159/000077815. Epub 2004 Apr 14.
• Background Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia--meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 2009 Apr;119(4):252-65. doi: 10.1111/j.1600-0447.2008.01326.x. Epub 2008 Feb 18.
• Background Schmidtke K, Hermeneit S. High rate of conversion to Alzheimer's disease in a cohort of amnestic MCI patients. Int Psychogeriatr. 2008 Feb;20(1):96-108. doi: 10.1017/S1041610207005509. Epub 2007 May 16.
• Background Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21.
• Background Mashour GA, Frank L, Batthyany A, Kolanowski AM, Nahm M, Schulman-Green D, Greyson B, Pakhomov S, Karlawish J, Shah RC. Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias. Alzheimers Dement. 2019 Aug;15(8):1107-1114. doi: 10.1016/j.jalz.2019.04.002. Epub 2019 Jun 19.
• Background Lonskaya I, Hebron M, Chen W, Schachter J, Moussa C. Tau deletion impairs intracellular beta-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models. Mol Neurodegener. 2014 Nov 10;9:46. doi: 10.1186/1750-1326-9-46.
• Background Chen Z, Trapp BD. Microglia and neuroprotection. J Neurochem. 2016 Jan;136 Suppl 1:10-7. doi: 10.1111/jnc.13062. Epub 2015 Mar 10.
• Background Sominsky L, De Luca S, Spencer SJ. Microglia: Key players in neurodevelopment and neuronal plasticity. Int J Biochem Cell Biol. 2018 Jan;94:56-60. doi: 10.1016/j.biocel.2017.11.012. Epub 2017 Dec 1.
• Background Skaper SD. Impact of Inflammation on the Blood-Neural Barrier and Blood-Nerve Interface: From Review to Therapeutic Preview. Int Rev Neurobiol. 2017;137:29-45. doi: 10.1016/bs.irn.2017.08.004. Epub 2017 Oct 16.
• Background Galvin JE. THE QUICK DEMENTIA RATING SYSTEM (QDRS): A RAPID DEMENTIA STAGING TOOL. Alzheimers Dement (Amst). 2015 Jun 1;1(2):249-259. doi: 10.1016/j.dadm.2015.03.003.
• Background Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998 Jun;20(3):310-9. doi: 10.1076/jcen.20.3.310.823.
• Background Breton A, Casey D, Arnaoutoglou NA. Cognitive tests for the detection of mild cognitive impairment (MCI), the prodromal stage of dementia: Meta-analysis of diagnostic accuracy studies. Int J Geriatr Psychiatry. 2019 Feb;34(2):233-242. doi: 10.1002/gps.5016. Epub 2018 Nov 27.
• Background Smith T, Gildeh N, Holmes C. The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry. 2007 May;52(5):329-32. doi: 10.1177/070674370705200508.
• Background Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.
• Background Motl RW, Cohen JA, Benedict R, Phillips G, LaRocca N, Hudson LD, Rudick R; Multiple Sclerosis Outcome Assessments Consortium. Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. Mult Scler. 2017 Apr;23(5):704-710. doi: 10.1177/1352458517690823. Epub 2017 Feb 16.
• Background Wong GKC, Mak JSY, Wong A, Zheng VZY, Poon WS, Abrigo J, Mok VCT. Minimum Clinically Important Difference of Montreal Cognitive Assessment in aneurysmal subarachnoid hemorrhage patients. J Clin Neurosci. 2017 Dec;46:41-44. doi: 10.1016/j.jocn.2017.08.039. Epub 2017 Sep 5.
• Background O'Connell ME, Gould B, Ursenbach J, Enright J, Morgan DG. Reliable change and minimum clinically important difference (MCID) of the Repeatable Battery for the Assessment of Neuropsychology Status (RBANS) in a heterogeneous dementia sample: Support for reliable change methods but not the MCID. Appl Neuropsychol Adult. 2019 May-Jun;26(3):268-274. doi: 10.1080/23279095.2017.1413575. Epub 2018 Jan 10.
• Background Burnham SC, Bourgeat P, Dore V, Savage G, Brown B, Laws S, Maruff P, Salvado O, Ames D, Martins RN, Masters CL, Rowe CC, Villemagne VL; AIBL Research Group. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer's disease pathophysiology (SNAP) or Alzheimer's disease pathology: a longitudinal study. Lancet Neurol. 2016 Sep;15(10):1044-53. doi: 10.1016/S1474-4422(16)30125-9. Epub 2016 Jul 20.
• Background Zheng W, Cui B, Han Y, Song H, Li K, He Y, Wang Z. Disrupted Regional Cerebral Blood Flow, Functional Activity and Connectivity in Alzheimer's Disease: A Combined ASL Perfusion and Resting State fMRI Study. Front Neurosci. 2019 Jul 24;13:738. doi: 10.3389/fnins.2019.00738. eCollection 2019.
• Background Mishra VR, Sreenivasan KR, Zhuang X, Yang Z, Cordes D, Walsh RR. Influence of analytic techniques on comparing DTI-derived measurements in early stage Parkinson's disease. Heliyon. 2019 Apr 9;5(4):e01481. doi: 10.1016/j.heliyon.2019.e01481. eCollection 2019 Apr.
• Background Gorges M, Muller HP, Liepelt-Scarfone I, Storch A, Dodel R; LANDSCAPE Consortium; Hilker-Roggendorf R, Berg D, Kunz MS, Kalbe E, Baudrexel S, Kassubek J. Structural brain signature of cognitive decline in Parkinson's disease: DTI-based evidence from the LANDSCAPE study. Ther Adv Neurol Disord. 2019 May 16;12:1756286419843447. doi: 10.1177/1756286419843447. eCollection 2019.
• Background Kuhn T, Becerra S, Duncan J, Spivak N, Dang BH, Habelhah B, Mahdavi KD, Mamoun M, Whitney M, Pereles FS, Bystritsky A, Jordan SE. Translating state-of-the-art brain magnetic resonance imaging (MRI) techniques into clinical practice: multimodal MRI differentiates dementia subtypes in a traditional clinical setting. Quant Imaging Med Surg. 2021 Sep;11(9):4056-4073. doi: 10.21037/qims-20-1355.
• Background Adamczuk K, Schaeverbeke J, Vanderstichele HM, Lilja J, Nelissen N, Van Laere K, Dupont P, Hilven K, Poesen K, Vandenberghe R. Diagnostic value of cerebrospinal fluid Abeta ratios in preclinical Alzheimer's disease. Alzheimers Res Ther. 2015 Dec 18;7(1):75. doi: 10.1186/s13195-015-0159-5.
• Background Berman SE, Koscik RL, Clark LR, Mueller KD, Bluder L, Galvin JE, Johnson SC. Use of the Quick Dementia Rating System (QDRS) as an Initial Screening Measure in a Longitudinal Cohort at Risk for Alzheimer's Disease. J Alzheimers Dis Rep. 2017;1(1):9-13. doi: 10.3233/ADR-170004. Epub 2017 Apr 28.
• Background Lin Y, Wang K, Ma C, Wang X, Gong Z, Zhang R, Zang D, Cheng Y. Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism. Front Aging Neurosci. 2018 Jul 27;10:227. doi: 10.3389/fnagi.2018.00227. eCollection 2018.

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Indications