An Open-Label Extension of XPro1595 in Patients With Alzheimer's Disease

Summary

The goal of this Phase 2 Open Label study is to evaluate long-term safety, tolerability, and efficacy of XPro1595 on measures of cognition, function and brain quality in individuals with Alzheimer's Disease.

Timeline

Start

2023-02-21

Primary completion

2024-06-05

Completion

2024-07-05

Outcome

Outcome not reported

Stopped: “Sponsor resource allocation”

Publications

• Background Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006 May 17;295(19):2275-85. doi: 10.1001/jama.295.19.2275.
• Background Chance SA, Clover L, Cousijn H, Currah L, Pettingill R, Esiri MM. Microanatomical correlates of cognitive ability and decline: normal ageing, MCI, and Alzheimer's disease. Cereb Cortex. 2011 Aug;21(8):1870-8. doi: 10.1093/cercor/bhq264. Epub 2011 Jan 14.
• Background Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis. CNS Drugs. 2016 Nov;30(11):1111-1120. doi: 10.1007/s40263-016-0374-z.
• Background Clark I, Atwood C, Bowen R, Paz-Filho G, Vissel B. Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer's disease links numerous treatment rationales. Pharmacol Rev. 2012 Oct;64(4):1004-26. doi: 10.1124/pr.112.005850. Epub 2012 Sep 10.
• Background Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M. Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging. 2007 Apr;28(4):533-6. doi: 10.1016/j.neurobiolaging.2006.02.012. Epub 2006 Mar 29.
• Background Buchhave P, Zetterberg H, Blennow K, Minthon L, Janciauskiene S, Hansson O. Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol Aging. 2010 Nov;31(11):1877-84. doi: 10.1016/j.neurobiolaging.2008.10.012. Epub 2008 Dec 13.
• Background Branders S, Bernard G and Pereira A. Leveraging historical data for high-dimensional regression adjustment, a machine learning approach. PSI annual conference, Amsterdam, 3 to 6 June 2018.
• Background Arnason et al., Neurology. 53, 457-465 (1999)
• Background Bradshaw MJ, Mobley BC, Zwerner JP, Sriram S. Autopsy-proven demyelination associated with infliximab treatment. Neurol Neuroimmunol Neuroinflamm. 2016 Jan 27;3(2):e205. doi: 10.1212/NXI.0000000000000205. eCollection 2016 Apr. No abstract available.
• Background Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol. 1997 Apr;56(4):321-39. doi: 10.1097/00005072-199704000-00001.
• Background Draft FDA Guidance for Industry: Adjusting for covariates in randomized clinical trials for drugs and biologics. Revision 1 May 2021 Biostatistics (https://www.fda.gov/media/148910/download).
• Background Finsterwalder S, Vlegels N, Gesierich B, Araque Caballero MA, Weaver NA, Franzmeier N, Georgakis MK, Konieczny MJ, Koek HL; Dominantly Inherited Alzheimer Network (DIAN); Karch CM, Graff-Radford NR, Salloway S, Oh H, Allegri RF, Chhatwal JP; DELCODE study group; Jessen F, Duzel E, Dobisch L, Metzger C, Peters O, Incesoy EI, Priller J, Spruth EJ, Schneider A, Fliessbach K, Buerger K, Janowitz D, Teipel SJ, Kilimann I, Laske C, Buchmann M, Heneka MT, Brosseron F, Spottke A, Roy N, Ertl-Wagner B, Scheffler K; Alzheimer's Disease Neuroimaging Initiative (ADNI); Utrecht VCI study group; Seo SW, Kim Y, Na DL, Kim HJ, Jang H, Ewers M, Levin J, Schmidt R, Pasternak O, Dichgans M, Biessels GJ, Duering M. Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients. Alzheimers Dement. 2020 Nov;16(11):1504-1514. doi: 10.1002/alz.12150. Epub 2020 Aug 18.
• Background Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G. Elevated circulating tumor necrosis factor levels in Alzheimer's disease. Neurosci Lett. 1991 Aug 19;129(2):318-20. doi: 10.1016/0304-3940(91)90490-k.
• Background Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R; Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018.
• Background James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009 Aug;37(8):1779-84. doi: 10.1124/dmd.108.026195. Epub 2009 May 13.
• Background Jiang H, Hampel H, Prvulovic D, Wallin A, Blennow K, Li R, Shen Y. Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease. Mol Neurodegener. 2011 Oct 6;6:69. doi: 10.1186/1750-1326-6-69.
• Background Kantor ED, Udumyan R, Giovannucci EL, Valdimarsdottir UA, Signorello LB, Montgomery S, Fall K. Association of Blood Marker of Inflammation in Late Adolescence With Premature Mortality. JAMA Pediatr. 2019 Nov 1;173(11):1095-1097. doi: 10.1001/jamapediatrics.2019.2835.
• Background Kiresuk TJ, Sherman RE. Goal attainment scaling: A general method for evaluating comprehensive community mental health programs. Community Ment Health J. 1968 Dec;4(6):443-53. doi: 10.1007/BF01530764.
• Background Konttinen H, Cabral-da-Silva MEC, Ohtonen S, Wojciechowski S, Shakirzyanova A, Caligola S, Giugno R, Ishchenko Y, Hernandez D, Fazaludeen MF, Eamen S, Budia MG, Fagerlund I, Scoyni F, Korhonen P, Huber N, Haapasalo A, Hewitt AW, Vickers J, Smith GC, Oksanen M, Graff C, Kanninen KM, Lehtonen S, Propson N, Schwartz MP, Pebay A, Koistinaho J, Ooi L, Malm T. PSEN1DeltaE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Reports. 2019 Oct 8;13(4):669-683. doi: 10.1016/j.stemcr.2019.08.004. Epub 2019 Sep 12.
• Background Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013 Feb;9(2):106-18. doi: 10.1038/nrneurol.2012.263. Epub 2013 Jan 8.
• Background Lutshumba J, Nikolajczyk BS, Bachstetter AD. Dysregulation of Systemic Immunity in Aging and Dementia. Front Cell Neurosci. 2021 Jun 22;15:652111. doi: 10.3389/fncel.2021.652111. eCollection 2021.
• Background MacPherson KP, Sompol P, Kannarkat GT, Chang J, Sniffen L, Wildner ME, Norris CM, Tansey MG. Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol Dis. 2017 Jun;102:81-95. doi: 10.1016/j.nbd.2017.02.010. Epub 2017 Feb 24.
• 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 McWilliams EC, Barbey FM, Dyer JF, Islam MN, McGuinness B, Murphy B, Nolan H, Passmore P, Rueda-Delgado LM, Buick AR. Feasibility of Repeated Assessment of Cognitive Function in Older Adults Using a Wireless, Mobile, Dry-EEG Headset and Tablet-Based Games. Front Psychiatry. 2021 Jun 25;12:574482. doi: 10.3389/fpsyt.2021.574482. eCollection 2021.
• Background Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM; New Collective Author. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem. 2001 Mar;47(3):426-30.
• Background Olleros ML, Guler R, Vesin D, Parapanov R, Marchal G, Martinez-Soria E, Corazza N, Pache JC, Mueller C, Garcia I. Contribution of transmembrane tumor necrosis factor to host defense against Mycobacterium bovis bacillus Calmette-guerin and Mycobacterium tuberculosis infections. Am J Pathol. 2005 Apr;166(4):1109-20. doi: 10.1016/S0002-9440(10)62331-0.
• Background Olleros ML, Vesin D, Lambou AF, Janssens JP, Ryffel B, Rose S, Fremond C, Quesniaux VF, Szymkowski DE, Garcia I. Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guerin (BCG) and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis. J Infect Dis. 2009 Apr 1;199(7):1053-63. doi: 10.1086/597204.
• Background Paganelli R, Di Iorio A, Patricelli L, Ripani F, Sparvieri E, Faricelli R, Iarlori C, Porreca E, Di Gioacchino M, Abate G. Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer's disease patients. Exp Gerontol. 2002 Jan-Mar;37(2-3):257-63. doi: 10.1016/s0531-5565(01)00191-7.
• Background Parker D, Sloane R, Pieper CF, Hall KS, Kraus VB, Kraus WE, Huebner JL, Ilkayeva OR, Bain JR, Newby LK, Cohen HJ, Morey MC. Age-Related Adverse Inflammatory and Metabolic Changes Begin Early in Adulthood. J Gerontol A Biol Sci Med Sci. 2019 Feb 15;74(3):283-289. doi: 10.1093/gerona/gly121.
• Background Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013 Jan;70(1):31-41. doi: 10.1001/2013.jamapsychiatry.4.
• Background Siegel CA, Melmed GY. Predicting response to Anti-TNF Agents for the treatment of crohn's disease. Ther Adv Gastroenterol. 2009 Jul;2(4):245-51. doi: 10.1177/1756283X09336364.
• Background Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P, Chirino AJ, Chung HH, Doberstein SK, Eivazi A, Filikov AV, Gao SX, Hubert RS, Hwang M, Hyun L, Kashi S, Kim A, Kim E, Kung J, Martinez SP, Muchhal US, Nguyen DH, O'Brien C, O'Keefe D, Singer K, Vafa O, Vielmetter J, Yoder SC, Dahiyat BI. Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science. 2003 Sep 26;301(5641):1895-8. doi: 10.1126/science.1081297.
• Background Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K. Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull. 2003 Aug 15;61(3):255-60. doi: 10.1016/s0361-9230(03)00088-1.
• Background Valcarce C, Dunn I, and Burstein A. Inflammatory Biomarkers, Brain Volumetric MRI, FDG-PET Results in Patients with Type 2 Diabetes in Azeligagonphase 3 Trial in Mild Alzheimer's Disease (AD).http://vtvtherapeutics.com/wp-content/uploads/2019/03/AD_PD-presentation_FINAL-March-30-2019_lisbon.pdf
• Background Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O'Brien C, Eivazi A, Kung J, Nguyen DH, Doberstein SK, Erard F, Ryffel B, Szymkowski DE. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J Immunol. 2007 Aug 1;179(3):1872-83. doi: 10.4049/jimmunol.179.3.1872.
• Background Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.
• Background TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology. 1999 Aug 11;53(3):457-65.
• Background Gao H, Danzi MC, Choi CS, Taherian M, Dalby-Hansen C, Ellman DG, Madsen PM, Bixby JL, Lemmon VP, Lambertsen KL, Brambilla R. Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis. Cell Rep. 2017 Jan 3;18(1):198-212. doi: 10.1016/j.celrep.2016.11.083.
• Background Jaeger, J. H., Clint; Loft, Henrick; Lim, Yen Ying; Aschenbrenner, Andrew; Segerdahl, Marta; Tong, Gary; Mielke, Michelle; Hassenstab, Jason; Stricker, Nikki (2017). The Early AD/ MCI Alzheimer's Cognitive Composite (EMACC): Development & preliminary validation across 4 longitudinal cohorts of a cognitive endpoint for clinical trials in MCI & Early AD stage disease. CTAD.
• Background Pegoretti V, Baron W, Laman JD, Eisel ULM. Selective Modulation of TNF-TNFRs Signaling: Insights for Multiple Sclerosis Treatment. Front Immunol. 2018 Apr 30;9:925. doi: 10.3389/fimmu.2018.00925. eCollection 2018.
• Background Probert L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience. 2015 Aug 27;302:2-22. doi: 10.1016/j.neuroscience.2015.06.038. Epub 2015 Jun 24.
• Background Robbins DS, Shirazi Y, Drysdale BE, Lieberman A, Shin HS, Shin ML. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J Immunol. 1987 Oct 15;139(8):2593-7.
• Background Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1200-5. doi: 10.1136/jnnp.74.9.1200.
• Background Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2. Epub 2017 Dec 21.
• Background Zhao A, Li Y, Deng Y; Alzheimer's Disease Neuroimaging Initiative. TNF receptors are associated with tau pathology and conversion to Alzheimer's dementia in subjects with mild cognitive impairment. Neurosci Lett. 2020 Nov 1;738:135392. doi: 10.1016/j.neulet.2020.135392. Epub 2020 Sep 15.
• Background Zheng C, Fillmore NR, Ramos-Cejudo J, Brophy M, Osorio R, Gurney ME, Qiu WQ, Au R, Perry G, Dubreuil M, Chen SG, Qi X, Davis PB, Do N, Xu R. Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: A propensity score matched retrospective cohort study in US veterans. Alzheimers Dement. 2022 Jun;18(6):1248-1259. doi: 10.1002/alz.12465. Epub 2021 Sep 27.
• Background Zhou M, Xu R, Kaelber DC, Gurney ME. Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer's disease in patients with rheumatoid arthritis and psoriasis. PLoS One. 2020 Mar 23;15(3):e0229819. doi: 10.1371/journal.pone.0229819. eCollection 2020.

Drugs

Indications