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18 - Clinical Trial Development in Frontotemporal Lobar Degeneration

from Section 3 - Alzheimer’s Disease Clinical Trials

Published online by Cambridge University Press:  03 March 2022

Jeffrey Cummings
Affiliation:
University of Nevada, Las Vegas
Jefferson Kinney
Affiliation:
University of Nevada, Las Vegas
Howard Fillit
Affiliation:
Alzheimer’s Drug Discovery Foundation
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Summary

Frontotemporal lobar degeneration (FTLD), a major cause of dementia worldwide, is an unrelenting and ultimately fatal set of pathological processes without any approved disease-modifying therapies. Clinical trial development in FTLD has previously been challenging, due to its pathological heterogeneity aand the clinical heterogeneity of frontotemporal dementia (FTD) and other clinical syndromes that arise from FTLD. Advances in FTLD basic science research have recently translated into a growing field of FTLD clinical trial development, with a particular focus on therapies tailored to distinct clinical syndromes with the highest specificity for particular FTLD pathophysiologies. The expansion of FTLD clinical programs has been fostered by a variety of advocacy groups and a number of large multi-site clinical research consortia, the latter of which have advanced the investigation of fluid biomarkers and clinical and neuroimaging measures for use in future clinical trials. This chapter covers the unique considerations of clinical trials in patients with FTLD pathology and review previous and current clinical trial programs investigating disease-modifying therapies targeting FTLD.

Type
Chapter
Information
Alzheimer's Disease Drug Development
Research and Development Ecosystem
, pp. 216 - 231
Publisher: Cambridge University Press
Print publication year: 2022

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References

Onyike, CU, Diehl-Schmid, J. The epidemiology of frontotemporal dementia. Int Rev Psychiatry 2013; 25: 130–7.Google ScholarPubMed
Perry, DC, Brown, JA, Possin, KL, et al. Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain 2017; 140: 3329–45.Google Scholar
Armstrong, MJ, Litvan, I, Lang, AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013; 80: 496503.Google Scholar
Höglinger, GU, Respondek, G, Stamelou, M, et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord 2017; 32: 853–64.Google Scholar
Rascovsky, K, Hodges, JR, Knopman, D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134: 2456–77.Google Scholar
Gorno-Tempini, M, Hillis, A, Weintraub, S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–14.CrossRefGoogle ScholarPubMed
Jadhav, S, Avila, J, Schöll, M, et al. A walk through tau therapeutic strategies. Acta Neuropathol Commun 2019; 7: 22.Google Scholar
Weingarten, MD, Lockwood, AH, Hwo, SY, Kirschner, MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975; 72: 1858–62.Google Scholar
Mackenzie, IRA, Neumann, M, Baborie, A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011; 122: 111–13.CrossRefGoogle ScholarPubMed
Svetoni, F, Frisone, P, Paronetto, MP. Role of FET proteins in neurodegenerative disorders. RNA Biol 2016; 13: 1089–102.Google Scholar
Spinelli, EG, Mandelli, ML, Miller, ZA, et al. Typical and atypical pathology in primary progressive aphasia variants. Ann Neurol 2017; 81: 430–43.CrossRefGoogle ScholarPubMed
Boxer, AL, Lang, AE, Grossman, M, et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled Phase 2/3 trial. Lancet Neurol 2014; 13: 676–85.Google Scholar
Forrest, SL, Kril, JJ, Stevens, CH, et al. Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain 2018; 141: 521–34.Google Scholar
Lee, SE, Rabinovici, GD, Mayo, MC, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011; 70: 327–40.CrossRefGoogle ScholarPubMed
Haynes, BA, Rhinn, H, Yeh, FL, et al. AL001 restores CSF PGRN levels and normalizes disease-associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene. Alzheimers Dement 2020; 16: e046114.Google Scholar
Boxer, AL, Moebius, HJ, Harris, B, et al. Phase 2a randomized, double-blind, placebo-controlled trial of the histone deacetylase inhibitor (HDACi), FRM-0334, in asymptomatic carriers of, or patients with frontotemporal lobar degeneration (FTLD) due to progranulin gene mutations. Alzheimer’s Association International Conference, Los Angeles, CA, 2019.Google Scholar
Sha, SJ, Miller, ZA, won, Min S, et al. An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. Alzheimers Dement (N Y) 2017; 3: 507–12.Google Scholar
The Angel Fund for ALS Research. Research at the day lab. Available at: https://theangelfund.org/research-at-day-lab/ (accessed December 28, 2020).Google Scholar
Boxer, A, Ljubenkov, P, VandeVrede, L, et al. A Phase 1b, randomized, double-blind, placebo-controlled, parallel cohort safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy study of intravenously infused BIIB092 in patients with four different tauopathy syndromes. 13th Clinical Trials on Alzheimer’s Disease (CTAD) Congress, November 4–7, 2020.Google Scholar
Boxer, AL, Gold, M, Feldman, H, et al. New directions in clinical trials for frontotemporal lobar degeneration: methods and outcome measures. Alzheimers Dement 2020; 16: 131–43.Google Scholar
ALLFTD. History. Available at: www.allftd.org/history (accessed December 30, 2020).Google Scholar
Richardson, E, Burnell, J, Adams, HR, et al. Developing and implementing performance outcome assessments: evidentiary, methodologic, and operational considerations. Ther Innov Regul Sci 2019; 53: 146–53.CrossRefGoogle ScholarPubMed
Gaasterland, CMW, Jansen-Van Der Weide, MC, Weinreich, SS, Van Der Lee, JH . A systematic review to investigate the measurement properties of goal attainment scaling, towards use in drug trials. BMC Med Res Methodol 2016; 16: 99.Google Scholar
Guinart, D, de Filippis, R, Rosson, S, et al. Development and validation of a computerized adaptive assessment tool for discrimination and measurement of psychotic symptoms. Schizophr Bull 2021; 47: 644–52.Google Scholar
Mioshi, E, Hsieh, S, Savage, S, Hornberger, M, Hodges, JR. Clinical staging and disease progression in frontotemporal dementia. Neurology 2010; 74: 1591–7.Google Scholar
Pfeffer, RI, Kurosaki, TT, Harrah, CH, Chance, JM, Filos, S. Measurement of functional activities in older adults in the community. J Gerontol 1982; 37: 323–9.Google Scholar
Miyagawa, T, Brushaber, D, Syrjanen, J, et al. Use of the CDR® plus NACC FTLD in mild FTLD: data from the ARTFL/LEFFTDS consortium. Alzheimers Dement 2020; 16: 7990.Google Scholar
Boeve, B, Rosen, H, Boxer, A, et al. The Multidomain Impairment Rating (MIR) Scale: initial reliability data on a multidimensional scale for FTLD (P5.1–010). Neurology 2019; 92;https://n.neurology.org/content/92/15_Supplement/P5.1-010.abstract.Google Scholar
Staffaroni, AM, Ljubenkov, PA, Kornak, J, et al. Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials. Brain 2019; 142: 443–59.Google Scholar
Toller, G, Ranasinghe, K, Cobigo, Y, et al. Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials. Neurology 2020; 94: e238495.Google Scholar
Staffaroni, AM, Bajorek, L, Casaletto, KB, et al. Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint. Alzheimers Dement 2020; 16: 1121.Google Scholar
FDA. Table of surrogate endpoints that were the basis of drug approval or licensure. www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure (accessed December 30, 2020).Google Scholar
Swift, IJ, Sogorb-Esteve, A, Heller, C, et al. Fluid biomarkers in frontotemporal dementia: past, present and future. J Neurol Neurosurg Psychiatry 2021; 92: 204–15.CrossRefGoogle ScholarPubMed
Palmqvist, S, Janelidze, S, Quiroz, YT, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 2020; 324: 772–81.CrossRefGoogle ScholarPubMed
Thijssen, EH, La Joie, R, Wolf, A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 2020; 26: 387–97.CrossRefGoogle ScholarPubMed
Paterson, RW, Slattery, CF, Poole, T, et al. Cerebrospinal fluid in the differential diagnosis of Alzheimer’s disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic. Alzheimers Res Ther 2018; 10: 32.Google Scholar
Meeter, LHH, Vijverberg, EG, Del Campo, M, et al. Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum. Neurology 2018; 90: e1231–9.Google Scholar
Rojas, JC, Karydas, A, Bang, J, et al. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann Clin Transl Neurol 2016; 3: 216–25.Google Scholar
Ljubenkov, PA, Staffaroni, AM, Rojas, JC, et al. Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann Clin Transl Neurol 2018; 5: 1250–63.Google Scholar
Meeter, LH, Dopper, EG, Jiskoot, LC, et al. Neurofilament light chain: a biomarker for genetic frontotemporal dementia. Ann Clin Transl Neurol 2016; 3: 623–36.Google Scholar
Gass, J, Cannon, A, Mackenzie, IR, et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006; 15: 29883001.CrossRefGoogle Scholar
Baker, M, Mackenzie, IR, Pickering-Brown, SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006; 442: 916–19.Google Scholar
Shankaran, SS, Capell, A, Hruscha, AT, et al. Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. J Biol Chem 2008; 283: 1744–53.Google Scholar
Kao, AW, McKay, A, Singh, PP, Brunet, A, Huang, EJ. Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 2017; 18: 325–33.Google Scholar
Meeter, LHH, Patzke, H, Loewen, G, et al. Progranulin levels in plasma and cerebrospinal fluid in granulin mutation carriers. Dement Geriatr Cogn Dis Extra 2016; 6: 330–40.Google Scholar
Finch, N, Baker, M, Crook, R, et al. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 2009; 132: 583–91.Google Scholar
Ash, PEA, Bieniek, KF, Gendron, TF, et al. Unconventional translation of C9orf72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013; 77: 639–46.CrossRefGoogle ScholarPubMed
Mori, K, Arzberger, T, Grässer, FA, et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 2013; 126: 881–93.CrossRefGoogle ScholarPubMed
Gendron, TF, Chew, J, Stankowski, JN, et al. Poly(GP) proteins are a useful pharmacodynamic marker for C9orf72-associated amyotrophic lateral sclerosis. Sci Transl Med 2017; 9: eaai7866.Google Scholar
Cammack, AJ, Atassi, N, Hyman, T, et al. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers. Neurology 2019; 93: E1605–17.Google Scholar
Lee, SE, Sias, AC, Kosik, EL, et al. Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers. Neuroimage Clin 2019; 22;DOI: https://doi.10.1016/j.nicl.2019.101751.Google Scholar
Jacova, C, Hsiung, GYR, Tawankanjanachot, I, et al. Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers. Neurology 2013; 81: 1322–31.Google Scholar
Binney, RJ, Pankov, A, Marx, G, et al. Data-driven regions of interest for longitudinal change in three variants of frontotemporal lobar degeneration. Brain Behav 2017; 7: e00675.Google Scholar
Staffaroni, AM, Cobigo, Y, Goh, S-YM, et al. Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration. Alzheimers Dement 2020; 16: 3748.Google Scholar
Cenik, B, Sephton, CF, Dewey, CM, et al. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem 2011; 286: 16101–8.Google Scholar
Lee, WC, Almeida, S, Prudencio, M, et al. Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet 2014; 23: 1467–78.Google Scholar
Paul, R. AL001 Phase 1b/2 update. Alzheimer’s Association International Conference, July 26–30, 2020.Google Scholar
Alector Inc. Alector showcases progress in immuno-neurology clinical programs and research portfolio at R&D day. Available at: www.globenewswire.com/news-release/2019/12/13/1960338/0/en/Alector-Showcases-Progress-in-Immuno-Neurology-Clinical-Programs-and-Research-Portfolio-at-R-D-Day.html (accessed February 17, 2020).Google Scholar
Passage Bio. Pipeline: frontotemporal dementia. Available at: www.passagebio.com/pipeline/frontotemporal-dementia/default.aspx. (accessed June 20, 2020).Google Scholar
Prevail Therapeutics. Prevail Therapeutics announces first patient dosed in Phase 1/2 PROCLAIM clinical trial evaluating PR006 for the treatment of frontotemporal dementia patients with GRN mutations. Available at: www.globenewswire.com/news-release/2020/12/11/2143673/0/en/Prevail-Therapeutics-Announces-First-Patient-Dosed-in-Phase-1-2-PROCLAIM-Clinical-Trial-Evaluating-PR006-for-the-Treatment-of-Frontotemporal-Dementia-Patients-with-GRN-Mutations.html (accessed December 27, 2020).Google Scholar
Denali. Our pipeline. Available at:https://denalitherapeutics.com/pipeline (accessed June 20, 2020).Google Scholar
Alzprotect. AZP2006: a mechanism of action with multiple effects, a unique solution for neurodegeneration. Available at: www.alzprotect.com/en/pipeline/azp2006?view=article&layout=alzprotect:hero-article (accessed December 30, 2020).Google Scholar
Taylor, JP, Brown, RH, Cleveland, DW. Decoding ALS: from genes to mechanism. Nature 2016; 539: 197206.CrossRefGoogle ScholarPubMed
DeVos, SL, Miller, TM. Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics 2013; 10: 486–97.CrossRefGoogle ScholarPubMed
Lim, KRQ, Maruyama, R, Yokota, T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 2017; 11: 533–45.Google Scholar
Hoy, SM. Nusinersen: first global approval. Drugs 2017; 77: 473–9.CrossRefGoogle ScholarPubMed
Miller, T, Cudkowicz, M, Shaw, PJ, et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med 2020; 383: 109–19.Google Scholar
Jiang, J, Zhu, Q, Gendron, TF, et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9orf72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 2016; 90: 535–50.Google Scholar
Sanders, DW, Kaufman, SK, DeVos, SL, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 2014; 82: 1271–88.Google Scholar
Yanamandra, K, Kfoury, N, Jiang, H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013; 80: 402–14.Google Scholar
Zhou, Y, Shi, J, Chu, D, et al. Relevance of phosphorylation and truncation of tau to the etiopathogenesis of Alzheimer’s disease. Front Aging Neurosci 2018; 10: 27.CrossRefGoogle Scholar
CurePSP. UCB pauses the development of bepranemab for progressive supranuclear palsy. Available at: www.psp.org/ucb-shift-2020/ (accessed December 28, 2020).Google Scholar
Novak, P, Schmidt, R, Kontsekova, E, et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimers Res Ther 2018; 10: 108.Google Scholar
Hung, S-Y, Fu, W-M. Drug candidates in clinical trials for Alzheimer’s disease. J Biomed Sci 2017; 24: 47.Google Scholar
Tsai, RM, Miller, Z, Koestler, M, et al. Reactions to multiple ascending doses of the microtubule stabilizer TPI-287 in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome: a randomized clinical trial. JAMA Neurol 2020; 77: 215–24.Google Scholar
Mignon, L, Kordasiewicz, H, Lane, R, et al. Design of the first-in-human study of IONIS-MAPTRx, a tau-lowering antisense oligonucleotide, in patients with Alzheimer disease (S2.006). Neurology 2018; 90.Google Scholar
Rodriguez-Martin, T, Anthony, K, Garcia-Blanco, MA, Mansfield, SG, Anderton, BH, Gallo, JM. Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing. Hum Mol Genet 2009; 18: 3266–73.Google Scholar
Wischik, CM, Edwards, PC, Lai, RYK, Roth, M, Harrington, CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci USA. 1996; 93: 11213–18.Google Scholar
Gauthier, S, Feldman, HH, Schneider, LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, Phase 3 trial. Lancet 2016; 388: 2873–84.Google Scholar
Tolosa, E, Litvan, I, Höglinger, GU, et al. A Phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord 2014; 29: 470–8.Google Scholar
Gentry, EG, Henderson, BW, Arrant, AE, et al. Rho kinase inhibition as a therapeutic for progressive supranuclear palsy and corticobasal degeneration. J Neurosci 2016; 36: 1316–23.Google Scholar
Woolsey Pharmaceuticals. PSP and CSP patients. Available at: www.woolseypharma.com/psp-cbs/ (accessed December 28, 2020).Google Scholar
Min, SW, Chen, X, Tracy, TE, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 2015; 21: 1154–62.Google Scholar
VandeVrede, L, Dale, ML, Fields, S, et al. Open-label Phase 1 futility studies of salsalate and young plasma in progressive supranuclear palsy. Mov Disord Clin Pract 2020; 7: 440–7.Google Scholar
Hastings, NB, Wang, X, Song, L, et al. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener 2017; 12: 116.Google Scholar
Asceneuron. R&D pipeline. Available at: www.asceneuron.com/pipeline (accessed December 28, 2020).Google Scholar
Giordano, R, Canesi, M, Isalberti, M, et al. Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a Phase I controlled, randomized clinical study. J Transl Med 2014; 12: 14.Google Scholar
Katsimpardi, L, Litterman, NK, Schein, PA, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014; 344: 630–4.Google Scholar
Villeda, SA, Plambeck, KE, Middeldorp, J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014; 20: 659–63.Google Scholar
Desmarais, P, Rohrer, JD, Nguyen, QD, et al. Therapeutic trial design for frontotemporal dementia and related disorders. J Neurol Neurosurg Psychiatry 2019; 90: 412–23.Google Scholar
Tao, JJ, Schram, AM, Hyman, DM. Basket studies: redefining clinical trials in the era of genome-driven oncology. Annu Rev Med 2018; 69: 319–31.Google Scholar
Berry, SM, Connor, JT, Lewis, RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA 2015; 313: 1619–20.Google Scholar

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