Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval (original) (raw)
- Review
- Open access
- Published: 12 August 2020
- Susan Abushakra1,
- John A. Hey1,
- Anton Porsteinsson2 &
- …
- Marwan Sabbagh3
Alzheimer's Research & Therapy volume 12, Article number: 95 (2020)Cite this article
- 47k Accesses
- 231 Citations
- 127 Altmetric
- Metrics details
Abstract
The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees. Aducanumab and gantenerumab partially target oligomers, while mostly clearing insoluble amyloid plaques; BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with vasogenic brain edema. Only the highest doses of aducanumab and BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic edema, especially in APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Aβ oligomers without clearing amyloid plaques. The most advanced selective anti-oligomer agent is ALZ-801, an optimized oral prodrug of tramiprosate, which demonstrated efficacy in homozygous APOE4/4 AD subjects. ALZ-801 selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic edema, and will be evaluated in a phase 3 trial in homozygous APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging biomarkers to gain further insights into the role of soluble Aβ oligomers in the pathogenesis of AD and their impact on disease progression.
Introduction
The central and early role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is supported by numerous genetic, biomarker, and genome-wide association studies in both familial (early-onset) and sporadic (late-onset) AD [[1](/articles/10.1186/s13195-020-00663-w#ref-CR1 "Tolar M, Abushakra S, Sabbagh M. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement 2019;1–8. https://doi.org/10.1016/j.jalz.2019.09.075
.")\]. The brain amyloid species consistently shown to be associated with acute neuronal toxicity and neurodegeneration in AD are the soluble amyloid oligomers, formed by the aggregation of misfolded Aβ monomers \[[1](#ref-CR1 "Tolar M, Abushakra S, Sabbagh M. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement 2019;1–8.
https://doi.org/10.1016/j.jalz.2019.09.075
."),[2](#ref-CR2 "Viola KL, Klein W. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129(2):183–206.
https://doi.org/10.1007/s00401-015-1386-3
."),[3](/articles/10.1186/s13195-020-00663-w#ref-CR3 "Selkoe DJ. A is for amyloid. J Prev Alz Dis. 2020;3(7):140–1.")\]. Several preclinical and clinical studies have shown that soluble Aβ oligomers, rather than insoluble aggregates that form plaques and fibrils, are the key amyloid species that initiate neurotoxicity and disease progression in AD \[[4](#ref-CR4 "Hong W, Wang Z, Liu W, O’Malley TT, Jin M, Willem M, et al. Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain. Acta Neuropathol. 2018;136(1):19–40.
https://doi.org/10.1007/s00401-018-1846-7
."),[5](#ref-CR5 "Gaspar RC, Villarreal SA, Bowles N, Hepler RW, Joyce JG, Shugrue P. Oligomers of beta-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model. Exp Neurol. 2010;223(2):394–400.
https://doi.org/10.1016/j.expneurol.2009.09.001
."),[6](#ref-CR6 "Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman, et al. Amyloid-beta oligomerization in Alzheimer dementia vs. high pathology controls. Ann Neurol 2013;73(1):104–119. doi:
https://doi.org/10.1002/ana.23748
."),[7](#ref-CR7 "Yang T, Li S, Xu H, Walsh DM, Selkoe DJ. Large soluble oligomers of amyloid-protein from Alzheimer’s brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci. 2017;37(1):152–63.
https://doi.org/10.1523/JNEUROSCI.1698-16.2016
."),[8](/articles/10.1186/s13195-020-00663-w#ref-CR8 "Bilousova T, Miller CA, Poon WW, Vinters HV, Corrada M, Kawas C, et al. Synaptic amyloid-β oligomers precede p-tau and differentiate high pathology control cases. Am J Pathol. 2016;186:185–98.
https://doi.org/10.1016/j.ajpath.2015.09.018
.")\]. Further evidence for the upstream role of Aβ in driving tau pathology and cognitive decline in AD patients comes from recent longitudinal amyloid and tau positron emission tomography (PET) imaging studies. These studies show that cortical amyloid burden must reach a critical threshold before tau pathology spreads from the medial temporal lobes to the neocortex, expediting cognitive decline \[[9](/articles/10.1186/s13195-020-00663-w#ref-CR9 "Hanseeuw BJ, Betensky RA, Jacobs H, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76(8):915–24.
https://doi.org/10.1001/jamaneurol.2019.1424
.")\]. This sequence of pathologies implies that amyloid targeted agents should reduce downstream tau pathology and cognitive decline, which is indeed what has been observed in recent clinical trials.Despite the substantial body of evidence supporting the toxic role of amyloid, only a few anti-amyloid agents have shown significant cognitive benefits in AD clinical trials. A systematic review of the positive and negative trials can provide insights into the critical factors underlying clinical efficacy and accelerate the future development of disease-modifying treatments for AD. In this analysis, we evaluated the mechanisms of action (MOA), selectivity for amyloid species, and pharmacological profiles of late-stage anti-amyloid agents in active development, and correlated these features with clinical and biomarker effects consistent with disease modification in long-duration trials. We also analyzed the benefit-risk profiles of these agents, which may become AD treatments in the near future, in the overall AD population as well as the subgroup of high-risk carriers of the ε4 allele of apolipoprotein E gene (APOE4).
Methods
This analysis focused on anti-amyloid agents that fulfilled the following criteria: (1) completed phase 3 or phase 2 trials in symptomatic AD patients; (2) demonstrated acceptable safety with treatment duration ≥ 12 months, the regulatory standard for long-term safety; (3) reported significant effects on clinical outcomes or on AD imaging or fluid biomarkers; (4) published mechanisms of action (MOA) and pharmacokinetic (PK) profiles; and (5) in active clinical development. Details of clinical trial designs were obtained from publications or listings on https://clinicaltrials.gov. The imaging biomarkers included volumetric magnetic resonance imaging (MRI) measures and PET imaging studies of amyloid and tau pathologies. The fluid biomarkers in these trials included plasma or cerebrospinal fluid (CSF) assays of amyloid and tau pathology and of downstream neuronal injury. The data on pharmacokinetic characteristics, efficacy, safety, and biomarker effects were tabulated to allow the analysis of benefit-risk profiles.
Results
Our analysis identified four agents that fulfilled prespecified selection criteria: the anti-amyloid antibodies aducanumab and BAN2401 administered by intravenous (IV) infusions, gantenerumab administered by subcutaneous (SC) injections, and a small molecule oral agent ALZ-801. Anti-amyloid agents that did not fulfill these criteria include antibodies bapineuzumab, solanezumab, and crenezumab that failed to show efficacy in phase 3 trials, and several oral gamma and beta secretase inhibitors that failed to show efficacy and were burdened by unacceptable toxicities in phase 3 trials. Phase 2 agents that did not fulfill these criteria include several active Aβ vaccines that failed to show efficacy, anti-amyloid antibody donanemab, and oral anti-oligomer agents PQ912 and CT1812 that lack both efficacy and long-term safety data.
The four agents that fulfilled all our criteria, aducanumab, BAN2401, gantenerumab, and ALZ-801, share a common feature, namely their interaction with neurotoxic soluble Aβ oligomers, based on published MOA and binding affinity studies. The three antibodies showed different levels of selectivity for soluble Aβ oligomers versus insoluble plaques and fibrils. The fourth agent, ALZ-801, is an oral prodrug of tramiprosate that inhibits the formation of amyloid oligomers without plaque interaction.
Differential selectivity for Aβ oligomers
Aducanumab, gantenerumab, and BAN2401 are human or humanized monoclonal antibodies that bind with high affinity to aggregated Aβ and promote its removal by Fc receptor-mediated phagocytosis, while showing much lower affinity to monomers [10,[11](#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6. https://doi.org/10.1038/nature19323
."),[12](#ref-CR12 "Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28(1):49–69."),[13](#ref-CR13 "Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95.
https://doi.org/10.1186/s13195-017-0318-y
."),[14](/articles/10.1186/s13195-020-00663-w#ref-CR14 "Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswalk G, et al. Safety and tolerability of BAN2401 - a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016;8(1):14.
https://doi.org/10.1186/s13195-016-0181-2
.")\]. However, these antibodies differ in their selectivity to soluble Aβ oligomers versus plaques or fibrils. A direct comparison study of the selectivity of aducanumab and BAN2401 for soluble amyloid oligomers versus insoluble plaques and fibrils reported a 10-fold higher selectivity of BAN2401 for oligomers \[[10](/articles/10.1186/s13195-020-00663-w#ref-CR10 "Lannfelt L, Söderberg L, Laudon H, Sahlin C, Johannesson M, Nygren P, et al. BAN2401 shows stronger binding to soluble aggregated amyloid-beta species than aducanumab. BioArctic poster presentation. Alzheimer’s Association International Conference: 14–18 July 2019; Los Angeles."), [11](/articles/10.1186/s13195-020-00663-w#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6.
https://doi.org/10.1038/nature19323
.")\]. Gantenerumab MOA studies showed partial interaction with oligomers \[[12](/articles/10.1186/s13195-020-00663-w#ref-CR12 "Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28(1):49–69.")\]; however, direct comparisons with the other two antibodies have not been reported. ALZ-801 selectively inhibits the misfolding of Aβ42 monomers and oligomer formation in an in vitro assay \[[15](#ref-CR15 "Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs. 2017;31(6):495–509.
https://doi.org/10.1007/s40263-017-0434-z
."),[16](#ref-CR16 "Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–61.
https://doi.org/10.1007/s40263-018-0554-0
."),[17](/articles/10.1186/s13195-020-00663-w#ref-CR17 "Liang C, Savinov SN, Fejzo J, Eyles SJ, Chen J. Modulation of amyloid-β42 conformation by small molecules through nonspecific binding. J Chem Theory Comput. 2019;15(10):5169–74.
https://doi.org/10.1021/acs.jctc.9b00599
.")\] and can fully block the formation of amyloid oligomers in the brain at the target clinical dose \[[16](/articles/10.1186/s13195-020-00663-w#ref-CR16 "Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–61.
https://doi.org/10.1007/s40263-018-0554-0
.")\]. ALZ-801/tramiprosate did not bind plaque in a transgenic model of AD \[[18](/articles/10.1186/s13195-020-00663-w#ref-CR18 "Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, et al. Targeting soluble Abeta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007;28(4):537–47.
https://doi.org/10.1016/j.neurobiolaging.2006.02.015
.")\]. The differential selectivity for soluble Aβ oligomers, clinical and biomarker efficacy data, and safety profiles of the late-stage anti-amyloid agents are summarized in Tables [1](/articles/10.1186/s13195-020-00663-w#Tab1) and [2](/articles/10.1186/s13195-020-00663-w#Tab2).Table 1 Late-stage anti-amyloid agents: selectivity for amyloid oligomers and clinical and biomarker effects in phase 2 and 3 studies
Table 2 Anti-amyloid antibodies in early AD trials: clinical efficacy, safety, and PET imaging effects
Clinical and biomarker efficacy data
Aducanumab showed significant efficacy in the reanalysis of the EMERGE phase 3 trial in early AD, while the ENGAGE phase 3 trial was negative [19]. The highest dose of 10 mg/kg monthly IV infusions showed significant effects on the primary outcome, the cognitive and functional composite measure Clinical Dementia Rating—Sum of Boxes (CDR-SB), and on the cognitive endpoint Alzheimer’s Disease Assessment Scale—cognitive subscale (ADAS-cog). While both phase 3 trials were stopped for futility after an interim analysis, the positive final analysis in the EMERGE trial was supported by significant biomarker effects on phosphorylated tau (p-tau) in CSF and on tau PET imaging [19].
BAN2401, in a large phase 2 trial in early AD, showed significant efficacy at the highest dose, 10 mg/kg IV infusion twice per month [23, 25]. BAN2401 showed significant and clinically meaningful effects on the primary outcome, the Alzheimer’s Disease Composite Score (ADCOMS) [26] and the ADAS-cog, which were larger in APOE4 carriers. BAN2401 also showed significant effects on CSF p-tau and on downstream markers of neuronal injury (neurofilament light chain, NfL) and synaptic integrity (neurogranin) [23, 25].
Gantenerumab, in phase 3 studies in prodromal and early AD, showed no clinical efficacy at 225 mg and 1200 mg doses administered monthly by subcutaneous (SC) injection, while significant effects on CSF p-tau and total tau (t-tau, marker of neuronal injury) were reported [[13](/articles/10.1186/s13195-020-00663-w#ref-CR13 "Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95. https://doi.org/10.1186/s13195-017-0318-y
."), [20](/articles/10.1186/s13195-020-00663-w#ref-CR20 "Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
https://doi.org/10.1186/s13195-019-0559-z
."), [22](/articles/10.1186/s13195-020-00663-w#ref-CR22 "Abi-Saab D, Andjelkovic M, Pross N, Delmar P, Voyle N, Klein G, et al. Update on the safety and tolerability of gantenerumab in the ongoing open-label extension (OLE) of the Marguerite Road study in patients with mild AD after approximately 2 years of study duration. Alzheimers Dement. 2018;14(7):241.
https://doi.org/10.1016/j.jalz.2018.06.2381
.")\]. A recently completed study in familial AD, led by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), enrolled approximately 50 subjects into each of placebo, solanezumab, and gantenerumab arms for 4 years of treatment \[[21](/articles/10.1186/s13195-020-00663-w#ref-CR21 "Bateman RJ. DIAN-TU-001 topline study results. Presentation at AAT-AD/PD Focus Meeting: 2 April 2020."), [27](/articles/10.1186/s13195-020-00663-w#ref-CR27 "Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU next generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8–19.
https://doi.org/10.1016/j.jalz.2016.07.005
.")\]. This study used the higher dose of 1200 mg monthly SC injection of gantenerumab that has shown acceptable long-term safety \[[20](/articles/10.1186/s13195-020-00663-w#ref-CR20 "Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
https://doi.org/10.1186/s13195-019-0559-z
.")\]. At this dose, gantenerumab showed significant effects on CSF p-tau, t-tau, and NfL at 4 years in the familial AD population, but no clinical efficacy. The antibody solanezumab which selectively binds to Aβ monomers and has minimal brain penetration \[[28](/articles/10.1186/s13195-020-00663-w#ref-CR28 "Willis BA, Sundell K, Lachno DR, Ferguson-Sells L, Case MG, Holdridge K, et al. Central pharmacodynamic activity of solanezumab in mild Alzheimer’s disease dementia. Alzheimers Dement. 2018;4:652–60.
https://doi.org/10.1016/j.trci.2018.10.001
.")\] showed no clinical or biomarker effects in the DIAN-TU study, in line with the negative data from the previous phase 3 trials \[[29](/articles/10.1186/s13195-020-00663-w#ref-CR29 "Honig L, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321–30.
https://doi.org/10.1056/NEJMoa1705971
.")\].ALZ-801 is an optimized prodrug of tramiprosate, which consists of tramiprosate conjugated to the essential amino acid valine, providing improved gastrointestinal tolerability and more consistent plasma levels that lead to increased brain penetration [[30](/articles/10.1186/s13195-020-00663-w#ref-CR30 "Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2018;57(3):315–33. https://doi.org/10.1007/s40262-017-0608-3
.")\]. Tramiprosate, the active agent in ALZ-801, was evaluated in a phase 3 study of mild to moderate AD that enrolled all APOE genotypes and did not show efficacy in the overall study population. Subgroup analyses showed clinical efficacy in the high-risk APOE4 carriers \[[24](/articles/10.1186/s13195-020-00663-w#ref-CR24 "Abushakra S, Porsteinsson A, Vellas B, Cummings J, Gauthier S, Hey JA, et al. Clinical benefits of tramiprosate in Alzheimer's disease are associated with higher number of APOE4 alleles: the “APOE4 gene-dose effect”. J Prev Alz Dis. 2016;3:219–28.
https://doi.org/10.14283/jpad.2016.115
.")\]. At the high dose, tramiprosate showed significant efficacy on both the ADAS-cog and CDR-SB co-primary outcomes in homozygous APOE4/4 subjects with mild AD \[[31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\]. In addition, a dose-dependent preservation of hippocampal volume was observed in the MRI sub-study \[[32](/articles/10.1186/s13195-020-00663-w#ref-CR32 "Gauthier S, Aisen PS, Ferris SH, Saumier D, Duong A, Haine A, et al. Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: exploratory analyses of the MRI sub-group of the Alphase study. J Nutr Health Aging. 2009;13:550–7.")\], further supporting a disease-modifying effect of ALZ-801/tramiprosate treatment.Safety results
The clearance of aggregated amyloid from brain vessels is associated with amyloid-related imaging abnormalities with edema (ARIA-E) or microhemorrhage (ARIA-H) and was first reported in trials with anti-amyloid antibodies [[33](/articles/10.1186/s13195-020-00663-w#ref-CR33 "Sperling R, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367–85. https://doi.org/10.1016/j.jalz.2011.05.2351
.")\]. The incidence of these events closely correlates with the clearance of cerebral amyloid on PET imaging and is summarized in Tables [1](/articles/10.1186/s13195-020-00663-w#Tab1) and [2](/articles/10.1186/s13195-020-00663-w#Tab2). At the doses used in phase 3 trials, aducanumab and gantenerumab reported ARIA-E rates of 30% or greater across all genotypes \[[19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego."), [20](/articles/10.1186/s13195-020-00663-w#ref-CR20 "Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
https://doi.org/10.1186/s13195-019-0559-z
.")\], while BAN2401 showed a lower rate of 10% \[[23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.")\], consistent with the lower affinity of BAN2401 for amyloid plaques \[[10](/articles/10.1186/s13195-020-00663-w#ref-CR10 "Lannfelt L, Söderberg L, Laudon H, Sahlin C, Johannesson M, Nygren P, et al. BAN2401 shows stronger binding to soluble aggregated amyloid-beta species than aducanumab. BioArctic poster presentation. Alzheimer’s Association International Conference: 14–18 July 2019; Los Angeles.")\]. The ARIA-E rates were higher in APOE4 carriers, 42% with aducanumab and 15% with BAN2401 \[[19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego."), [23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.")\]. Treatment with ALZ-801/tramiprosate did not cause any ARIA-E events in 426 AD subjects followed by serial MRIs, even in APOE4 carriers \[[31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\], suggesting a lack of interaction with amyloid plaque and vascular amyloid.Pharmacokinetic properties
The pharmacokinetic (PK) properties, their impact on target engagement of Aβ oligomers, and their translation into clinical benefit were analyzed for the four late-stage anti-amyloid agents. In addition to selectivity for neurotoxic soluble Aβ oligomers, an essential feature of an amyloid-targeted drug is its ability to cross the blood-brain barrier and to achieve sustained therapeutic brain concentrations at levels sufficient to persistently remove oligomers or inhibit their formation, even at trough levels between doses. The time to peak brain levels of a drug is approximately 5 times its plasma half-life (_t_1/2) or 5 times the dosing interval, if the dosing interval is longer than the _t_1/2. The key features of each product, including dose, route of administration, dosing regimen, and PK profile [[11](/articles/10.1186/s13195-020-00663-w#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6. https://doi.org/10.1038/nature19323
."), [14](/articles/10.1186/s13195-020-00663-w#ref-CR14 "Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswalk G, et al. Safety and tolerability of BAN2401 - a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016;8(1):14.
https://doi.org/10.1186/s13195-016-0181-2
."), [30](/articles/10.1186/s13195-020-00663-w#ref-CR30 "Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2018;57(3):315–33.
https://doi.org/10.1007/s40262-017-0608-3
."), [34](/articles/10.1186/s13195-020-00663-w#ref-CR34 "Portron A, Jordan P, Draper K, Muenzer C, Dickerson D, van Iersel T, et al. A phase 1 study to assess the effect of speed of injection on pain, tolerability, and pharmacokinetics after high-volume subcutaneous administration of gantenerumab in healthy volunteers. Clin Ther. 2020;42(1):108–20.
https://doi.org/10.1016/j.clinthera.2019.11.015
.")\], are summarized in Table [3](/articles/10.1186/s13195-020-00663-w#Tab3).Table 3 Late-stage anti-amyloid agents: phase 3 dosing regimens and pharmacokinetic profiles
The key differentiating PK feature of an anti-amyloid agent is the time to achieve steady state concentration in plasma, which allows it to cross the blood-brain barrier and engage and neutralize neurotoxic soluble Aβ oligomers. Due to the relatively long plasma _t_1/2 of aducanumab and gantenerumab [[11](/articles/10.1186/s13195-020-00663-w#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6. https://doi.org/10.1038/nature19323
."), [34](/articles/10.1186/s13195-020-00663-w#ref-CR34 "Portron A, Jordan P, Draper K, Muenzer C, Dickerson D, van Iersel T, et al. A phase 1 study to assess the effect of speed of injection on pain, tolerability, and pharmacokinetics after high-volume subcutaneous administration of gantenerumab in healthy volunteers. Clin Ther. 2020;42(1):108–20.
https://doi.org/10.1016/j.clinthera.2019.11.015
.")\], the time to peak brain levels at steady state, which is required for maximum efficacy, is approximately 5 months. Indeed, with the 6-month titration regimen for aducanumab in phase 3 trials, 10 months of continuous exposure to the highest 10 mg/kg monthly dose was necessary to achieve clinical efficacy \[[19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego.")\], which aligns well with the time to achieve sustained peak brain levels. BAN2401 is projected to achieve peak brain exposure in \~ 2.5 months, based on the 10 mg/kg twice monthly dosing selected for the ongoing phase 3 CLARITY AD trial \[[35](/articles/10.1186/s13195-020-00663-w#ref-CR35 "Lynch SY, Irizarry M, Dhadda S, Zhang Y, Wang J, Bogoslovsky T, et al. BAN2401 in early Alzheimer’s disease: a placebo-controlled, double-blind, parallel-group, 18-month study with an open-label extension phase to confirm safety and efficacy (Clarity AD). Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego.")\]. Considering that no titration period is included in the CLARITY AD trial, the onset of clinical efficacy may occur earlier with BAN2401 than aducanumab.Higher brain penetration of aducanumab versus BAN2401 does not appear to translate to better efficacy of aducanumab, suggesting that the superior selectivity for oligomers of BAN2401 is a key factor. In addition, the total dose of BAN2401 at the phase 2 and 3 dosing regimens is approximately double that of aducanumab, which may explain some of the efficacy differences. The relatively low brain penetration of anti-amyloid antibodies of less than 1.5% results in low steady state brain concentrations and, when combined with long _t_1/2 and dosing intervals, may contribute to variability in pharmacodynamic target engagement and clinical efficacy in individual patients. In contrast, oral ALZ-801 with a shorter plasma _t_1/2 and twice daily dosing reaches high steady state peak brain concentrations in ~ 1 week, facilitated by a robust 40% brain penetration [[30](/articles/10.1186/s13195-020-00663-w#ref-CR30 "Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2018;57(3):315–33. https://doi.org/10.1007/s40262-017-0608-3
.")\]. This PK profile of ALZ-801 assures that full inhibition of Aβ oligomer formation is achieved at the target clinical dose, and explains the earlier onset of clinical efficacy in AD patients treated with ALZ-801/tramiprosate compared to antibody treatments \[[31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\].Because the interdose interval of all late-stage antibody treatments is longer than the plasma _t_1/2, the peak steady state brain levels are lower than the maximal exposure that could be attained if the interdose interval was equal to or shorter than the _t_1/2. The sub-optimal dosing frequency of antibodies further lowers their steady state brain levels and increases the variability in pharmacodynamic target engagement and clinical efficacy, with patients who achieve lower steady state concentrations showing less efficacy.
The time to peak brain levels is an important factor for achieving optimal target engagement and, together with peak brain exposure, drives the clinical benefit. However, even after the peak brain exposure is attained, there is a lag period before the manifestation of maximum clinical benefit, which is dependent on the period of time needed to remove amyloid oligomers or substantially reduce their neurotoxicity [36]. This latency to clinical benefit may be further modified by an individual’s Aβ oligomer burden, APOE4 genotype, age, and disease stage. These factors, when combined with PK variability, can lead to an increase in variability in drug response. Consistent with how these factors interact to impact efficacy, aducanumab’s EMERGE phase 3 results showed the strongest clinical benefit and significance only at the highest dose of 10 mg/kg monthly IV infusion, and only after sufficient number of patients reached sustained peak exposure [19]. The 265 mg dose of ALZ-801 administered twice daily as an oral tablet achieved sustained brain exposures in AD patients that are 5-fold higher than the brain concentration required for full inhibition of formation of neurotoxic oligomers [[15](/articles/10.1186/s13195-020-00663-w#ref-CR15 "Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs. 2017;31(6):495–509. https://doi.org/10.1007/s40263-017-0434-z
."), [16](/articles/10.1186/s13195-020-00663-w#ref-CR16 "Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–61.
https://doi.org/10.1007/s40263-018-0554-0
.")\]. The sustained CSF drug levels at this dose explain the clinical efficacy observed in APOE4 carriers in the tramiprosate phase 3 trials \[[24](/articles/10.1186/s13195-020-00663-w#ref-CR24 "Abushakra S, Porsteinsson A, Vellas B, Cummings J, Gauthier S, Hey JA, et al. Clinical benefits of tramiprosate in Alzheimer's disease are associated with higher number of APOE4 alleles: the “APOE4 gene-dose effect”. J Prev Alz Dis. 2016;3:219–28.
https://doi.org/10.14283/jpad.2016.115
."), [31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\].For the four late-stage anti-amyloid agents, the rank order for the time to peak exposure and the onset of action is ALZ-801 < < BAN2401 < aducanumab ≈ gantenerumab, as highlighted in Table 3. In summary, PK properties have important implications for the onset of efficacy, time to maximum clinical benefit, and individual variability in clinical response. Given the relatively short time frame available to stabilize the rate of AD decline, and the importance of the perception of efficacy for patient compliance, these PK features are critical for the success of a treatment in a real-world setting.
Discussion
Major progress has been achieved in AD drug development, with several anti-amyloid agents recently reporting promising clinical and biomarker effects in late-stage trials. The three antibodies aducanumab, gantenerumab, and BAN2401, and the small molecule ALZ-801, have also shown acceptable long-term safety. Therefore, confirmation of their efficacy may lead to the approval and marketing of this first wave of disease-modifying treatments over the next 3 to 5 years.
Engagement of amyloid oligomers drives clinical and biomarker efficacy
A substantial body of evidence supports the role of Aβ oligomers as early triggers of AD pathology [[1](#ref-CR1 "Tolar M, Abushakra S, Sabbagh M. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement 2019;1–8. https://doi.org/10.1016/j.jalz.2019.09.075
."),[2](#ref-CR2 "Viola KL, Klein W. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129(2):183–206.
https://doi.org/10.1007/s00401-015-1386-3
."),[3](/articles/10.1186/s13195-020-00663-w#ref-CR3 "Selkoe DJ. A is for amyloid. J Prev Alz Dis. 2020;3(7):140–1.")\]. Brain levels of neurotoxic soluble Aβ oligomers, rather than plaques or fibrils, correlate closely with onset and progression of AD symptoms \[[6](/articles/10.1186/s13195-020-00663-w#ref-CR6 "Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman, et al. Amyloid-beta oligomerization in Alzheimer dementia vs. high pathology controls. Ann Neurol 2013;73(1):104–119. doi:
https://doi.org/10.1002/ana.23748
."), [8](/articles/10.1186/s13195-020-00663-w#ref-CR8 "Bilousova T, Miller CA, Poon WW, Vinters HV, Corrada M, Kawas C, et al. Synaptic amyloid-β oligomers precede p-tau and differentiate high pathology control cases. Am J Pathol. 2016;186:185–98.
https://doi.org/10.1016/j.ajpath.2015.09.018
."), [37](/articles/10.1186/s13195-020-00663-w#ref-CR37 "Sengupta U, Nilson N, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. E Bio Med. 2016;6:42–9.
https://doi.org/10.1016/j.ebiom.2016.03.035
.")\]. Aβ oligomers damage synapses, induce tau hyperphosphorylation and neuroinflammation, and impair memory formation in preclinical models, as well as brains of AD patients \[[8](/articles/10.1186/s13195-020-00663-w#ref-CR8 "Bilousova T, Miller CA, Poon WW, Vinters HV, Corrada M, Kawas C, et al. Synaptic amyloid-β oligomers precede p-tau and differentiate high pathology control cases. Am J Pathol. 2016;186:185–98.
https://doi.org/10.1016/j.ajpath.2015.09.018
."), [37](#ref-CR37 "Sengupta U, Nilson N, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. E Bio Med. 2016;6:42–9.
https://doi.org/10.1016/j.ebiom.2016.03.035
."),[38](#ref-CR38 "Chabrier MA, Blurton-Jones M, Agazaryan AA, Nerhus JL, Martinez-Coria H, LaFerla FM. Soluble Aβ promotes wild-type tau pathology in vivo. J Neurosci. 2012;32(48):17345–50.
https://doi.org/10.1523/JNEUROSCI.0172-12.2012
."),[39](/articles/10.1186/s13195-020-00663-w#ref-CR39 "Brkic M, Balusu S, Van EW, Gorlé N, Benilova I, Kremer A, et al. Amyloid oligomers disrupt blood–CSF barrier integrity by activating matrix metalloproteinases. J Neurosci. 2015;35(37):12766–78.
https://doi.org/10.1523/JNEUROSCI.0006-15.2015
.")\]. The most synaptotoxic species are the small oligomers, ranging from dimers to dodecamers, and pyroglutamate forms of Aβ oligomers \[[40](/articles/10.1186/s13195-020-00663-w#ref-CR40 "Thal DR, Walter J, Takaomi C. Saido TC, Fändrich M. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol 2015;129:167–182. doi:
https://doi.org/10.1007/s00401-014-1375-y
.")\]. Recent clinical trial results with aducanumab, BAN2401, and gantenerumab confirmed that agents that engage amyloid oligomers also reduce downstream tau pathology \[[13](/articles/10.1186/s13195-020-00663-w#ref-CR13 "Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95.
https://doi.org/10.1186/s13195-017-0318-y
."), [19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego."), [20](/articles/10.1186/s13195-020-00663-w#ref-CR20 "Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
https://doi.org/10.1186/s13195-019-0559-z
."), [22](/articles/10.1186/s13195-020-00663-w#ref-CR22 "Abi-Saab D, Andjelkovic M, Pross N, Delmar P, Voyle N, Klein G, et al. Update on the safety and tolerability of gantenerumab in the ongoing open-label extension (OLE) of the Marguerite Road study in patients with mild AD after approximately 2 years of study duration. Alzheimers Dement. 2018;14(7):241.
https://doi.org/10.1016/j.jalz.2018.06.2381
."), [23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona."), [27](/articles/10.1186/s13195-020-00663-w#ref-CR27 "Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU next generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8–19.
https://doi.org/10.1016/j.jalz.2016.07.005
.")\] and cognitive decline \[[19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego."), [23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.")\].The four late-stage anti-amyloid agents with clinical efficacy and biomarker effects include three injectable antibodies and the oral small molecule, ALZ-801. The common characteristic shared by these agents is their ability to target neurotoxic soluble Aβ oligomers [[2](/articles/10.1186/s13195-020-00663-w#ref-CR2 "Viola KL, Klein W. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129(2):183–206. https://doi.org/10.1007/s00401-015-1386-3
."), [3](/articles/10.1186/s13195-020-00663-w#ref-CR3 "Selkoe DJ. A is for amyloid. J Prev Alz Dis. 2020;3(7):140–1.")\]. Aducanumab and gantenerumab preferentially target insoluble amyloid plaques and fibrils and engage oligomers only partially \[[11](/articles/10.1186/s13195-020-00663-w#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6.
https://doi.org/10.1038/nature19323
."), [12](/articles/10.1186/s13195-020-00663-w#ref-CR12 "Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28(1):49–69.")\], while BAN2401 preferentially targets oligomers over plaques \[[10](/articles/10.1186/s13195-020-00663-w#ref-CR10 "Lannfelt L, Söderberg L, Laudon H, Sahlin C, Johannesson M, Nygren P, et al. BAN2401 shows stronger binding to soluble aggregated amyloid-beta species than aducanumab. BioArctic poster presentation. Alzheimer’s Association International Conference: 14–18 July 2019; Los Angeles.")\], and ALZ-801 selectively blocks the formation of Aβ oligomers without binding amyloid plaque \[[15](#ref-CR15 "Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs. 2017;31(6):495–509.
https://doi.org/10.1007/s40263-017-0434-z
."),[16](#ref-CR16 "Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–61.
https://doi.org/10.1007/s40263-018-0554-0
."),[17](/articles/10.1186/s13195-020-00663-w#ref-CR17 "Liang C, Savinov SN, Fejzo J, Eyles SJ, Chen J. Modulation of amyloid-β42 conformation by small molecules through nonspecific binding. J Chem Theory Comput. 2019;15(10):5169–74.
https://doi.org/10.1021/acs.jctc.9b00599
.")\].The degree of Aβ oligomer selectivity appears to be a key factor that together with PK properties determines the clinical profile of each anti-amyloid agent. Both aducanumab phase 3 data and BAN2401 phase 2 data showed significant effects on cognition and function [19, 23], and the degree of benefit parallels their respective selectivity for soluble oligomers versus insoluble amyloid plaques (Table 1), with BAN2401 delivering larger clinical benefits likely due to better selectivity for oligomers. Gantenerumab did not show clinical efficacy in the SCarlet RoAD or Marguerite RoAD phase 3 trials [[13](/articles/10.1186/s13195-020-00663-w#ref-CR13 "Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95. https://doi.org/10.1186/s13195-017-0318-y
."), [20](/articles/10.1186/s13195-020-00663-w#ref-CR20 "Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
https://doi.org/10.1186/s13195-019-0559-z
."), [22](/articles/10.1186/s13195-020-00663-w#ref-CR22 "Abi-Saab D, Andjelkovic M, Pross N, Delmar P, Voyle N, Klein G, et al. Update on the safety and tolerability of gantenerumab in the ongoing open-label extension (OLE) of the Marguerite Road study in patients with mild AD after approximately 2 years of study duration. Alzheimers Dement. 2018;14(7):241.
https://doi.org/10.1016/j.jalz.2018.06.2381
.")\] and is currently being evaluated in two additional GRADUATE phase 3 trials in early AD to assess the high dose of 1020 mg SC injection administered monthly. Gantenerumab also recently failed on clinical endpoints in the DIAN-TU study in familial AD, potentially due to the small sample size, the mix of presymptomatic and symptomatic subjects, and the late introduction of the higher gantenerumab dose, where only 37% of the subjects received the high dose of 1200 mg monthly SC injections \[[21](/articles/10.1186/s13195-020-00663-w#ref-CR21 "Bateman RJ. DIAN-TU-001 topline study results. Presentation at AAT-AD/PD Focus Meeting: 2 April 2020.")\]. ALZ-801 which selectively blocks the formation of Aβ oligomers showed significant, clinically meaningful effects on cognition and function in APOE4/4 homozygotes \[[31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\], which were similar in magnitude to BAN2401 benefits in APOE4 carriers \[[23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.")\]. One explanation for the higher efficacy of these agents in APOE4 carriers versus noncarriers is their several-fold higher burden of soluble Aβ oligomers \[[41](/articles/10.1186/s13195-020-00663-w#ref-CR41 "Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid peptide. J Neurosci. 2012;32(43):15181–92.
https://doi.org/10.1523/JNEUROSCI.1542-12.2012
.")\].In remarkable contrast to the association between the level of engagement of soluble Aβ oligomers and clinical efficacy, no such association has been reported for the clearance of insoluble amyloid plaques and clinical efficacy. Aducanumab and BAN2401 showed compelling dose-dependent lowering of amyloid plaques in phase 3 and 2 trials [[11](/articles/10.1186/s13195-020-00663-w#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6. https://doi.org/10.1038/nature19323
."), [19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego."), [23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.")\], with several doses robustly clearing plaque on amyloid PET imaging, yet only long exposures to the highest doses of aducanumab and BAN2401 resulted in significant efficacy, suggesting that prolonged engagement of Aβ oligomers at the highest doses is necessary for clinical benefit. Therefore, plaque clearance alone does not explain clinical efficacy, and amyloid plaque formation may be a protective mechanism by which soluble oligomers are sequestered to limit their neurotoxicity \[[42](/articles/10.1186/s13195-020-00663-w#ref-CR42 "Gaspar RC, Villarreal SA, Bowles N, Hepler RW, Joyce JG, Shugrue P. Oligomers of β-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model. Exp Neurol. 2010;223(2):394–400.")\]. In line with this hypothesis, the anti-amyloid antibody bapineuzumab and other agents that target primarily amyloid plaques and fibrils failed to show efficacy \[[43](/articles/10.1186/s13195-020-00663-w#ref-CR43 "Salloway S, Sperling R, Fox N, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33.
https://doi.org/10.1056/NEJMoa1304839
.")\]. Agents that target amyloid monomers, such as the anti-amyloid antibody solanezumab, failed in multiple phase 3 trials \[[29](/articles/10.1186/s13195-020-00663-w#ref-CR29 "Honig L, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321–30.
https://doi.org/10.1056/NEJMoa1705971
.")\], or even caused cognitive worsening as observed in phase 3 trials of several beta secretase inhibitors that inhibit the formation of monomers.All three anti-amyloid antibodies reduced CSF p-tau, the biomarker which best correlates with tau pathology and cognitive decline. While the effective levels of antibodies achieved in the brain and their specificity for amyloid oligomers were predictive of cognitive benefit, this was not the case for CSF p-tau. Although gantenerumab in the DIAN-TU study showed larger p-tau effects than aducanumab and BAN2401 (31% versus 13–15%), it failed to show efficacy on clinical endpoints in the DIAN-TU study or other trials. In addition to CSF p-tau, aducanumab also showed effects on tau PET imaging in the EMERGE trial [19]. Both BAN2401 and gantenerumab phase 2 data showed significant effects on CSF NfL [[13](/articles/10.1186/s13195-020-00663-w#ref-CR13 "Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95. https://doi.org/10.1186/s13195-017-0318-y
."), [23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona."), [27](/articles/10.1186/s13195-020-00663-w#ref-CR27 "Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU next generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8–19.
https://doi.org/10.1016/j.jalz.2016.07.005
.")\], and gantenerumab also showed consistent effects on t-tau. Both NfL and t-tau are considered downstream biomarkers of neuronal injury \[[44](/articles/10.1186/s13195-020-00663-w#ref-CR44 "Olsson B, Portelius E, Cullen NC, Sendelius E, Zetterberg H, Andreasson U, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders. JAMA Neurol. 2019;76(3):318–25.
https://doi.org/10.1001/jamaneurol.2018.3746
."), [45](/articles/10.1186/s13195-020-00663-w#ref-CR45 "Blennow K, Shaw LM, Stomrud E, Mattsson N, Toledo JB, Buck K, et al. Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel elecsys Aβ(1–42), p-Tau and t-Tau CSF immunoassays. Sci Rep. 2019;9(1):19024.
https://doi.org/10.1038/s41598-019-54204-z
.")\]. The consistency of amyloid antibody effects on CSF p-tau, t-tau, and NfL supports the important role of these biomarkers in future AD trials.Hippocampal atrophy assessed by volumetric MRI measurements is considered the most reliable structural biomarker of AD progression as noted in the recent draft guidances from both the US Food and Drug Administration (FDA) and European Medicines Agency. Tramiprosate, in the MRI sub-study of a phase 3 trial, showed a dose-dependent decrease in hippocampal atrophy [32], providing the only evidence to date of a significant drug effect on preventing brain atrophy. The effects of ALZ-801 on fluid biomarkers and volumetric MRI measures will be evaluated in a phase 2 study in APOE4 carriers with early AD, as well as a phase 3 trial in APOE4/4 homozygotes with early AD.
The consistency of clinical and biomarker effects of these four anti-amyloid agents provides robust evidence for the role of Aβ oligomers as upstream initiator of AD pathogenesis that triggers tau pathology, neurodegeneration, and resultant cognitive impairment (Table 1). The recent development of sensitive plasma assays for p-tau and NfL applied across the clinical AD continuum provides additional support for the early, initiating role of Aβ in AD pathogenesis and will further facilitate the use of fluid biomarkers in clinical trials [[46](#ref-CR46 "Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer’s disease. JAMA Neurol. 2019;76(7):791–9. https://doi.org/10.1001/jamaneurol.2019.0765
."),[47](#ref-CR47 "Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE, et al. Plasma p-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26(3):379–86.
https://doi.org/10.1038/s41591-020-0755-1
."),[48](/articles/10.1186/s13195-020-00663-w#ref-CR48 "Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, et al. Blood phosphorylated tau181 as a biomarker in Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422–33.
https://doi.org/10.1016/S1474-4422(20)30071-5
.")\].Differences in oligomer selectivity and pharmacokinetic properties determine safety profiles
The selectivity for Aβ oligomers and the individual PK properties underlie the different safety profiles of the anti-amyloid agents, namely the risk of brain edema, ARIA-E, and microhemorrhage, ARIA-H (Tables 1 and 2). The risk of ARIA-E is especially important in APOE4 carriers who carry a higher burden of vascular amyloid. The high ARIA-E rates of aducanumab (35%) and gantenerumab (28–42%), and the lower rate of BAN2401 (10%) in the overall population, parallel their affinity for amyloid plaque binding, and the degree of selectivity for soluble oligomers versus insoluble plaques. ALZ-801/tramiprosate, which does not bind amyloid plaque, has not been associated with events of ARIA-E. The other common adverse events reported with these agents include headache in 20% of patients treated with aducanumab, infusion-related reactions leading to discontinuations in 2.5% of patients treated with BAN2401, and injection site erythema reported in 13% of patients treated with gantenerumab. In the tramiprosate trials, mild to moderate nausea was reported in 20% of patients and vomiting occurred in 14% of patients. The incidence and severity of nausea and vomiting were reduced ~ 50% by the optimized ALZ-801 formulation. In addition to the convenience of oral dosing, the absence of ARIA-E highlights the value of selective oral small molecules that can inhibit the formation or block the effects of Aβ oligomers, without causing activation of immune-mediated plaque clearance and brain edema.
Benefit-risk profiles of anti-amyloid agents in APOE4 carriers
APOE4 carriers, who are at higher risk of early AD progression and constitute ~ 65% of AD patients, provide an optimal group for clinical efficacy studies and initial approval for drugs targeting neurotoxic soluble Aβ oligomers, since these patients carry a several-fold higher burden of Aβ oligomers compared to noncarriers [[41](/articles/10.1186/s13195-020-00663-w#ref-CR41 "Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid peptide. J Neurosci. 2012;32(43):15181–92. https://doi.org/10.1523/JNEUROSCI.1542-12.2012
.")\]. APOE4 carriers also have higher levels of insoluble amyloid deposits in brain vessels, which increases their risk of ARIA-E and ARIA-H when treated with anti-amyloid antibodies \[[33](/articles/10.1186/s13195-020-00663-w#ref-CR33 "Sperling R, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367–85.
https://doi.org/10.1016/j.jalz.2011.05.2351
.")\]. Therefore, careful evaluation of efficacy and safety of anti-amyloid agents in APOE4 carriers is important to determine the benefit-risk profile in this large subgroup of AD patients with increased risk and earlier onset of the disease. Due to the rapid removal of amyloid plaque deposits from brain vessels, treatment with antibodies aducanumab, gantenerumab, and BAN2401 is associated with a substantial risk of ARIA-E in APOE4 carriers. While the efficacy of aducanumab in APOE4 carriers has not yet been disclosed, the incidence of ARIA-E in APOE4 carriers was \~ 42% in this group versus \~ 35% in the overall population \[[11](/articles/10.1186/s13195-020-00663-w#ref-CR11 "Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6.
https://doi.org/10.1038/nature19323
."), [19](/articles/10.1186/s13195-020-00663-w#ref-CR19 "Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego.")\]. BAN2401 showed more robust clinical efficacy in APOE4 carriers \[[23](/articles/10.1186/s13195-020-00663-w#ref-CR23 "Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.")\]; however, this was associated with a higher incidence of ARIA-E of \~ 15% versus 10% in the overall study population. In APOE4/4 homozygotes, ALZ-801/tramiprosate showed substantial cognitive and functional benefits with no events of ARIA-E \[[31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\] and may offer an optimal benefit-risk profile in APOE4 carriers.The next generation of selective anti-oligomer agents
The next generation of anti-oligomer therapeutics with improved selectivity and product profiles includes the following agents and mechanisms: (1) PMN310, an anti-amyloid antibody that selectively clears formed Aβ oligomers; (2) CT1812, a small molecule that inhibits Aβ oligomer binding to specific neuronal receptors that mediate neurotoxicity; and (3) PQ912 and ALZ-801, small molecules that prevent the formation of neurotoxic soluble Aβ oligomers. An example of an antibody designed to be highly selective to Aβ oligomers is PMN310 from ProMIS Neuroscience [[49](/articles/10.1186/s13195-020-00663-w#ref-CR49 "Gibbs E, Silverman JM, Zhao B, Peng X, Wang J, Wellington CL, et al. A rationally designed humanized antibody selective for amyloid beta oligomers in Alzheimer’s disease. Sci Rep. 2019;9(1):9870. https://doi.org/10.1038/s41598-019-46306-5
.")\], which is in preclinical development. CT1812 is an oral small molecule from Cognition Therapeutics that inhibits the binding of Aβ oligomers to sigma-2 receptors \[[50](/articles/10.1186/s13195-020-00663-w#ref-CR50 "Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014;9(11):e111899.
https://doi.org/10.1371/journal.pone.0111899
.")\], which is thought to mediate some of the oligomer-induced synaptic toxicity. CT1812 is currently being tested in phase 2 studies. PQ912 is an oral small molecule inhibitor of glutaminyl cyclase from Vivoryon Therapeutics that inhibits the formation of pyroglutamate forms of Aβ oligomers, which are thought to be highly toxic to synapses. In a small phase 2 study of 12-week duration, PQ912 showed promising effects on a biomarker of neuroinflammation in CSF \[[51](/articles/10.1186/s13195-020-00663-w#ref-CR51 "Scheltens P, Hallikainen M, Grimmer T, Duning T, Gouw AA, Teunissen CE, et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther. 2018;10(1):107.
https://doi.org/10.1186/s13195-018-0431-6
.")\].ALZ-801 is an oral agent, which efficiently crosses the blood-brain barrier, selectively interacts with Aβ monomers to inhibit misfolding, and blocks the formation of neurotoxic soluble Aβ oligomers in a dose-dependent manner, without affecting insoluble amyloid plaques or fibrils [[15](#ref-CR15 "Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs. 2017;31(6):495–509. https://doi.org/10.1007/s40263-017-0434-z
."),[16](#ref-CR16 "Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–61.
https://doi.org/10.1007/s40263-018-0554-0
."),[17](#ref-CR17 "Liang C, Savinov SN, Fejzo J, Eyles SJ, Chen J. Modulation of amyloid-β42 conformation by small molecules through nonspecific binding. J Chem Theory Comput. 2019;15(10):5169–74.
https://doi.org/10.1021/acs.jctc.9b00599
."),[18](/articles/10.1186/s13195-020-00663-w#ref-CR18 "Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, et al. Targeting soluble Abeta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007;28(4):537–47.
https://doi.org/10.1016/j.neurobiolaging.2006.02.015
.")\]. ALZ-801 is a prodrug of tramiprosate with improved gastrointestinal absorption and tolerability, which achieved excellent brain penetration of \~ 40%, with low intersubject variability in over 130 elderly volunteers and AD patients \[[30](/articles/10.1186/s13195-020-00663-w#ref-CR30 "Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2018;57(3):315–33.
https://doi.org/10.1007/s40262-017-0608-3
.")\]. ALZ-801 is ready to enter phase 3 based on a large body of clinical data in AD patients, including (1) favorable safety profile from tramiprosate safety database of > 2000 AD patients treated for 18 months \[[24](/articles/10.1186/s13195-020-00663-w#ref-CR24 "Abushakra S, Porsteinsson A, Vellas B, Cummings J, Gauthier S, Hey JA, et al. Clinical benefits of tramiprosate in Alzheimer's disease are associated with higher number of APOE4 alleles: the “APOE4 gene-dose effect”. J Prev Alz Dis. 2016;3:219–28.
https://doi.org/10.14283/jpad.2016.115
."), [31](/articles/10.1186/s13195-020-00663-w#ref-CR31 "Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56.
https://doi.org/10.14283/jpad.2017.26
.")\]; (2) well-defined target clinical dose that fully blocks the formation of Aβ oligomers in the brain based on clinical data from the phase 3 AD trials and from an in vitro Aβ oligomer inhibition assay \[[15](/articles/10.1186/s13195-020-00663-w#ref-CR15 "Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs. 2017;31(6):495–509.
https://doi.org/10.1007/s40263-017-0434-z
."), [30](/articles/10.1186/s13195-020-00663-w#ref-CR30 "Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2018;57(3):315–33.
https://doi.org/10.1007/s40262-017-0608-3
.")\]; and (3) precision medicine approach initially focusing on high-risk homozygous APOE4/4 patients with early AD \[[1](/articles/10.1186/s13195-020-00663-w#ref-CR1 "Tolar M, Abushakra S, Sabbagh M. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement 2019;1–8.
https://doi.org/10.1016/j.jalz.2019.09.075
.")\]. Oral ALZ-801 provides convenient at-home dosing for elderly patients and their caregivers, as well as potential preventive treatment of presymptomatic subjects with high risk for AD.Conclusions
Substantial clinical and biomarker data from late-stage anti-amyloid programs signals a promising new era for AD drug development and provides compelling evidence for the prominent role of neurotoxic soluble amyloid oligomers in the pathogenesis of AD and as therapeutic targets. Considering the pressing need, regulators have shown increasing engagement with drug developers and potential flexibility with respect to conditions and criteria for drug approval. A recent draft guidance from the US FDA on demonstrating substantial evidence of effectiveness [[52](/articles/10.1186/s13195-020-00663-w#ref-CR52 "U.S. Department of Health and Human Services, Food and Drug Administration. Draft guidance for industry: demonstrating substantial evidence of effectiveness for human drug and biological products. December 2019. [ https://www.fda.gov/media/133660/download
] Accessed on 14 Feb 2020.")\] seems to allow more flexibility in the evidentiary standards of efficacy. This may pave the way for the approval of these AD drugs in the near future.This progress also presents an opportunity to build upon the recent data and to develop therapeutics with superior efficacy, safety, and convenience. The benefit-risk profiles of future agents, in particular, the magnitude of clinical benefit and ease of administration, will be key differentiators for patients and their families, physicians, and payers.
Availability of data and materials
Not applicable
Abbreviations
Aβ:
Beta amyloid
AD:
Alzheimer’s disease
ADAS-cog:
Alzheimer’s Disease Assessment Scale—cognitive subscale
ADCOMS:
Alzheimer’s Disease Composite Score
APOE:
Apolipoprotein E
ARIA-E:
Amyloid-related imaging abnormalities with effusion or edema
ARIA-H:
Amyloid-related imaging abnormalities with hemosiderin deposits
CDR-SB:
Clinical Dementia Rating—Sum of Boxes
CSF:
Cerebrospinal fluid
DIAN-TU:
Dominantly Inherited Alzheimer’s Network Trials Unit
FDA:
Food and Drug Administration
IgG:
Immunoglobulin G
IV:
Intravenous
MOA:
Mechanism of action
MRI:
Magnetic resonance imaging
NfL:
Neurofilament light chain
PET:
Positron emission tomography
PK:
Pharmacokinetic
p-tau:
Phosphorylated tau
SC:
Subcutaneous
t 1/2 :
Half-life
t-tau:
Total tau
References
- Tolar M, Abushakra S, Sabbagh M. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement 2019;1–8. https://doi.org/10.1016/j.jalz.2019.09.075.
- Viola KL, Klein W. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129(2):183–206. https://doi.org/10.1007/s00401-015-1386-3.
Article CAS PubMed PubMed Central Google Scholar - Selkoe DJ. A is for amyloid. J Prev Alz Dis. 2020;3(7):140–1.
Google Scholar - Hong W, Wang Z, Liu W, O’Malley TT, Jin M, Willem M, et al. Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain. Acta Neuropathol. 2018;136(1):19–40. https://doi.org/10.1007/s00401-018-1846-7.
Article CAS PubMed PubMed Central Google Scholar - Gaspar RC, Villarreal SA, Bowles N, Hepler RW, Joyce JG, Shugrue P. Oligomers of beta-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model. Exp Neurol. 2010;223(2):394–400. https://doi.org/10.1016/j.expneurol.2009.09.001.
Article CAS PubMed Google Scholar - Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman, et al. Amyloid-beta oligomerization in Alzheimer dementia vs. high pathology controls. Ann Neurol 2013;73(1):104–119. doi: https://doi.org/10.1002/ana.23748.
- Yang T, Li S, Xu H, Walsh DM, Selkoe DJ. Large soluble oligomers of amyloid-protein from Alzheimer’s brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci. 2017;37(1):152–63. https://doi.org/10.1523/JNEUROSCI.1698-16.2016.
Article CAS PubMed PubMed Central Google Scholar - Bilousova T, Miller CA, Poon WW, Vinters HV, Corrada M, Kawas C, et al. Synaptic amyloid-β oligomers precede p-tau and differentiate high pathology control cases. Am J Pathol. 2016;186:185–98. https://doi.org/10.1016/j.ajpath.2015.09.018.
Article CAS PubMed PubMed Central Google Scholar - Hanseeuw BJ, Betensky RA, Jacobs H, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76(8):915–24. https://doi.org/10.1001/jamaneurol.2019.1424.
Article PubMed Central PubMed Google Scholar - Lannfelt L, Söderberg L, Laudon H, Sahlin C, Johannesson M, Nygren P, et al. BAN2401 shows stronger binding to soluble aggregated amyloid-beta species than aducanumab. BioArctic poster presentation. Alzheimer’s Association International Conference: 14–18 July 2019; Los Angeles.
- Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–6. https://doi.org/10.1038/nature19323.
Article CAS PubMed Google Scholar - Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28(1):49–69.
Article CAS PubMed Google Scholar - Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95. https://doi.org/10.1186/s13195-017-0318-y.
Article CAS PubMed PubMed Central Google Scholar - Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswalk G, et al. Safety and tolerability of BAN2401 - a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016;8(1):14. https://doi.org/10.1186/s13195-016-0181-2.
Article CAS PubMed PubMed Central Google Scholar - Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs. 2017;31(6):495–509. https://doi.org/10.1007/s40263-017-0434-z.
Article CAS PubMed PubMed Central Google Scholar - Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs. 2018;32(9):849–61. https://doi.org/10.1007/s40263-018-0554-0.
Article CAS PubMed PubMed Central Google Scholar - Liang C, Savinov SN, Fejzo J, Eyles SJ, Chen J. Modulation of amyloid-β42 conformation by small molecules through nonspecific binding. J Chem Theory Comput. 2019;15(10):5169–74. https://doi.org/10.1021/acs.jctc.9b00599.
Article CAS PubMed PubMed Central Google Scholar - Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, et al. Targeting soluble Abeta peptide with tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007;28(4):537–47. https://doi.org/10.1016/j.neurobiolaging.2006.02.015.
Article CAS PubMed Google Scholar - Budd-Haeberlein S, Von Hein C, Tian Y, Chalkias S, Muralidharan KK, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego.
- Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101. https://doi.org/10.1186/s13195-019-0559-z.
Article CAS PubMed PubMed Central Google Scholar - Bateman RJ. DIAN-TU-001 topline study results. Presentation at AAT-AD/PD Focus Meeting: 2 April 2020.
- Abi-Saab D, Andjelkovic M, Pross N, Delmar P, Voyle N, Klein G, et al. Update on the safety and tolerability of gantenerumab in the ongoing open-label extension (OLE) of the Marguerite Road study in patients with mild AD after approximately 2 years of study duration. Alzheimers Dement. 2018;14(7):241. https://doi.org/10.1016/j.jalz.2018.06.2381.
Article Google Scholar - Swanson CJ, Zhang Y, Dhadda S, Wang J, Koyama A, Kaplow J, et al. Clinical and biomarker updates from BAN2401 Study 201 in early AD. Clinical Trials on Alzheimer’s Disease Conference: 24–27 October 2018; Barcelona.
- Abushakra S, Porsteinsson A, Vellas B, Cummings J, Gauthier S, Hey JA, et al. Clinical benefits of tramiprosate in Alzheimer's disease are associated with higher number of APOE4 alleles: the “APOE4 gene-dose effect”. J Prev Alz Dis. 2016;3:219–28. https://doi.org/10.14283/jpad.2016.115.
Article CAS Google Scholar - Swanson C, Zhang Y, Dhadda S, Wang J, Kaplow J, Bradley H, et al. The GAP study of BAN2401 study 201 in early AD. Persistence of BAN2401-mediated amyloid reductions post-treatment: a preliminary comparison of amyloid status between the core phase of BAN2401-g000-201 and baseline of the open-label extension phase in subjects with early Alzheimer’s disease. Clinical Trials on Alzheimer’s Disease conference: 4–7 December 2019; San Diego.
- Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry. 2016;87(9):993–9.
Article PubMed Google Scholar - Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU next generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 2017;13(1):8–19. https://doi.org/10.1016/j.jalz.2016.07.005.
Article PubMed Google Scholar - Willis BA, Sundell K, Lachno DR, Ferguson-Sells L, Case MG, Holdridge K, et al. Central pharmacodynamic activity of solanezumab in mild Alzheimer’s disease dementia. Alzheimers Dement. 2018;4:652–60. https://doi.org/10.1016/j.trci.2018.10.001.
Article Google Scholar - Honig L, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321–30. https://doi.org/10.1056/NEJMoa1705971.
Article CAS PubMed Google Scholar - Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet. 2018;57(3):315–33. https://doi.org/10.1007/s40262-017-0608-3.
Article CAS PubMed Google Scholar - Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alz Dis. 2017;4:149–56. https://doi.org/10.14283/jpad.2017.26.
Article CAS Google Scholar - Gauthier S, Aisen PS, Ferris SH, Saumier D, Duong A, Haine A, et al. Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: exploratory analyses of the MRI sub-group of the Alphase study. J Nutr Health Aging. 2009;13:550–7.
Article CAS PubMed Google Scholar - Sperling R, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367–85. https://doi.org/10.1016/j.jalz.2011.05.2351.
Article PubMed PubMed Central Google Scholar - Portron A, Jordan P, Draper K, Muenzer C, Dickerson D, van Iersel T, et al. A phase 1 study to assess the effect of speed of injection on pain, tolerability, and pharmacokinetics after high-volume subcutaneous administration of gantenerumab in healthy volunteers. Clin Ther. 2020;42(1):108–20. https://doi.org/10.1016/j.clinthera.2019.11.015.
Article CAS PubMed Google Scholar - Lynch SY, Irizarry M, Dhadda S, Zhang Y, Wang J, Bogoslovsky T, et al. BAN2401 in early Alzheimer’s disease: a placebo-controlled, double-blind, parallel-group, 18-month study with an open-label extension phase to confirm safety and efficacy (Clarity AD). Clinical Trials on Alzheimer’s Disease Conference: 4–7 December 2019; San Diego.
- Sharma A, Jusko W. Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. Br J Clin Pharmacol. 1998;45(3):229–39.
Article CAS PubMed PubMed Central Google Scholar - Sengupta U, Nilson N, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. E Bio Med. 2016;6:42–9. https://doi.org/10.1016/j.ebiom.2016.03.035.
Article Google Scholar - Chabrier MA, Blurton-Jones M, Agazaryan AA, Nerhus JL, Martinez-Coria H, LaFerla FM. Soluble Aβ promotes wild-type tau pathology in vivo. J Neurosci. 2012;32(48):17345–50. https://doi.org/10.1523/JNEUROSCI.0172-12.2012.
Article CAS PubMed PubMed Central Google Scholar - Brkic M, Balusu S, Van EW, Gorlé N, Benilova I, Kremer A, et al. Amyloid oligomers disrupt blood–CSF barrier integrity by activating matrix metalloproteinases. J Neurosci. 2015;35(37):12766–78. https://doi.org/10.1523/JNEUROSCI.0006-15.2015.
Article CAS PubMed PubMed Central Google Scholar - Thal DR, Walter J, Takaomi C. Saido TC, Fändrich M. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol 2015;129:167–182. doi: https://doi.org/10.1007/s00401-014-1375-y.
- Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid peptide. J Neurosci. 2012;32(43):15181–92. https://doi.org/10.1523/JNEUROSCI.1542-12.2012.
Article CAS PubMed PubMed Central Google Scholar - Gaspar RC, Villarreal SA, Bowles N, Hepler RW, Joyce JG, Shugrue P. Oligomers of β-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model. Exp Neurol. 2010;223(2):394–400.
Article CAS PubMed Google Scholar - Salloway S, Sperling R, Fox N, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33. https://doi.org/10.1056/NEJMoa1304839.
Article CAS PubMed PubMed Central Google Scholar - Olsson B, Portelius E, Cullen NC, Sendelius E, Zetterberg H, Andreasson U, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders. JAMA Neurol. 2019;76(3):318–25. https://doi.org/10.1001/jamaneurol.2018.3746.
Article PubMed Google Scholar - Blennow K, Shaw LM, Stomrud E, Mattsson N, Toledo JB, Buck K, et al. Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel elecsys Aβ(1–42), p-Tau and t-Tau CSF immunoassays. Sci Rep. 2019;9(1):19024. https://doi.org/10.1038/s41598-019-54204-z.
Article CAS PubMed PubMed Central Google Scholar - Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer’s disease. JAMA Neurol. 2019;76(7):791–9. https://doi.org/10.1001/jamaneurol.2019.0765.
Article PubMed PubMed Central Google Scholar - Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE, et al. Plasma p-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26(3):379–86. https://doi.org/10.1038/s41591-020-0755-1.
Article CAS PubMed Google Scholar - Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, et al. Blood phosphorylated tau181 as a biomarker in Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422–33. https://doi.org/10.1016/S1474-4422(20)30071-5.
Article CAS PubMed Google Scholar - Gibbs E, Silverman JM, Zhao B, Peng X, Wang J, Wellington CL, et al. A rationally designed humanized antibody selective for amyloid beta oligomers in Alzheimer’s disease. Sci Rep. 2019;9(1):9870. https://doi.org/10.1038/s41598-019-46306-5.
Article CAS PubMed PubMed Central Google Scholar - Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014;9(11):e111899. https://doi.org/10.1371/journal.pone.0111899.
Article CAS PubMed PubMed Central Google Scholar - Scheltens P, Hallikainen M, Grimmer T, Duning T, Gouw AA, Teunissen CE, et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther. 2018;10(1):107. https://doi.org/10.1186/s13195-018-0431-6.
Article CAS PubMed PubMed Central Google Scholar - U.S. Department of Health and Human Services, Food and Drug Administration. Draft guidance for industry: demonstrating substantial evidence of effectiveness for human drug and biological products. December 2019. [https://www.fda.gov/media/133660/download] Accessed on 14 Feb 2020.
Acknowledgements
Not applicable
Funding
Supported by Alzheon, Inc., NIH COBRE 5P20GM109025, NIH R01 AG059008, and the Keep Memory Alive Foundation (Dr. Sabbagh).
Author information
Authors and Affiliations
- Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA
Martin Tolar, Susan Abushakra & John A. Hey - University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Anton Porsteinsson - Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA
Marwan Sabbagh
Authors
- Martin Tolar
You can also search for this author inPubMed Google Scholar - Susan Abushakra
You can also search for this author inPubMed Google Scholar - John A. Hey
You can also search for this author inPubMed Google Scholar - Anton Porsteinsson
You can also search for this author inPubMed Google Scholar - Marwan Sabbagh
You can also search for this author inPubMed Google Scholar
Contributions
The authors read and approved the final manuscript.
Corresponding author
Correspondence toMartin Tolar.
Ethics declarations
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
Dr. Martin Tolar serves as the Founder, President, and Chief Executive Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc.
Dr. Susan Abushakra serves as the Chief Medical Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc.
Dr. John A. Hey serves as the Chief Scientific Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc.
Dr. Anton Porsteinsson receives research support from the National Institutes of Health and U.S. Department of Defense. He also receives grants from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, Janssen, Novartis, Merck, and Toyama. He receives personal fees from Acadia Pharmaceuticals, Avanir, BioXcel, Eisai, Functional Neuromodulation, Grifols, Lundbeck, Merck, Neurim Pharmaceuticals, Pfizer, Tetra Discovery Partners, and Toyama.
Dr. Marwan Sabbagh receives research support from the NIH and the Keep Memory Alive Foundation. He has consulting agreements with Allergan, Biogen, Bracket, Cortexyme, Grifols, Sanofi, Neurotrope, and Roche-Genentech. He has ownership interest in Brain Health Inc., Versanum Inc., Neurotrope Inc., and uMethod Health.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supported by Alzheon, Inc., NIH COBRE 5P20GM109025, NIH R01 AG059008, and the Keep Memory Alive Foundation (Dr. Sabbagh).
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Tolar, M., Abushakra, S., Hey, J.A. et al. Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval.Alz Res Therapy 12, 95 (2020). https://doi.org/10.1186/s13195-020-00663-w
- Received: 26 February 2020
- Accepted: 30 July 2020
- Published: 12 August 2020
- DOI: https://doi.org/10.1186/s13195-020-00663-w