E. Siemers1, P.S. Aisen2, M.C. Carrillo3
1. Siemers Integration LLC, Zionsville, IN, USA; 2. Alzheimer’s Therapeutic Research Center, University of Southern California, San Diego, CA, USA; 3. Alzheimer’s Association, Chicago, IL, USA
Corresponding Author: E. Siemers, Siemers Integration LLC, Zionsville, IN, USA, email@example.com
J Prev Alz Dis 2021;
Published online September 17, 2021, http://dx.doi.org/10.14283/jpad.2021.54
Very recently, the Food and Drug Administration (FDA) in the United States gave an “accelerated approval” to aducanumab, the first new drug to be available to patients with Alzheimer’s disease (AD) in nearly two decades and the first ever that targets the underlying neuropathology. The accelerated approval pathway is based on a biomarker effect, in this case reduction in brain amyloid as measured by PET scan, that is “reasonably likely” to predict clinical efficacy. While there were numerous complexities surrounding the approval, this event was nevertheless seminal for the treatment of AD and for the amyloid hypothesis.
The amyloid hypothesis is frequently discussed as a monolithic viewpoint; however, there are many important nuances within the broad theory. As noted vide infra, Aβ monomers may be targeted by both γ-secretase and β-Amyloid Cleavage Enzyme (BACE) inhibitors, as well as certain monoclonal antibodies. Amyloid plaques, composed of anti-parallel β-pleated sheets of Aβ monomers (primarily Aβ1-42) (1) are targeted by a number of monoclonal antibodies, including aducanumab. Aβ protofibrils and Aβ oligomers have been targeted less frequently by monoclonal antibodies but represent plausible targets within the amyloid framework.
Thus, the broad categorization of the amyloid hypothesis has important sub-types which will be discussed. Amyloid accumulation in brain is a defining feature of AD. Much evidence, particularly tight linkage of amyloid pathways to all genetic forms of AD, support amyloid as a therapeutic target. The relative value of targeting the various forms of amyloid is widely debated.
Very importantly, a growing consensus is forming that Aβ aggregation in the brain begins early and is followed by inflammation and the accumulation and spread of tau tangles in areas of the brain important for cognition (2, 3). Based on other biomarker and genetic data, a number of other targets for AD are clearly worth pursuing (4). These include tau, inflammatory mechanisms, and even other “non-amyloid non-tau” (“NANT”) mechanisms that should be investigated. An emerging consensus in the field of AD research is that that no single drug is likely to provide optimal treatment of AD, and that combination therapy using drugs with different mechanisms is most likely to provide the best therapy for the disorder (5). While this paper will focus on the amyloid hypothesis broadly, other mechanisms should continue to be pursued vigorously alone and in combination.
Gamma secretase inhibitors
Among the first potential disease-modifying drugs to be tested in clinical trials for AD are the γ-secretase inhibitors (6). γ-secretase is an aspartyl protease which cleaves the amyloid precursor protein (APP) following cleavage by BACE leading to the formation of the amyloid-β (Aβ) peptide (7). Inhibition of γ-secretase leads to reduction in the synthesis of Aβ in the central compartment (8). Despite this effect on Aβ synthesis, two γ-secretase inhibitors taken into the clinic did not cause slowing of disease progression and in fact caused slight cognitive worsening (9, 10). While unexpected and unfortunate, this worsening of cognition may have been related to multiple other substrates of γ-secretase and inhibition of their cleavage (7).
BACE inhibitors collectively received a great deal of enthusiasm as several of these small molecules moved into Phase 2 and Phase 3 studies. This enthusiasm may have been due to robust reductions of Aβ in cerebrospinal fluid (CSF), and also a report of a polymorphism in the APP gene at the BACE cleavage site that reduced BACE cleavage of APP and had an apparent protective effect with regard to AD in an Icelandic population (11). Despite this promising background, unfortunately trials of several BACE inhibitors were stopped due to negative results, with cognitive worsening in some studies, or due to futility as reviewed by Imbimbo et al (12). Like γ-secretase, BACE has multiple substrates in addition to APP (12) which may be related to these disappointing results. The fact that the “Icelandic mutation” was in the APP gene means that the effect of BACE on its other substrates was unimpaired in that population, thus providing protection from AD without the adverse effects associated with BACE inhibitors. Alternatively, the similar cognitive worsening with γ-secretase and BACE inhibition raises the possibility that substantial reduction of Aβ levels adversely affects synaptic function.
Despite the disappointments of the γ-secretase and BACE inhibitor studies, monoclonal antibodies targeting various forms of Aβ or amyloid plaque have led to more encouraging results. Monoclonal antibodies may be engineered to bind primarily to Aβ monomers, Aβ oligomers, protofibrils or deposited amyloid plaques. Many antibodies have some degree of binding to multiple forms of Aβ/amyloid.
Monoclonal antibodies primarily targeting amyloid plaques or protofibrils
Antibodies which were developed to primarily target deposited amyloid plaques include aducanumab (13-15), donanumab (16, 17), and gantenerumab (18-20). While these antibodies can lead to a substantial lowering of amyloid plaque load as assessed by amyloid positron emission tomography (PET), they are all accompanied by amyloid-related imaging abnormalities (ARIA) to some degree. While ARIA may be asymptomatic, it can also be accompanied by relatively minor symptoms such as headache, and can in some cases lead to hospitalization. Dose titration and surveillance with magnetic resonance imaging (MRI) is necessary when using these antibodies. Positive clinical data have been reported for aducanumab; however, statistical significance was not achieved for the primary outcome measure in one of two pivotal trials (13, 15) as noted in Table 1. Positive clinical data were also achieved for a Phase 2 trial of donanumab (17). Phase 3 trials using an increased dose of gantenerumab are currently ongoing.
The monoclonal antibody lecanemab (BAN2401) was developed to bind to protofibrils that have been associated with the “Arctic mutation” (21). Trial results show that the antibody is associated with substantial plaque reduction based on amyloid PET and the fact that it causes ARIA. As summarized in Table 1, clinical efficacy results from a Phase 2 study were also encouraging (22).
Bapineuzumab was one of the first monoclonal antibodies to enter the clinic and was the first to be associated with ARIA. Largely due to concerns about ARIA, doses were very limited compared to those now used with other antibodies and the amount of plaque reduction as determined by PET was very limited (23-27). In hindsight, given the small doses and small effects on plaque load, the lack of clinical efficacy is not unexpected.
Monoclonal antibodies targeting Aβ monomers
Solanezumab is a monoclonal antibody binding the mid-domain of Aβ and has binding largely restricted to Aβ monomers (28, 29). Given that solanezumab does not bind to amyloid plaques, it does not reduce plaque load based on PET and is not associated with ARIA (30, 31). Solanezumab was studied in two large pivotal trials in patients with mild-moderate dementia (EXPEDITION and EXPEDITION-2), and a third trial (EXPEDITION-3) that was limited to patients with mild dementia who were also known to be amyloid positive based on PET or CSF. While the EXPEDITION and EXPEDITION-2 studies did not meet their primary outcomes in the mild-moderate populations (30), planned secondary analyses did show promising results for patients with mild dementia only (32). The EXPEDITION-3 study also did not achieve statistical significance for the primary outcome measure, but consistent trends favoring a drug effect were present (31) as noted in Table 1.
Crenezumab is a monoclonal antibody based on an IgG4 background that was developed in part as a safer alternative to IgG1 antibodies (33). Similar to solanezumab, this antibody binds to the mid-domain of Aβ and does bind Aβ monomers (34-36); however, it also binds to other Aβ species including Aβ oligomers (33, 36). Given the large excess of Aβ monomers compared to oligomers in brain, the significance of the binding to oligomers is unclear. In clinical trials, crenezumab did not demonstrate clinical benefit at doses up to 15 mg/kg, but like solanezumab also did not result in ARIA (34, 35). In January 2019 the Phase 3 trials of crenezumab using a higher dose of 60 mg/kg were stopped based on futility, but the data from these Phase 3 studies are not yet available.
Monoclonal antibodies primarily targeting Aβ oligomers
At this time, only one antibody with specificity for Aβ oligomers has entered Phase 1 clinical trials (37, 38). As reviewed by Cline et al (37) Aβ oligomers may target an Aβ species that has substantial toxicity, and targeting this Aβ species may not be associated with ARIA. Future clinical data will determine whether this target and antibody have important advantages over other antibodies as previously discussed.
Summary of clinical data for monoclonal antibodies showing possible clinical efficacy in Phase 2 or 3 clinical trials
Several monoclonal antibodies have shown probable efficacy with varying degrees of statistical significance. The general consistency of outcomes with various monoclonal antibodies as shown in Table 1 suggests strongly that these changes are biologically mediated. The obvious outliers in these studies are the results for the CDR-SB and MMSE for the aducanumab ENGAGE trial. The reasons for these discrepancies are not fully clear, but higher drug exposure in EMERGE than ENGAGE is a likely factor. Table 1 provides a comparison of these results from different monoclonal antibodies studied in different clinical trials and shows an overall consistency in drug effects.
Future directions in AD drug development
The accelerated approval by FDA of aducanumab marks a new era of AD treatment. Studies of four different antibodies indicate that substantial reduction of fibrillar amyloid or Aβ monomers in brain is feasible and is associated with slowing of cognitive/clinical progression. Aducanumab and the other antibodies in clinical development are unlikely to be a complete solution to the epidemic of AD. Nevertheless, there is now an opportunity to build upon this initial success. Other targets such as tau as well as microglia and other NANT targets may provide additional benefit alone or in combination. Many investigators in the field believe that earlier intervention, at the pre-symptomatic stage of the Alzheimer’s continuum, will lead to better outcomes (39, 40).
The treatment of Human Immunodeficiency Virus (HIV) has evolved from a modest effect on an ultimately fatal disease to potent combination therapies which have changed the infection to a manageable chronic disease (41). In AD, we have now seen the equivalent of the first serine protease inhibitor for the treatment of HIV. With further drug development in AD, this disease can be changed from an inexorable and fatal decline in cognition and function in late life, to a manageable condition that allows patients and families to enjoy their retirements, travel, and grandchildren.
Acknowledgements: The assistance of Karen Sundell BS in review of the manuscript and references is greatly appreciated.
Conflict of interests: Dr. Siemers reports personal fees from Acumen Pharmaceuticals Inc., personal fees from Acelot Inc., personal fees from Aquestive Therapeutics Inc., personal fees from Athira Pharma, Inc., personal fees from Biogen, Inc., personal fees from Cogstate, Ltd., personal fees from Cortexyme, Inc., personal fees from Gates Ventures, LLC, personal fees from Hoffman La-Roche, Ltd., personal fees from Indiana University, personal fees from LuMind Research Down Syndrome, personal fees from Partner Therapeutics, Inc., personal fees from Pinteon Therapeutics, Inc., personal fees from Prothena, Inc., personal fees from Vaccinex, Inc., personal fees from Washington University (St. Louis), outside the submitted work. Dr. Aisen reports grants from Janssen, grants from Lilly, grants from Eisai, grants from NIA, grants from the Alzheimer’s Association, grants from FNIH, personal fees from Biogen, personal fees from Roche, personal fees from Merck, personal fees from Abbvie, personal fees from Shionogi, personal fees from Immunobrain Checkpoint, outside the submitted work. Dr. Carrillo has nothing to disclose.
1. Fukumoto H A-OA, Suzuk N, Shimada H, Ihara Y, Iwatsubo T. Amyloid Beta Protein Deposition in Normal Aging Has the Same Characteristics as That in Alzheimer’s Disease. American Journal of Pathology;148(1):259-265.
2. Jack CR, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. The Lancet Neurology 2013;12(2):207-216. DOI: 10.1016/s1474-4422(12)70291-0.
3. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012;367(9):795-804. DOI: 10.1056/NEJMoa1202753.
4. Siemers E. Commentary: Combination Therapy for Alzheimer’s Disease: Perspectives of the EU/US CTAD Task Force. J Prev Alzheimers Dis 2019;6(3):180-181. DOI: 10.14283/jpad.2019.19.
5. Hendrix JA, Bateman RJ, Brashear HR, et al. Challenges, solutions, and recommendations for Alzheimer’s disease combination therapy. Alzheimers Dement 2016;12(5):623-30. DOI: 10.1016/j.jalz.2016.02.007.
6. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019;15(2):73-88. DOI: 10.1038/s41582-018-0116-6.
7. Steiner H, Fluhrer R, Haass C. Intramembrane proteolysis by gamma-secretase. J Biol Chem 2008;283(44):29627-31. DOI: 10.1074/jbc.R800010200.
8. Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 2009;66(1):48-54. DOI: 10.1002/ana.21623.
9. Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 2013;369(4):341-50. DOI: 10.1056/NEJMoa1210951.
10. Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012;69(11):1430-40. DOI: 10.1001/archneurol.2012.2194.
11. Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 2012;488(7409):96-9. DOI: 10.1038/nature11283.
12. Panza F, Lozupone M, Watling M, Imbimbo BP. Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease? Expert Rev Neurother 2019;19(7):599-602. DOI: 10.1080/14737175.2019.1621751.
13. Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 2016;537(7618):50-6. DOI: 10.1038/nature19323.
14. Budd Haeberlein S, O’Gorman J, Chiao P, et al. Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer’s Disease. J Prev Alzheimers Dis 2017;4(4):255-263. DOI: 10.14283/jpad.2017.39.
15. Alexander GC, Emerson S, Kesselheim AS. Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA 2021. DOI: 10.1001/jama.2021.3854.
16. Demattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron 2012;76(5):908-20. DOI: 10.1016/j.neuron.2012.10.029.
17. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. New England Journal of Medicine 2021. DOI: 10.1056/NEJMoa2100708.
18. Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012;69(2):198-207. DOI: 10.1001/archneurol.2011.1538.
19. Bohrmann B, Baumann K, Benz J, et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis 2012;28(1):49-69. DOI: 10.3233/JAD-2011-110977.
20. Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017;9(1):95. DOI: 10.1186/s13195-017-0318-y.
21. Lannfelt L, Relkin NR, Siemers ER. Amyloid-ss-directed immunotherapy for Alzheimer’s disease. J Intern Med 2014;275(3):284-95. DOI: 10.1111/joim.12168.
22. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer’s Research & Therapy 2021;13(1). DOI: 10.1186/s13195-021-00813-8.
23. Rinne JO, Brooks DJ, Rossor MN, et al. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. The Lancet Neurology 2010;9(4):363-372. DOI: 10.1016/s1474-4422(10)70043-0.
24. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. The Lancet Neurology 2012;11(3):241-249. DOI: 10.1016/s1474-4422(12)70015-7.
25. Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther 2016;8(1):18. DOI: 10.1186/s13195-016-0189-7.
26. Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009;73(24):2061-70. DOI: 10.1212/WNL.0b013e3181c67808.
27. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370(4):322-33. DOI: 10.1056/NEJMoa1304839.
28. Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 2012;8(4):261-71. DOI: 10.1016/j.jalz.2011.09.224.
29. Siemers ER, Friedrich S, Dean RA, et al. Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 2010;33(2):67-73. DOI: 10.1097/WNF.0b013e3181cb577a.
30. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370(4):311-21. DOI: 10.1056/NEJMoa1312889.
31. Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med 2018;378(4):321-330. DOI: 10.1056/NEJMoa1705971.
32. Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement 2016;12(2):110-120. DOI: 10.1016/j.jalz.2015.06.1893.
33. Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 2012;32(28):9677-89. DOI: 10.1523/JNEUROSCI.4742-11.2012.
34. Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018;90(21):e1889-e1897. DOI: 10.1212/WNL.0000000000005550.
35. Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res Ther 2018;10(1):96. DOI: 10.1186/s13195-018-0424-5.
36. Ultsch M, Li B, Maurer T, et al. Structure of Crenezumab Complex with Abeta Shows Loss of beta-Hairpin. Sci Rep 2016;6:39374. DOI: 10.1038/srep39374.
37. Cline EN, Bicca MA, Viola KL, Klein WL. The Amyloid-beta Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis 2018;64(s1):S567-S610. DOI: 10.3233/JAD-179941.
38. Cline E. VK, Klein W., Wang X., Bacskai B., Rammes G., Dodart J., Palop J., Siemers E., Jerecic J., Krafft G. Synaptic intervention in alzheimer’s disease: soluble aβ oligomer directed ACU193 monoclonal antibody therapeutic for treatment of early alzheimer’s disease. J Prevent Alzheimer’s Dis 2019;6:Supplement 1:S151.
39. Aisen PS, Cummings J, Jack CR, Jr., et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther 2017;9(1):60. DOI: 10.1186/s13195-017-0283-5.
40. Sperling RA, Jack CR, Jr., Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med 2011;3(111):111cm33. DOI: 10.1126/scitranslmed.3002609.
41. Gunthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA 2016;316(2):191-210. DOI: 10.1001/jama.2016.8900.