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THE UPS AND DOWNS OF AMYLOID IN ALZHEIMER’S

 

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, eric.siemers@earthlink.net

J Prev Alz Dis 2021;
Published online September 17, 2021, http://dx.doi.org/10.14283/jpad.2021.54


 

Introduction

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

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.

 

Monoclonal antibodies

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.

Table 1. Impact of Therapy on Disease Progression in Recent Phase 2-3 AD Anti-Amyloid mAb Studies*

 

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.

 

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