The vice president and chief medical officer of the Neurology Business Group at Eisai discussed the company's decision to continue efforts on amyloid therapy despite prior setbacks.
To say that the road to finding a treatment for Alzheimer disease (AD) has been rough is quite the understatement. Countless hours and research dollars have been expended in a pursuit that has left some of the world’s most brilliant clinical minds scratching their heads.
In what seems to be failure after failure, some bright spots have emerged. In a surprising reversal, Biogen announced in October that they would pursue regulatory approval for aducanumab, an investigational, amyloid-targeting agent in development with Eisai that had been shelved earlier in 2019 after a disappointing futility analysis. However, additional analysis revealed that patients who received a higher dose of the drug for a longer time showed improvements in cognitive measures, reinvigorating the clinical research team.
Biogen and Eisai are 2 of the last-standing pharmaceutical companies that have continued to pursue amyloid-targeting agents despite multiple previous failures. Driven by the disease’s well established pathophysiology, Biogen and Eisai continue to stand firmly behind aducanumab as well as BAN2401, a humanized monoclonal antibody that selectively binds to soluble protofibrils that is in phase 2b/3 studies.
In an interview with NeurologyLive®, Harald J. Hampel, MD, PhD, MA, MSc, vice president and chief medical officer, Neurology Business Group at Eisai, discussed why the company has stayed the course on the amyloid theory despite many signals pointing in other directions.
In October, Eisai and Biogen announced that after consulting with the FDA, Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early AD. This news, combined with previously presented BAN2401 data, strengthens the relevance of the amyloid biochemical pathway in the pathophysiology of AD and for targeted disease-modifying therapy.
It is well established that AD pathophysiology—including production, clearance, and brain accumulation of soluble and insoluble forms of amyloid-β and phosphorylated tau proteins— commences decades before any clinical symptomatic manifestation. A characteristic early temporal and spatial progression of AD pathophysiology during the asymptomatic preclinical stages involves distinct neuroanatomic structures, including the precuneus and the cingulate cortex. These brain areas belong to the so-called “default mode network,” which is a central functional brain network where neurotoxic amyloid-β evolves, accumulates, and aggregates. Novel techniques using molecular neuroimaging enable the in vivo assessment of the presence and progression of aggregated fibrillar amyloid-β across affected regions of the brain, such as the default mode network.
Moreover, functional magnetic resonance imaging studies indicate that hyperconnectivity exists within brain regions of the default mode network during the preclinical phase of AD. Such a hyperconnectivity may represent a very early compensatory mechanism of the brain that, after reaching a certain threshold, can break down, initiating a decompensation process characterized by the progressive loss of synaptic function across neurons within networks. The later event of this progressive detrimental path is represented by widespread failure of synaptic systems in neuronal networks that represent cognitive functions, the processes underlying AD cognitive and behavioral symptoms along its clinical continuum. Therefore, accumulating evidence does point at amyloid-β as an initiator, trigger, and subsequently driver of progressive loss of brain homeostasis, function, and structure, which ultimately leads to mild cognitive impairment and AD dementia. What the scientists are finding is that the contribution of the amyloidogenic cycle to Alzheimer pathophysiology is getting increasingly clear. So, rather than thinking of this biochemical pathway as a linear cascade, which I think is deceiving, we should see this more like a nonlinear, dynamic, chronically evolving cyclic proteinopathic pathway.
The idea would be that the compounds that are actually effectively targeting important soluble aggregated perpetrator molecules of this cyclic pathway would then reduce the bulk of the neurotoxic onslaught. Then, the brain’s immune system, through surrounding glia cells, both microglia and astrocytes, can digest and get rid of the rest and not be overwhelmed. This is partly hypothetical, but it’s getting increasingly substantiated, through evolving evidence, that brain glial cells play an important role. All of these critical elements of the pathophysiological pathway are getting increasingly clear from preclinical, ex vivo, animal research, and human clinical research, in early clinical, preclinical, asymptomatic cohorts that are systematically longitudinally observed. Also being studied are cohorts of autosomal dominant amyloid-β mutation carriers.
It also becomes clear that these cascades are modulated by the individual’s biological background, including human genetic variation.
The Arctic mutation, found in a Swedish family with a history of familial early-onset AD, has been essential to untangle the role of a particular critical form of the cyclic amyloid pathway, the amyloid-β protofibrils. The word is from the ancient Greek prôtos, “first,” plus fibrils or filaments, and protofibrils are a particularly toxic species of soluble aggregated amyloid-β. Like many autosomal dominant mutations in the amyloid precursor protein gene, patients bearing the Arctic mutation display high rates of synaptic and neuronal toxicity with an overall fast disease progression, including an early onset— usually their 50s or even 40s. This mutation leads to a substantially increased rate of formation of the soluble aggregated amyloid-β protofibrils. Subsequent studies conducted in the Arctic mutation family indicated that the amyloid-β protofibrils are particularly toxic species within the amyloid-β cycle.
An ever-increasing number of mutations—more than 200—have been found within the APP and PSEN 1 and 2 genes, often causing an overstimulation of the pathological amyloidogenic pathway. This results in high rates of production of amyloid-β byproducts, including the particularly toxic amyloid-β oligomers and protofibrils. These genetic mutations, however, account for only a small fraction of AD individuals. Most patients suffer from multigenetic, “sporadic,” late-onset forms of AD, which are likely characterized by imbalances between production and clearance of amyloid-β, rather than only overproduction. The accumulation of toxic amyloid-β species occurs gradually first in brain areas of the default mode network and then spreads strategically throughout important cortical areas of the brain related to cognitive functions, such as memory, learning, and attention.
The Alzheimer biomarker science is currently gaining momentum and evolving in a dynamic and very positive way. For example, the BAN2401 phase 2 clinical trial gives confidence that in an early AD population, you see a consistent impact of treatment on core feasible biomarkers of Alzheimer pathophysiology. It is very useful to have these validated and standardized biomarkers that are very informative in regard to the underlying key molecular mechanisms of active pathophysiological pathways in AD. The research field is currently evolving from valuable cerebrospinal fluid biomarkers to blood-based biomarkers, and in the coming years, this will ultimately enhance the options of broad early detection and diagnostic use. We might even see use for patient screening algorithms and further implementation in clinical therapy trials.
The phase 2 data analysis of the BAN2401 trial showed a significant reduction of the cerebrospinal fluid (CSF) concentrations of a number of core pathophysiological biomarkers. These included 1) neurogranin, a surrogate marker of synaptic dysfunction; 2) neurofilament light chain (NfL) protein, a biomarker of axonal damage; and 3) phosphorylated tau protein, a biomarker of tau-related pathophysiology, which is another driver of synaptic toxicity and neurodegeneration that acts in detrimental coexistence with amyloid-β, apparently driving disease progression. Of note, these study results were reported from a comparison investigation between 23 BAN2401- treated patients versus 16 placebo-treated controls. Therefore, these promising data need to be corroborated in a larger sample, which is currently being pursued in the large-scale phase 3 Clarity AD trial.
These biomarkers reflect AD pathophysiological hallmarks, and their development is ongoing and increasingly supporting clinical trials. In collaboration with Japan-based Sysmex (the US regional affiliate of Kobe), Eisai is currently developing a blood-based biomarker assay that is very robust and has the potential to provide, in coming years, a plasma assessment of amyloid-β peptides 1-40 and 1-42. Blood-based biomarkers could represent a future first-line screening tool, enabling a globally feasible and accessible large-scale multistep diagnostic process, starting in primary care, to accurately identify amyloid-positive people in the earlier, clinically silent stages of the disease. Such a tool may perhaps be able to reduce the use of expensive and invasive positron emission tomography (PET) scans and lumbar punctures, which also are not globally accessible. Sysmex-based plasma amyloid-β 1-40 and 1-42 concentrations correspond with CSF measurements. A robust body of studies already indicated that plasma amyloid-β 1-40 and 1-42 concentrations have concordance with results obtained using amyloid PET scans. A recent study indicates that plasma amyloid-β 1-40 and 1-42 concentrations might be even more sensitive and be positive earlier than CSF assessment and PET scanning, at the earliest preclinical stages of disease. Therefore, it seems particularly promising that blood-based assays may become available and support a timely and comprehensive identification of at-risk individuals with initial cerebral amyloid upregulation. To follow, other biomarkers currently measurable in CSF, such as NfL, YKL-40, tau proteins, neurogranin, and others, may soon be validated in blood.
Global biomarker development is progressing rapidly. Globally accessible, reliable, and qualified tools might become available even for primary care in the near future to screen and identify asymptomatic individuals in a timely fashion. By evaluating distinct active pathophysiological pathways in the brain, including the amyloid pathway, [the earliest stages of AD] could be effectively targeted with an evolving spectrum of potential pathway-based disease-modifying therapies, such as the investigational candidates aducanumab and BAN2401.