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Discovery & Development Clinical Trials, Drug Discovery, Translational Science

Getting on Target for Alzheimer’s

In October 2019, Biogen sent shockwaves through the Alzheimer’s community when it reanimated aducanumab, its previously dismissed therapy candidate for Alzheimer’s disease. Upon analysis of additional data supporting aducanumab’s efficacy in patients with longer term, high-dose exposure, Biogen plans to now submit the drug candidate for FDA approval in early 2020. If approved, aducanumab will be the first disease-modifying therapy for Alzheimer’s, which, as a reminder, is currently the only disease on the “top ten” causes of death without treatment. 

Biogen’s surprising, but welcome, reversal not only puts hope on the horizon for a near-term Alzheimer’s treatment, it also – perhaps more importantly – revitalizes work supporting next-generation amyloid beta (Aß)-targeting candidates that can selectively target only its toxic form, beta-amyloid oligomers (AßOs). 

Aducanumab gets us only partially there: 35 percent of patients experienced ARIA-E (brain swelling), revealing the critical need for improved AßO-targeting precision to achieve both greater safety and efficacy. At high doses, aducanumab binds more AßOs, supporting its efficacy, but it also binds amyloid plaque, which is off-target and triggers brain swelling. This unwanted binding of an otherwise benign clump of insoluble protein is what leads to this significant dose-limiting side effect of ARIA-E. Regrettably, definitive data demonstrating the neurotoxic role of AßOs were just becoming available when the clinical development program for aducanumab was devised.  

By way of background, Aβ is a protein that occurs naturally in the brain and its monomeric form has an important role in cell-to-cell communication. Hundreds of scientific and clinical studies support its role in sporadic AD, which led researchers to propose the so-called amyloid hypothesis in the early 1990s. The hypothesis posited that, in susceptible individuals, high levels of Aβ monomers in the brain lead to the formation of aggregates that eventually combine to form fibrils, and ultimately plaque deposits. At the time, researchers believed that plaque deposits were responsible for the neurotoxicity and atrophy observed in the brains of Alzheimer’s patients.

Biogen has bravely followed its data. Should aducanumab prevail, the Alzheimer’s community owes its researchers a great deal of gratitude.

This early hypothesis guided Alzheimer’s drug development for several decades while researchers continued to study the role of Aβ in the progression of Alzheimer’s disease. Over time, they learned that amyloid plaque was only minimally neurotoxic and, therefore, incapable of causing the massive neuronal cell death found in AD. However, several large studies targeting plaque were already well underway. As these trials continued, researchers continued to amass evidence that sharpened our understanding of the neurotoxic role of AβOs, offering a more precise target for drug development. Between 2000 to 2010, the target was further defined: data showed that soluble, toxic Aβ oligomers propagating in a prion-like manner were in fact the drivers of neurodegeneration and cognitive decline in AD patients, and the causative agent in AD. The Aß hypothesis was revised to reflect this emerging consensus.

What happened next was perplexing. Despite clear indications that targeting Aß plaque would not be an effective strategy for disease-modifying AD therapy, therapeutic R&D continued to focus on plaque. Call it exuberance. Call it desperation. Call it a cabal. Whatever the reason, drug makers didn’t end their Aβ plaque trials. Even more dumbfounding, they created new ones, all focused on the wrong form of Aß.

As study failures mounted – somewhat spectacularly in phases II and III – enthusiasm for the amyloid hypothesis disintegrated; along with it, the community’s most validated, advanced effort toward long-awaited therapy. Things looked bleak for all involved: big pharma had largely abandoned interest in Alzheimer’s disease; small biotechs engaged in next-generation efforts targeting the correct molecular species of Aβ faced dire uncertainty, and; millions of patients and their desperate families were left stranded, literally without a life line. 

Then came Biogen’s stunning reversal. On October 22, Biogen said re-analyses of data from their late-stage phase 3 studies show that aducanumab, given at higher doses over a long duration, did indeed reduce the rate of patients’ cognitive decline. Biogen brought these data to a seemingly receptive FDA, which invited Biogen’s regulatory submission. These largely unprecedented events both revived interest in Aß toxicity and validated decades of research that deepened our understanding of it. 

A closer look at Biogen’s data reveals a model consistent with one that many proponents of the AßO hypothesis have concluded: a safe, effective disease-modifying therapy for Alzheimer’s must be highly selective for the toxic form – and only the toxic form – of Aß (i.e, the Aß oligomer). As noted above, despite improvement revealed in Biogen’s close examination of its final clinical outcome data, 35 percent of patients still experienced adverse ARIA-E despite attempts to minimize this swelling by titrating aducanumab. Clinical benefit is dependent upon the amount of the therapeutic antibody that reaches the toxic oligomers. However, higher dosing with aducanumab cannot be achieved without an even higher risk of ARIA-E because of its off-target binding to plaque and vascular deposits of beta-amyloid. The bottom line: aducanumab is only weakly selective for the toxic Aβ oligomers. What’s needed—and anticipated—is an antibody that selectively targets Aβ oligomers to provide greater clinical benefit and safety.

Biogen has bravely followed its data. Should aducanumab prevail, the Alzheimer’s community owes its researchers a great deal of gratitude, not only for delivering the first therapy for this devastating disease but also for reopening a window of promising possibilities for next-generation candidates targeting soluble toxic Aβ oligomers – not plaque, not monomers and not fibrils. Significantly, recent advances in fluid-based biomarkers will enable earlier “go/no go” decisions as drug candidates move through clinical development. When next-generation therapeutics become available for clinical testing, we will not have to wait until phase 3 to decide whether they provide real value to patients. We daresay, the tide is finally turning.

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About the Authors
Neil Cashman

Chief Scientific Officer at ProMIS Neurosciences

James Kupiec

Chief Medical Officer at ProMIS Neurosciences

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