James Kupiec, MD

2020 is emerging as a landmark year for Alzheimer disease (AD) as we anticipate Biogen’s regulatory submission for aducanumab, its reanimated drug candidate for AD. If approved by the FDA, aducanumab will truly represent the first disease-modifying therapy for the disease. Perhaps more importantly, aducanumab’s forward progression has propelled the necessary innovation to drive the next generation of therapies that incorporate the learnings and consensus of the past 2 decades of drug development struggles.

The Most Vexing Challenge for Drug Developers

Few would debate that AD is one the largest, most expensive, and most vexing public health challenges for the current generation of drug developers. For the past 2 decades, AD drug development has been marked by frustration, anguish, and controversy following the successive failures of each drug candidate that attempted to neutralize the neurotoxicity believed to be the root cause of AD. As a result, AD remains the only top 10 cause of death in the United States without effective treatment.

Biogen’s aducanumab has been no exception. After initially showing promise by slowing the progression of AD, an interim futility analysis in phase 3 indicated that aducanumab’s chance of successfully meeting its primary end point in the final analysis was less than 20%. In response, Biogen 

 both phase 3 clinical trials in March 2019.

Many considered the discontinuation to represent the final nail in the coffin for the so-called amyloid-beta (Aβ) hypothesis, the long-held theory of the root cause of AD that guided drug development for decades. By way of background, Aβ is a protein that occurs naturally in the brain and has an important physiologic role. However, numerous scientific and clinical studies also supported its role in sporadic AD, which led researchers to propose the Aβ hypothesis in the early 1990s.

The Aβ 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, amyloid plaque deposits. Researchers believed that plaque deposits were responsible for the neurotoxicity and atrophy observed in the brains of patients with AD and were thus the appropriate target for drug development efforts. Drug makers responded by developing potential candidates that targeted Aβ plaque.

Researchers continued to study the role of Aβ in the progression of AD. Over time, they learned that insoluble amyloid plaque was only minimally neurotoxic and, therefore, incapable of causing the massive neuronal cell death found in AD. However, many large clinical trials with immunotherapies targeting plaque were already well underway. As these trials progressed, scientists continued to amass evidence that advanced our understanding of the neurotoxic role of Aβ oligomers (AßOs), which offered 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 patients with AD, and thus the causative agent in AD. The Aß hypothesis was revised to reflect this emerging consensus. Since 2013, more than 2000 scientific papers have supported this revised view: that AßOs—not Aβ plaque&mdash;are the pathogenic cause of toxicity in the brain.

 on Amyloid-Targeted Strategies in Alzheimer Disease Management 

Despite these data, therapeutic R&D regrettably continued to focus on Aß plaque. As study failures mounted—somewhat spectacularly in phases 2 and 3&mdash;enthusiasm for the amyloid hypothesis disintegrated: big pharma’s interest in AD waned, and innovation supporting the amyloid oligomer hypothesis faced significant uncertainty. The abrupt discontinuation of aducanumab’s development on the heels of the multiple past failures raised questions&mdash;once again and with greater ferocity&mdash;about the validity of the amyloid hypothesis without acknowledging the old view had been long abandoned by researchers driving the innovation that supported the amyloid oligomer hypothesis.

On October 22, 2019, Biogen announced that the conclusions from 

aducanumab’s interim futility analysis were incorrect

. The reanalysis of a larger dataset showed that aducanumab was effective in slowing the progression of AD at higher doses. Data released at the Clinical Trials in Alzheimer’s Disease (CTAD) meeting in San Diego in December 2019 clearly strengthened aducanumab’s potential to become the first disease-modifying therapy for AD. This stunning reversal not only resurrected hope for a near-term therapy for AD, it also—perhaps more importantly&mdash;reinvigorated innovation supporting next-generation therapies that demonstrate more precise selectivity for AßOs, not Aβ plaque.

 to support their conclusion: high-dose, long-duration aducanumab exposure can modify the AD process and provide clinical benefit. This conclusion was supported by a distinguished scientific panel of experts who supported Biogen’s analyses, indicating that the efficacy results were clinically meaningful and that aducanumab represents the first treatment targeting the core pathology of AD. The aducanumab data reaffirmed amyloid as the most validated drug development target for AD. However, it also convincingly showed that amyloid plaque reduction is not an adequate explanation for clinical benefit.

Aducanumab is effective because it offers some binding of AßOs. The reanalysis showed that 

 was effective in patients receiving a higher dose (10 mg/kg), suggesting that more drug reached the intended target. However, at this dose, the incidence of adverse ARIA-E (brain swelling) affected 35% of study participants even after attempts to minimize it with drug titration.

These findings underscore the pressing need for an improved therapeutic with precise selectivity for only AßOs, the toxic species of Aß.

Next-generation drug candidates that demonstrate superior selectivity for toxic AßOs should provide greater clinical benefit and safety. Such drugs in development demonstrate a high degree of binding to toxic oligomers without binding to non-toxic forms of Aß, offering the potential to avoid ARIA-E and allow for higher dosing to achieve greater efficacy. Preclinical data demonstrate that next-generation AßO-targeting drug candidates have greater therapeutic potency compared with other Aß-directed antibodies. Moreover, new blood and CSF biomarkers that measure disease progression will expedite clinical trials by dramatically improving the speed and cost-effectiveness of development.

If approved by the FDA, aducanumab will be the first treatment for AD, emphasizing—once and for all&mdash;that removing amyloid from the brain has a beneficial impact. However, its biggest impact on the future of treatment for AD might be its pivotal role in paving the way for next-generation therapies that are safer, more effective, and target AßOs (and only AßOs).

 for patients formerly enrolled in the phase 3 aducanumab trials. Patients will start receiving the drug again, at the highest tolerated dose, as early as March. Aducanumab’s resurrection has reinvigorated the fight against AD. Its anticipated progress, the promising findings with next-generation AßO-targeted drug candidates, and the emergence of fluid-based biomarkers for rapid and cost-efficient clinical trials have led to a resurgence of both financial investment and enthusiasm in finally making meaningful strides toward a treatment.

At the beginning of a new decade, treatment for AD is marked by genuine promise. While aducanumab will likely be the first drug approved for AD, it will certainly not be the last—or the best.

Disclosure: James Kupiec, MD, is chief medical officer for ProMIS Neurosciences, which is currently developing PMN310, an investigational antibody that binds to neurotoxic Aβ oligomers. 

Articles

The chief medical officer of ProMIS Neurosciences comments on how aducanumab will help propel innovation needed to drive the next generation of therapies for Alzheimer disease.

James Kupiec, MD

Articles

Aducanumab Reinvigorates the Fight Against Alzheimer Disease