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Moving Beyond Traditional Approaches to Alzheimer’s Disease


The recent FDA approval regarding Biogen’s controversial drug aducanumab is the first drug approved in Alzheimer’s disease in nearly 20 years, and highlights the urgent need for new disease modifying approaches in drug development in this indication.

Previously, FDA-approved treatments for Alzheimer’s disease are symptomatic agents without the power to be “disease-modifying”, which mean they don’t alter or change the underlying course of the disease. Given that it’s been nearly 20 years since any new therapeutic has been approved for the treatment of Alzheimer’s, aducanumab’s approval marks an important milestone. However, the need for treatments with outcomes that translate to disease-modification for patients remains. It is past time we take a new approach, and consider science-backed and clinically validated, new modalities, targets, and a new approach to clinical endpoints that translate to clinically meaningful outcomes for patients, caregivers, and physicians.

Brent Vaughan

Brent Vaughan

The FDA’s recent aducanumab decision again highlights the need for new therapies. While monoclonal antibodies (MAb) have been shown to effectively address beta-amyloid, the companies leading the charge on this front have seen mixed results when attempting to translate their effect on beta-amyloid into clinically meaningful improvements or delays in progression. There is also a lack of correlation with functional outcomes and the safety concerns seen with the MAb studies. The FDA’s decision this makes it clear that it’s time to break down the silos between those focused upon beta-amyloid or tau and consider low risk modalities that can address multiple points on the pathological cascade, and truly delay progression of this devastating disease.

Aducanumab is one of the latest of a decade’s worth of MAbs targeting beta-amyloid including bapinenzumab, solanzumab, crenezumab, and gantenerumab. Many of the studies with these drug candidates have shown decreases in beta-amyloid as measured by PET and yet improvement in that biomarker has not generally correlated with functional improvement in patients. When combined with failed vaccine approaches that also target increases in Abs to beta-amyloid, it becomes evident that the field needs to expand from its amyloid-centric focus for both treatment and biomarkers of efficacy.

Besides its mechanism of action, Biogen’s drug aducanumab also shares some of the safety concerns of other beta amyoid-targeted MAbs, so there will remain significant unmet needs in Alzheimer’s disease due to the adverse side-effect profiles of ARIA, vasoedema and brain inflammatory responses. Novel mechanisms of action that focus beyond amyloid-beta and tau will remain a critical unmet need. Multi-targeted treatments of amyloid-beta, tau, and reduction in decline of brain volume will be the next generation of therapies for Alzheimer’s disease which will make a significant impact.

It has long been known that Alzheimer’s patients also exhibit decreased synaptic plasticity and increased brain atrophy (volumetric loss) associated with Alzheimer’s disease progression. These pathologies, as well as abnormalities in the brain’s electrophysiology represent both promising therapeutic targets as well as potentially more informative biomarkers that have the opportunity to correlate with clinically meaningful functional outcomes in Alzheimer’s patients.

A 2017 study1 by the Rand Corporation, that was sponsored by Biogen, predicted that Alzheimer’s patients would have to wait an average of 18.6 months for treatment in 2020. This was primarily due to a limited capacity of dementia specialists, access to imaging testing and to infusion centers.

This study also raised the question of whether the U.S. healthcare system is prepared to handle the expected large number of patients. Around 15 million Americans with mild cognitive impairment, which could be an early sign of the disease, will have to be evaluated by specialists, undergo diagnostic testing, and be treated. It is clear that the time for pursuing the same targets in the same way is passing. We are at the inflection point now, and should be encouraged to take a bolder approach that recognizes the multi-factorial nature of Alzheimer’s and achieves meaningful delays in progression for patients.

Improvement in cognition is a key goal for patients with cognitive impairment, so symptomatic agents are still needed, while relief of behavioral symptoms impacts quality of life of patients and caregivers and delays institutionalization. However, it is increasingly clear that the industry needs to embrace broader pathological targets to develop a disease-modifying agent in Alzheimer’s.

A goal that has long evaded drug development and which also represents one of the largest unmet patient needs in CNS diseases continues to be disease modification therapies — those that can slow or reverse disease progression for Alzheimer’s. Unlike many other difficult therapeutic areas that still represent unmet needs, disease modification in Alzheimer’s has had the benefit of billions of dollars of research yet aducanumab is the only new therapy for Alzheimer’s to have been approved by the FDA since 2003.

Moving forward requires a multi-stakeholder approach and is up to biotech and pharma companies to make sure we develop therapeutic interventions that have a good risk-benefit profile and cost analysis for the healthcare system. There is a huge sense of urgency to start collaborating on addressing these potential barriers, and we believe a combination approach, similar to oncology treatment, with novel therapies and novel modalities that attack different parts of the disease will be the ultimate answer.

Brent Vaughan is CEO, Cognito Therapeutics.


1. https://www.rand.org/content/dam/rand/pubs/research_reports/RR2200/RR2272/RAND_RR2272.pdf

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