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In this article, we revisit the many twists and turns of the aducanumab clinical trials and explore the scientific community's response to the latest analysis of the data.



On October 22, Biogen surprised the scientific community by announcing their plans to apply for US Food and Drug Administration (FDA) marketing approval for aducanumab, an investigational treatment for Alzheimer's disease (AD). Why was this surprising? Just a few months earlier on March 21, the biotechnology company declared that they were discontinuing the drug’s development on the basis that two Phase III AD trials, ENGAGE (NCT 02477800) and EMERGE (NCT 02484547), were "unlikely to meet their primary endpoint upon completion."





What is adunacumab? The brains of AD patients are often found to be riddled by amyloid plaques that disrupt healthy neuronal function and cause toxicity, ultimately leading to cognitive decline. Aducanumab is a monoclonal antibody (mAb) designed to bind to aggregated forms of β-amyloid to clear it. The drug was originally developed by Neurimmune via a reverse translational medicine approach, in which the antibody was extracted from older individuals who have not developed AD.



Where has the extra data come from? Understanding ENGAGE and EMERGE



At an investor's conference on Oct 22, Biogen released the additional data.



Lon Schneider, Professor of Psychiatry, Neurology, and Gerontology at the Keck School of Medicine of the University of Southern California, eloquently assessed the data sets in his article for the Lancet. The major key finding was an apparent dose-responsive effect in the CDR-SB scale for the larger EMERGE data set. However, parallels could not be found in the ENGAGE data, where participants actually showed a decline in performance on the CDR-SB scale when compared to placebo, but a dose-responsive improvement in the ADAS-Cog13 and the ADAS-ADL-MCI scales.



Safe to say, the results left the scientific community feeling somewhat perplexed. In his article, Derek Lowe commented, "I have no idea why four different dementia rating systems should give such different results, and to a first approximation, no one else seems to have a good idea, either."



Schneider said, "Biogen's slide presentation at the investors conference contained sparse information on clinical outcomes, mainly percentage differences and lone p values." He continued, "Although Biogen claims that the positive results of the EMERGE trial were driven by greater exposure to a higher dose in the larger dataset, the effect could just as likely been due to greater worsening in the placebo group."



The hope, therefore, was that Biogen would provide some clarity on the disparity in the results at the 12th Clinical Trials on Alzheimer's Disease (CTAD) conference that took place on December 5.





Did Biogen deliver?

Biogen – "rule breakers"?

Providing a sense of false hope?





The lack of efficacious treatments for AD is an emotive issue. Patients and loved ones are desperate for a cure for a disease that robs them of memories built over a lifetime. There is a worry that approval of aducanumab by the FDA based on current data could ultimately lead to false hope.



Liu, when asked about the impact these data may have on AD patients, says “I don't think that they should be downstream of what effectively is a large drug company with a great deal of investors to answer to. They are the ones who have suffered the effects of incomplete data reporting, and an objective analysis is really what's needed for everyone.”



Routledge adds, “Regulators now have a critical decision to make - are the benefits seen in these two 18-month-long trials large enough to make a meaningful difference to the lives of people with dementia? That decision will ultimately determine who may get access to aducanumab, and other drugs like it, in future and under what restrictions."









Video credit: The Alzheimer's Association



Routledge says "We are now in unchartered territory for an Alzheimer’s drug, and there will be huge anticipation around how the FDA decides to proceed. “Studies like these add hugely to our understanding of diseases like Alzheimer’s and the best approach to treat them. Dementia research is making strides and gaining momentum. It’s testament to the commitment of scientists, funders and those who take part in trials like this that we’re moving closer to the first life-changing treatment for Alzheimer’s.”





Time to take a fresh look at an older theory?

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