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β-amyloid clinical trials: An Expensive Lesson

Robert G. Ungard

PhD Candidate, McMaster University

posted:March 29th, 2019

On March 21st 2019, two pharmaceutical companies, Biogen Inc and Eisai Co, announced that they would terminate two Phase III trials (ENGAGE and EMERGE) investigating their anti-β-amyloid monoclonal antibody aducanumab for treatment of Alzheimer’s disease 1. This decision was made after an independent monitoring committee determined from preliminary data that neither trial would meet their primary endpoints of slowing cognitive and functional impairment in people with early-stage Alzheimer's vs placebo treatment.

 

The announcement rapidly had catastrophic effects on the stock prices of both companies as investors seeking an anticipated $10 billion/year blockbuster drug quickly dumped both companies 2. The results were also, yet again, extremely disappointing for researchers and patients who have seen their high expectations for new Alzheimer’s therapeutics go repeatedly unmet. 

 

One of the characteristic features of Alzheimer’s disease is the accumulation in the brain of neurotoxic soluble β-amyloid oligomers and pathological neurofibrillary plaques also made largely of β-amyloid 3.

 

Mouse models that were subsequently designed to mimic this structural pathology reliably also displayed cognitive deficits – a seemingly excellent animal model of the disease. Experimental targeting of β-amyloid and its precursors in these animal models has repeatedly reduced the levels of amyloid in the brain, and improved indicators of cognition – results that paved the way for human investigation of these therapies 4.

 

However, these results have repeatedly failed to translate into a clinical benefit in human studies, and these newest early clinical trial terminations are far from the first late-stage investigative failure of therapeutics targeting β-amyloid. Many of the world’s largest drugmakers including Pfizer, Merck, Johnson & Johnson, AstraZeneca, and most recently Eli Lilly in 2018 and Roche in 2019 have also experienced major disappointments with late-stage negative clinical results or safety concerns with β-amyloid therapeutics, and most have abandoned that line of inquiry.

 

While the repeated failure of antibodies targeting β-amyloid has been the most famous, disappointing, and incredibly expensive translational flop in Alzheimer’s research, in all, over 400 clinical trials for potential Alzheimer’s disease therapeutics have been conducted, still with no strongly outcome-altering therapeutic ever having been developed 4.

 

This has led researchers to a reckoning with the β-amyloid hypothesis of Alzheimer’s. While the association between the two are undeniable, the lack of clinical effectiveness of any interventions to date has led to the strong consideration of other hypotheses for future drug development. These include Tau protein – similar to other neurodegenerative conditions including Chronic Traumatic Encephalopathy.

 

The story of these repeated failures, despite so much effort, investment, and perceived mechanistic certainty, is a sad lesson for researchers. Hopefully new thinking and lines of inquiry will produce in the not-so-distant future some reliable new drug candidates for the millions suffering from this currently untreatable disease.

 

 

 

References

1.        Biogen scraps two Alzheimer drug trials, wipes $18 billion from market value | Reuters. Available at: https://www.reuters.com/article/us-biogen-alzheimers/biogen-eisai-scrap-alzheimer-drug-trials-idUSKCN1R213G. (Accessed: 23rd March 2019)

2.        Alzheimer’s Disease: Could New Approach Lead to a Breakthrough? | Fortune. Available at: http://fortune.com/longform/alzheimers-disease-cure-breakthrough/. (Accessed: 24th March 2019)

3.        Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007).

4.        King, A. The search for better animal models of Alzheimer’s disease. Nature 559, S13–S15 (2018).