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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT #21.17

The FDA grants an accelerated approval for Biogen’s aducanumab for the treatment of Alzheimer’s disease

The U.S. FDA approves today Biogen’s aducanumab for the treatment of Alzheimer’s disease in stating “the drug consistently and very conviningly reduced the level of amyloid plaques in the brain”. The U.S. agency decision comes as a surprise for many researchers, biostatisticians, clinicians and observers who were not convinced by the data submitted by Biogen and by evidence that the drug did slow down patients’ cognitive decline. It is noteworthy to indicate that the FDA only granted an accelerated approval and that Biogen will still have to conduct a confirmatory study with unknown endpoints at this stage.

The aim of this report is not to comment the U.S. FDA decision, but rather to outlay a personal perspective on the field of Alzheimer’s research and development, which we have been closely monitoring over the last ten years.

In December 2018, at a presentation dedicated at neurosciences, made at Alcimed, a consulting company based in Paris, we had pinpointed at the extreme complexity of all brain related  diseases. We had challenged the “single target” orthodoxy aimed at discovering selective agents that focus just on neuron activity and indicated that this approach had not yielded novel active treatments for schizophrenia, autism, major depressive disorders, epilepsy or Parkinson’s and Alzheimer’s diseases. “Billions of dollars have been spend on development of products to no avail, leading several biopharmaceutical companies and many start-ups to abandon the field” we wrote in the MedNous issue of February 2019.

This is particularly true in the area of Alzheimer’s disease treatments, where for almost 30 years, the field has been dominated by a single theory: the amyloid hypothesis which claims that the removal of amyloid plaques was the best way to tackle the disease. According to our internal survey, more than 20 late-stage clinical candidates, aiming at the amyloid pathway, have failed to show signs of efficacy in slowing down Alzheimer’s patients’ memory loss. We believe this constitutes the largest and most expensive defeat the biopharmaceutical industry has ever been facing and the U.S. FDA positive decision on Biogen’s aducanumab does not radically change the picture. The amyloid hypothesis will never become the most attractive way to cure Alzheimers’ disease and one should not expect a major clinical benefit from drugs targeting just the amyloid pathway.

For many years investors and Venture Capitalists have stopped funding projects with the reduction of the amyloid plaque as the main target. Consequently only very large biopharmaceutical companies such as Biogen Eli Lilly, J&J, Merck, Pfizer and Roche have stayed somehow active in the field.

With the repetitive failure of amyloid drugs at slowing patients memory loss, the business world opened up to alternative approaches and started listening and considering research groups which had been sidelined and were dismissed for many years.

Most recently a list of alternative approaches have gained momentum and deserve to be clinically assessed. The most often cited are : synapse modulation, brain immune system stimulation, oxidative stress and chronic neuro-inflammation reduction, activation of TREM2- a receptor on microglia – and surprisingly kinase inhibition. Many of them aim at removing molecular debris from the brain or insulate neurons from injury. The repertoire of interesting targets is larger than ever before but there is still a lot of fundamental work which needs to be done before tackling the disease with some kind of efficiency. To achieve this goal a so called “ménage à trois” approach, where the neuronal system, the immune system and the vascular system are part of the equation, is currently what we consider most prone to success.

With the rather unexpected aducanumab approval of today, the amyloid hypothesis is not dead but it has nevertheless lost considerable momentum and there remains few outspoken proponents who believe the approach will become the most promising drug treatment in decades.

A recent performed intelligence analysis indicates that just a handful of startups have nevertheless been able to raise a few hundred millions of dollars to develop drugs that are not amyloid targeted. The survey shows that of all the 27 Alzheimer’s drugs currently in phase 1 clinical trials, only one tackles the amyloid pathway.

Paris, June 7, 2021.

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