Conference Coverage

Alzheimer’s disease: Alternative mechanisms make clinical progress


 

AT AAIC 2022

– In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.

To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.

Chasing the wrong target?

At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.

Later in the session, researchers presented strategies to counter Alzheimer’s disease and other neurodegenerative conditions using strategies including modulation of metabolism and inflammation, support of brain homeostasis, and suppression of a broader range of neurotoxic proteins.

One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.

After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”

A diverse clinical pipeline

The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.

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