Alzheimer’s Disease continues to be an enigma that cannot be resolved as the traditional beta-amyloid hypothesis has been failing over and over again in the clinic. In Kineticos most recent panel discussion, we bring together 4 industry experts to discuss what’s next with Alzheimer’s research.

Moderator

  • Kevin Hampton – Chief Commercial Officer, Kineticos

Panelists

  • Aaron Burstein – Senior Vice President of Clinical Development, vTv Therapeutics
  • Sharon Rosenzweig-Lipson – Vice President of R&D, AgeneBio
  • Jay Mohr – Chief Business Officer, AZTherapies
  • Jason Kralic – Co-Founder and CEO, Tellus Therapeutics

Kineticos: What’s been the biggest challenge with the “beta-amyloid hypothesis”. For example, is it just hard to select patients and design a trial or are we starting to think the science is off?

AB: A challenge may be the evolution of our understanding as to the role of beta amyloid as it relates to the stage of disease and severity. Have we been targeting initiating therapy too late in the disease and how early do you need to identify patients for such therapies to be beneficial? Speaking from the neuroinflammation aspect, we believe that our molecule at vTv is primarily targeting the inflammation aspect. In the mild stage of disease in which we are focusing our development, removal of amyloid may be too late versus focusing on the neuroinflammatory cascade that’s already been triggered.

The other challenge with this hypothesis is that it’s been such a focus that advancing the development of molecules with novel pharmacology is challenging in terms of educating the scientific community as to why such a novel mechanism of action would be expected to be of benefit and why this approach should be an area for research investment.

SR: The hypothesis has now been very well tested as you go from mild cognitive impairment to mild to moderate Alzheimer’s disease. We really hit this in every direction and there’s data from both the gamma- and base-inhibitors that show that these compounds worsen cognition. You have to ask yourself how early in the disease would you want to intervene to retest the amyloid hypothesis and, given the results to date, would you consider putting subjects at risk by intervening even earlier. That’s something that we have to pay attention to. Once the cascade is in motion, it may not matter what you do anymore. It also may be a by-product and may not be the driver of the disease. All of the investment in the amyloid programs lead to limited investment in alternative strategies. I can remember when the base-inhibitor program took precedence over everything. The amyloid hypothesis was a reasonable hypothesis, but it has been tested from every angle and it’s time to move on.

Kineticos: If we believe hypothesis is off, how close are we to abandoning the approach or is there more research that needs to be done before we do that? Should we be focusing on comfort care, as it may be more realistic than a medical cure?

JM: We believe patient selection in clinical trials is a critical factor. The amyloid target, and the antibodies that have been developed, may have worked too well. This approach created the side effects that made these trials, at times, difficult to complete. Even if they had been successful in reaching their primary endpoint, I would argue from a business standpoint, the business model wouldn’t even work. With the Abeta-targeted antibodies, you have an IV infusion coupled with the potential of life-threatening side effects without any real effect on outcomes, specifically a clinical one. At AZTherapies, we are studying early stage Alzheimer’s disease patients and we’re selecting patients based on a younger aged population, no older than 79.  We’re performing lumbar punctures on every patient to screen them based on their Abeta-42 levels to ensure they’re falling in a certain range that would confirm they have early stage Alzheimer’s.

Furthermore, we are focusing on the concept of the resilient brain – taking patients who have had confirmed diagnoses of both Alzheimer’s disease and cognitive impairment, looking at their brains and comparing them to the brains of their same age cohort. Both would have evidence of plaque and tangles, but a fundamental difference would be that those with Alzheimer’s possess clear evidence of prolonged inflammation. Those that didn’t have evidence of dementia were generally very cognitively alert. There’s more interest in this concept of the resilient brain and candidates that are being developed to address underlying inflammation. They can modify or slow the progression of the disease. There’s a step in between comfort care and medical care, slowing progression. That may be a much more realistic way of looking at addressing Alzheimer’s disease. Much like Multiple Sclerosis in the early days, we were trying to slow progression of the disease rather than cure it.

JK: We can all agree that beta-amyloids are relevant to the disease but the way that we’ve gone about targeting the disease hasn’t worked and borrowing from an analogy, it seems that what we’ve done so far is remove the gravestones when we need to find and stop the assassin. For the beta-amyloid hypothesis, selecting patients with relevant etiology and pathology seems necessary for current approaches. Alternative approaches will rely on similar consideration of the trial population, but do not obfuscate prior failed trials. We are constantly learning how to approach the disease by trial and error.


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