Alzheimer’s Disease Research Finds New Beginnings

The field of Alzheimer’s Disease (AD), while poses a significant opportunity, has been faced with big challenges, and massive late-phase trial failures. Some argue that trial design was the culprit, however, many believe the science was to blame. Despite subsequent setbacks in the field, emerging biopharmaceutical companies are still pursuing AD therapies with new science, and different preclinical and clinical trial models. In this interview, Dr. Daniel Alkon, President & Chief Science Officer at Neurotrope will discuss novel approaches to AD therapy development.

Moe Alsumidaie: Why is Alzheimer’s disease an area of great challenge with many trial failures?

Daniel Alkon

Daniel Alkon:When Alois Alzheimer discovered the disease around 1906, it didn’t have any traction. In 1984, two scientists identified a protein called amyloid beta. When that happened,everyone thought,"Oh this will be a real breakthrough because we now know what key protein is involved. And it was involved in what are called amyloid plaques and tau tangles, neurofibrillary tangles,which are the pathologichall marks. The main approach, neuro-pharmacologic approach, is where researchers tried to develop drugs to address other deficits that people had thought attended those pathologic deposits, such as the loss of cholinergic neurons, which contribute to memory and attention deficits. This worked to the point where we developed drugs that provided mild symptomatic relief, but, did not treat the disease. So, the industry started to focus on getting rid of amyloid beta buildup, as they believed the disease was caused by that protein. There have been many approaches to try to reduce amyloid-beta. One is to use animal antibodies to combine with and eliminate amyloid-beta; another involves activating enzymes in the brain to degrade amyloid-beta, another is to inhibit enzymes in the brain that help form A-Beta such as inhibitors of Beta Secretase; none of these approaches worked.  Many scientists had thought that amyloid plaque and tau tangles were destroying brain neurons and synapses; this theory was also disproven.

MA: What have you discovered is the main contributor to AD?

DA:  I worked on memory at the NIH and then at the Rockefeller Neuroscience Institutefor 15 years, and we implicated certain key molecular pathways that were responsible for memory formation. In memory formation, we found that we could demonstrate with electron microscopy the formation of new synapses and once we understood that and the pathology that had been acquired with human brain samples,we hypothesized that we could facilitate not only memory formation but also the formation of synapses, which might be a regenerative or restorative approach to AD. That motivated us to work on clinical trials, first with a compassionate use trial with patients suffering from advanced AD. We generated successful results, hence, we went to a Phase II trial, and we published the results recently in the Journal of Alzheimer's Disease.

Alexander Neumeister: What is your hypothesis?

DA: Our hypothesis is that since wesaw an improvement in patients who underwent the compassionate use trial,we pursued a larger number of patients to see if we could achieve similar results. Results from that study demonstrate clear signals including not only a reduction in degradation, but, also a reversal in memory loss and an improvement in their conventional psychometric measurements. Even one month post study completion, and after all treatment had been stopped, results were consistent with a new and constructed wiring. These findings have encouraged us to continue development with this hypothesis. 

MA: What did other researchers miss in their animal models?

DA: I think a lot of the industry was misled by some of the animal models that they used. For example, there was one double transgenic amyloid precursor protein(APP) model that the industry used. The APP model makes a huge amount of amyloid, so much amyloid that it acts like a tumor occupying space in the animal’s brain. So, if there is a reduction in that amyloid and it's not so huge anymore, the animal tends to get better. But that's not what happens in AD, we tend to observe a gradual build-up of much less amyloid.

MA: Why did you target patients with advanced AD?

DA:While we have every reason to believe that we can treat much milder cases and even prevention, we chose patients with advanced AD because we saw benefits in the compassionate use patients, which were very advanced. And it's because the industry basically has abandoned that niche and we wanted to see whether we could undertake that challenge.

MA: What challenges did you experience with recruiting and retaining patients with advanced AD?

DA: Patients with advanced AD are a challenge to recruit. But fortunately we had 27 sites with principa linvestigators at each site and a dedicated team of researchers. We were pleasantly surprised that we could recruit the patients even though they were advanced based on their caregivers making the decision, and we believe that we saw such good recruitment figures because of our relationship with our investigators and their relationship with their patients and caregivers. We also believe what contributed to this success was the hope of reversing AD with these patients; we saw very few dropouts, and we think that was fueled by the hope that our medical product could improve those patients’ lives. For instance, in the compassionate use trial, one patient who has a familial gene for early onset AD(by the time she was 31 or so), and couldn’t speak, swallow or move at the beginning of the trial, saw a significant improvement in speech, movement, and her livelihood. That story got around, and the story fueled recruitment and retention.
 

Alex Neumeister is Head of Medical Affairs at CliniBiz and specializes in protocol design, drug safety and clinical trial management. Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials