Improvements in Alzheimer Pipeline, Development of Biomarkers

October 5, 2018

Although the history of developments in Alzheimer has been littered with failures, there remains reason to be hopeful about the future.

Howard Fillit, MD

Alzheimer disease has been plagued by a slew of failed therapies, negative clinical trials, and slow development of overall improvements to the treatment paradigm.

Howard Fillit, MD, the founding executive director and chief scientific officer of the Alzheimer’s Drug Discovery Foundation (ADDF), has been there since the early days of Alzheimer research. No stranger to the slower-than-desirable development in the field, Fillit noted that the ADDF has taken up the mantle of helping researchers fill in the remaining gaps.

Despite an overall lack of success, there has been an uptick in recent years in the number of therapies and biomarkers with real potential. In an interview with NeurologyLive, Fillit provided further insight into how the pipeline has changed.

NeurologyLive: How has the development pipeline in Alzheimer disease changed in recent years?

We've had a 100% failure rate in our drug development since 2004 but you have put it in a historical perspective. We've been doing cancer trials since like the 1940s, 1950s—that's 60 to 70 years of running cancer trials, learning about the disease, learning how to run cancer trials, and what the parameters are. Today, we have precision medicine for cancer. We don't even think about the X-rays anymore. It's not about the tumor, it's about the cells, regardless of what organ they're in. It's so different than it used to be.

We haven't been running clinical trials that long in Alzheimer, and we haven't been running really good clinical trials. The recent studies are the first time in the last 5 years or so where we've actually used biomarkers to define the disease and the targets that we’re going after. I mean, this sort of rigor in clinical trials in Alzheimer is just starting to happen. Precision medicine, where we can actually show target engagement of the drugs being tested. We’re testing anti-amyloid agents in people that have positive amyloid scans, so we know they actually have the target that we're going after. Lily showed about 4 or 5 years ago that 35% of the people that were being entered into their anti-amyloid trials with an anti-amyloid drug didn't have amyloid in their brain. The thing was destined to fail.

When I think about back at all the trials that we've run over the years, and what the rigor of those were, we were just learning how to do trials. I think today, we have a much better chance at having successful trials because we've learned how to do better trials with better drugs because we've been able to translate this basic research that we've done into drug discovery and development over this period of the last couple of decades.

How important to you is the development of biomarkers for Alzheimer?

I'm proud to say our foundation actually funded in the earliest stages, the first 5 years or so, of the development of the first biomarker approved by the FDA as a diagnostic for Alzheimer disease—the PET amyloid scan, Amyvid. We funded it from the year 2000 to 2004.

Biomarkers have been a critical part of our mission from day 1. They're critical, not just for early diagnosis in the clinic, but also for inclusion criteria, as target engagement, or defining a disease state in the clinical trials, and also using them for monitoring the efficacy of a drug. What's happening now is that we're starting to get more biomarkers for Alzheimer disease. We have PET-tau imaging coming online. I believe in the next couple of years will see PET-tau imaging agents that can find these tangles that correlate very well with cognition. We're having PET inflammatory biomarkers come online. We're funding a lot of research looking at inflammation in the brain because studies show that people with Alzheimer disease who don't have inflammation don't progress, and people with Alzheimer's disease who do have inflammation as defined by biomarkers—either PET imaging or spinal fluid, elevation of cytokines, or even blood elevation of cytokines—progress more rapidly. Those would be people that we would target in our anti-inflammatory trials.

In other words, back in the 1990s, there were a lot of really large anti-inflammatory trials done, and they all failed. Well, they were mixed. There were people in those trials that had inflammation in their brain and people who didn't. We're very proud that we've partnered with Bill Gates, and we have a very big initiative now, upwards of $35 million so far, to develop new blood tests for Alzheimer's disease. I do think that in the next few years we're going to have a blood test, and that's really going to change our field because now people can be easily diagnosed in the community. The same way the cholesterol revolutionized heart disease in every way—we're going to have that in Alzheimer's disease.

Transcript edited for clarity.