“We are at a pivotal time in Alzheimer’s research”

March 7, 2019 0 By S Harachand

Dr Howard Fillit, MD is Founding Executive Director and Chief Science Officer of Alzheimer’s Drug Discovery Foundation (ADDF), New York.ADDF is a nonprofit organisation which supports scientists around the globe who are investigating novel drugs to prevent, treat and cure Alzheimer’s disease. A geriatrician and neuroscientist Dr Fillit says, “We are committed to conquer Alzheimer’s through drug discovery”. Edited excerpts from an interview with FM:

What is the course of Alzheimer’s drug discovery today? What are the potential new targets?

For many years, most drugs reaching late-stage trials had a single target: misfolded beta-amyloid proteins that comprise plaques. But the pipeline is becoming diversified with drugs that target the biology of aging. We know that aging is the greatest risk factor for Alzheimer’s. It can result in a cascade of dysfunction in our brains involving inflammation, mitochondrial dysfunction, oxidation, cellular stress, and vascular and epigenetic changes.

The Alzheimer’s Drug Discovery Foundation’s (ADDF) 2017 Clinical Trials Report found that 30 of the 126 drugs in trials for Alzheimer’s are still targeting beta-amyloid. However, drugs for novel targets are gaining ground including inflammation, aspects of mitochondrial dysfunction, and vascular targets have also made it to the clinic.

Aging is the leading risk factor for Alzheimer’s disease. Both aging and Alzheimer’s disease are due to complex multifactorial causes. This means we need “multiple shots on goal” to discover effective drugs, and as in cancer, we will need multiple drugs addressing multiple targets to effectively treat the disease.
A recent paper I authored with other ADDF scientists published in the journal Neurology explores novel approaches that could slow or prevent Alzheimer’s beyond the common amyloid theory.

A look at the current drug discovery pipeline shows that most of the drugs in late-phase trails are targeting either beta-amyloid or tau. And beta amyloid’s exact mechanism in Alzheimer’s is yet to be conclusively established. How do you comment on it?

Historically, drug development in Alzheimer’s has focused on the damaged proteins, amyloid and tau, the hallmarks of Alzheimer’s disease. Although we don’t understand the exact mechanism, most researchers are not ready to abandon beta-amyloid (or tau) as targets. It is currently not known if these classic pathologies (amyloid and tau) represent valid drug targets and if these targets alone are enough to treat Alzheimer’s disease. Although therapeutic attempts to remove or decrease the production of beta-amyloid have been largely unsuccessful in altering the disease course of Alzheimer’s disease, researchers learned important information from those clinical trials even if they didn’t immediately result in treatments for Alzheimer’s patients. And recent clinical trials suggest that problems with clearance of beta-amyloid may yet prove fruitful.

While many late-stage clinical trials are targeting amyloid, it’s likely we’ll need more than one drug to treat Alzheimer’s, like with cancer, because it has multiple causes. At the ADDF, our scientific strategy is based on the biology of aging – the leading risk factor for Alzheimer’s disease. Alzheimer’s has a complex and interrelated set of causes, so drugs targeting more than one of those causes will be needed to effectively treat it. Targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases, such as Alzheimer’s.

Can you give us a brief idea about the most promising candidates for Alzheimer’s which ADDF is currently supporting?

Since 1998, the ADDF has awarded over $120 million to fund over 580 drug development programs in 19 countries. We support a diverse pipeline of drug targets beyond beta-amyloid. Alzheimer’s drugs aimed at neuroinflammation, genetics and epigenetics, neuroprotection, and metabolic and mitochondrial dysfunction are now in clinical trials or nearly there. We need to pursue all these targets and look for new ones. We need more rigorous trials. Alzheimer’s is a complex disease; likely involve combination therapy – an approach that’s standard of care in diseases like diabetes, heart disease, cancer, HIV/AIDS.

An epigenetic drug being developed for Alzheimer’s—ORY-2001 by Oryzon Genomics—is preparing for phase 2 trials. It works by inhibiting a protein that “turns down” the expression of several genes that are beneficial to the brain. By helping these genes express more, ORY-2001 may slow cognitive impairment and restore memory deficits in patients with Alzheimer’s and other disorders. The ADDF supported Oryzon with funding to help prepare for human clinical trials. A phase 1 study in 40 volunteers successfully demonstrated the drug’s safety. Another phase 1 clinical trial is currently underway to determine its optimal dose. And phase 2 clinical trials are being planned for later this year.

Another promising candidate is C-31 (also called LM11A-31), which was developed by Dr. Frank Longo, a professor at the Stanford School of Medicine and founder of the biotechnology firm PharmatrophiX. Dr. Longo is working on a remarkable drug candidate that could restore lost cognitive function and lead to the first regenerative therapy for Alzheimer’s. He received his first grant from the ADDF in 2000 for what was then just an idea. He thought that affecting the p75 receptor on the surface of neurons might keep those neurons alive and slow the progression of Alzheimer’s disease. With seed funding from the ADDF, he set out to find compounds to do just that. We’ve been funding this research for almost 18 years. Dr. Longo is now testing the effectiveness of C-31 in phase 2 clinical trials in Alzheimer’s patients including sites in Europe.

A third example is the work of Dr. Michela Gallagher, professor of Psychology and Neuroscience and heads the Neurogenetics and Behavior Center at Johns Hopkins University. She is also the founder of AgeneBio, Inc. a pharmaceutical development company that has initiated a Phase 3 trial recently to slow the progression of Alzheimer’s dementia. The ADDF is a funder of Dr. Gallagher’s therapeutic development of AGB-101, the first and only treatment to target hippocampal hyperactivity, a condition characteristic of the amnestic mild cognitive impairment stage of Alzheimer’s disease.

Dr. Gallagher’s research could yield the first drug to dramatically slow or stop the progression of amnestic mild cognitive impairment, altering the course of Alzheimer’s disease and restoring normal brain function. The enormous potential of her research is why ADDF has supported Dr. Gallagher’s work for nearly a decade.

Diagnostic Accelerator, in partnership with Bill Gates, is reportedly exploring the possibility of a blood test for Alzheimer’s. What is the present status of the study?

Critical to our success in finding effective ways to prevent and treat Alzheimer’s is the development of reliable, affordable, and accessible biomarkers – just as cholesterol is an early biomarker for heart disease. This will allow us to better understand how the disease progresses, more easily identify people for clinical trials, and more accurately monitor their response to treatments. That is why the Alzheimer’s Drug Discovery Foundation partnered with Bill Gates, the Dolby family, and the Charles and Helen Schwab Foundation to create the Diagnostics Accelerator.

The Diagnostics Accelerator is a potential game-changer for Alzheimer’s disease. The response to our initial request for proposals from the scientific community is overwhelming, with nearly 300 applications from 27 countries spanning six continents.
This initiative will help to accelerate the development of novel biomarkers from blood and other peripheral fluid and tissue. It is my hope that in the next few years a blood test will be available for the diagnosis of Alzheimer’s disease.

Using the biomarker specific model of precision medicine, we will be able to predict more accurately which treatment and prevention strategies will work in different at-risk populations of people who have Alzheimer’s disease or other forms of dementia, as we can now do in cancer, heart diseases, and other chronic diseases of aging and old age.
Ultimately, biomarkers can determine which therapies would be most effective for an individual.

Despite the increasing burden of the disease, there are not many real breakthroughs in Alzheimer’s drug research. Is it because of the poor understanding of the disease or due to other hurdles?

Today we know more about Alzheimer’s and the human brain than at any other time in history.

Alzheimer’s research did not result in real progress until the mid-1980s. One of the reasons is that Alzheimer’s disease and related dementias were thought to be a normal part of aging. So, until it was realized that Alzheimer’s disease was not a normal part of aging there was little interest in finding treatments for it.

It typically takes at least 30 years for drugs to be developed out of basic scientific research. The first drug to treat Alzheimer’s was not approved by the U.S. Food and drug administration until 1993, decades after drugs for cancer and heart disease were approved. Today’s breakthrough in heart disease and cancer therapies are built on yesterday’s investments in basic science.

Another major challenge has been the lack of affordable and noninvasive biomarkers as tools to better diagnose, monitor disease progression and make clinical trials more efficient and rigorous. That is why the ADDF Diagnostics Accelerator initiative is so important.

Where do you see Alzheimer’s drug discovery in the next five years down the lane?

Even though we don’t yet have a cure for Alzheimer’s disease, I’ve never been as optimistic as I am now about the potential for new drugs to prevent and treat this devastating disease. We are at a pivotal time in Alzheimer’s research with better diagnostics, a solid scientific understanding, and more than 120 drugs in clinical trials looking at novel treatments for Alzheimer’s disease. Many of these trials are in phase 2 and expected to read out within the next few years.

New therapeutics for Alzheimer’s disease will come from this understanding of the effects of aging on the brain. Our success in fighting Alzheimer’s disease will likely come from combination therapies -Because Alzheimer’s disease has multiple underlying causes, it will likely require a combination of drugs to effectively treat it. Precision medicine using combination therapy is likely needed for better treatment outcomes in Alzheimer’s disease, just as it is for cancer.

Now more than ever, we need to push forward the opportunity for new drug discoveries.