Once again, I was privileged to host a panel featuring leading scientists on the front lines of Alzheimer’s discovery. This discussion took place before the annual luncheon of the Melvin R. Goodes Prize for Excellence in Alzheimer’s Drug Discovery. We were fortunate to have all five Goodes Prize recipients present to discuss their work—all of which tackles the question: "What’s Next After Amyloid Failures?”
THE BIOLOGY OF AGING
Until recently, Alzheimer’s drug development has been largely focused on beta amyloid plaques and tau tangles in the brain, the classic hallmarks of Alzheimer’s disease. Unfortunately, these attempts have yielded less successful results than had been anticipated. Sharing the ADDF’s long-held belief that aging is the main cause of Alzheimer’s disease, these visionary scientists have taken the field in new directions—investigating drugs that impact multiple symptoms of aging, not just plaques and tangles. Their body of work represents some of the most novel, non-amyloid approaches to the discovery and development of drugs for Alzheimer’s and related dementias. It was exciting to hear each of the participants discuss what could become the “next big thing” in Alzheimer’s research.
SLOWING ALZHEIMER’S PROGRESSION BY REPURPOSING A PARKINSON’S DRUG: Dr. Jeffrey Cummings
Jeffrey Cummings, MD, ScD, Research Professor of the Department of Brain Health at the University of Nevada, Las Vegas and Director of the Center for Neurodegeneration and Translational Neuroscience at the Cleveland Clinic Lou Ruvo Center for Brain Health, is the 2019 Goodes Prize awardee. He is currently conducting a phase 2 clinical trial of rasagiline, an FDA-approved treatment for Parkinson’s disease, that holds promise for slowing the progression of Alzheimer’s disease in patients with mild cognitive impairment. His work is based on the observation that rasagiline controls cognitive symptoms as well as motor skill deficits in Parkinson’s patients. Dr. Cummings discussed the positive results of a phase 2 study among 50 Alzheimer’s patients where statistically significant benefits were seen in brain metabolism in the treatment vs. placebo group—slowing down the formation of tau tangles.
Dr. Cummings explained how repurposing an existing drug accelerates the drug development timeline. “The drug development timeline for a repurposed drug is 40% shorter versus a drug that starts out as a white powder and has to be tested in animals,” he said. He expressed gratitude to the ADDF for directing him to scientists who know how to do the metabolic brain imaging and tau imaging necessary for his research. Hopefully, rasagiline can become a treatment option for those suffering from mild Alzheimer’s.
TARGETING NEUROINFLAMMATION AND LOSS OF CONNECTIONS IN THE BRAIN: Dr. Daniel Martin Watterson
Daniel Martin Watterson, PhD (2016 Goodes Prize awardee), a John G. Searle Professor of Molecular Biology and Biochemistry, Northwestern University Feinberg School of Medicine, is a medicinal chemist and founder of NeuroKine Therapeutics, a biotech company developing a new class of drugs that focuses on brain inflammation and the loss of connections between brain cells. In the past, the idea of inflammation in Alzheimer’s was discounted as trials of certain anti-inflammatory agents failed. But many researchers now think that neuro anti-inflammatories that specifically affect cells in the brain could prove promising. In fact, the largest part of the ADDF portfolio is now related to neuro anti-inflammatories, including an investment in Dr. Watterson’s company.
Dr. Watterson revealed that initial testing of his neuro-anti-inflammatories was successful, and he is now planning for phase 2, the first in-patient trials. Dr. Watterson noted, “Other funders looked askance at this because it wasn't directly attacking amyloid.” He added the Goodes Prize helped to fast-track the approvals of phase 1A and 1B. “I would call ADDF not only an innovation funder, but a catalyst of progression,” Dr. Watterson said.
POSSIBLE REGENERATION OF THE ALZHEIMER’S BRAIN: Dr. Roberta Diaz Brinton
Roberta Diaz Brinton, PhD (2017 Goodes Prize awardee), inaugural Director of the Center for Innovation in Brain Science at the University of Arizona, where she also serves as Professor of Pharmacology and Neurology in the College of Medicine, Tucson, is conducting research focusing on the bioenergetic and regenerative systems of the brain. For the past 40 years, Dr. Brinton has been working on a neuroactive metabolite of progesterone called allopregnanolone—a substance found in the body, that declines with age, with tremendous metabolic effects.
Early on the ADDF funded Dr. Brinton’s work, as she discovered that the allopregnanolone molecule seemed to stimulate the proliferation of stem cells and create new nerve cells. This process, called “neurogenesis,” has the potential to restore lost cognitive function in Alzheimer's patients by essentially regenerating the degenerated Alzheimer’s brain.
Dr. Brinton explained that she is moving forward with a phase 2 clinical trial funded by a grant from the National Institute of Aging (NIA), built on ADDF support, including the Goodes Prize. “It appears that allopregnanolone is most beneficial in those who carry the risk factor gene for Alzheimer’s disease,” she explained. As such, she is looking at a precision medicine approach for therapeutic development of allopregnanolone for Alzheimer’s in this high-risk population. While the initial trial involved intravenous infusion, thanks to the Goodes Prize, Dr. Brinton hopes to be able to investigate and patent formulations of this molecule with alternate delivery systems.
COMBATTING OVER-ACTIVITY IN THE AGING BRAIN: Dr. Michela Gallagher
Michela Gallagher, MD (2018 Goodes Prize awardee) is the Krieger-Eisenhower Professor of Psychology and Neuroscience, head of the Neurogenetics and Behavior Center at Johns Hopkins University and founder of the therapeutics company AgeneBio. Her work also holds the potential to slow symptoms of Alzheimer’s disease in patients with mild cognitive impairment. To my knowledge, Dr. Gallagher’s drug trial is the only phase 3 for Alzheimer’s disease that is a non-amyloid approach.
Dr. Gallagher explained her discovery that memories get degraded when over-activity occurs in specialized circuits for memory in the brain, leading to a condition that is pathological even for healthy neurons. “We found a drug that can normalize that over-activity,” Dr. Gallagher said. Her phase 3 trial aims to discover whether it’s possible to halt the progression of impairment and prevent dementia. Dr. Gallagher estimates that if we can prolong the usually decade-long transition from mild cognitive impairment to dementia for five years, we could decrease the number of people with dementia by 50 percent. She revealed funding from the Goodes Prize is helping to analyze the progress of patients in treatment using tau imaging that observes the spreading of tau in the brain at baseline and after treatment.
Dr. Gallagher discussed her appreciation for ADDF’s involvement in a separate project exploring a potential biomarker in cerebrospinal fluid that may predict whether people have a problem in the regulation of brain activity that could lead to Alzheimer’s disease. “We want the biomarker because we can use it in people in their 40s and 50s. If you start seeing this substance dropping, it would be like taking statins for high cholesterol.”
RESTORING LOST SYNAPTIC ACTIVITY: Dr. Frank Longo
Frank Longo, MD, PhD (2015 Goodes Prize awardee), George E. and Lucy Becker Professor and Chair of the Department of Neurology and Neurological Sciences, Stanford Medicine; Board Chairman and Founder of the biopharmaceutical firm PharmatrophiX, is currently working on a truly remarkable drug candidate (C-31), now in phase 2 clinical trials. This agent could restore lost cognitive function and lead to one of the first neuroprotective therapies for Alzheimer’s and other forms of dementia. It is my belief that if this drug works, it will be revolutionary.
Dr. Longo discussed how in Alzheimer’s disease we lose synaptic connections—the means of communication between brain neurons. He explained that each cell of our body has a chemical signaling process that tells the cell what to do; to divide or not; to keep a connection or let it degenerate. As we age, and certainly in Alzheimer’s disease, the chemical signaling of the neurons is telling those synapses to degenerate. Receptors on the surface of the neurons control this degenerative signaling. As Dr. Longo explained, the goal is to target these receptors with therapeutics.
Dr. Longo successfully developed drugs that target two particular receptors to counteract the degenerative process and normalize synaptic function. Disagreeing with the thinking that late treatment of Alzheimer’s is hopeless, Dr. Longo commented, “I’m not going to give up on the 50 million people in the world who have a diagnosis of Alzheimer’s. We can create therapies to get synaptic function back at least to a significant extent.”
Howard Fillit, MD is the Founding Executive Director and Chief Science Officer at the ADDF.