ADDF’s 21st International Conference on Alzheimer’s Drug Discovery Showcases Depth and Breadth of Alzheimer’s Research Advances

The Alzheimer’s Drug Discovery Foundation (ADDF) hosted the 21^st International Conference on Alzheimer’s Drug Discovery virtually on October 5-6, 2020. The conference welcomed more than 700 attendees to hear presentations and join in discussions about recent discoveries and drug developments in preclinical, clinical, and biomarker research programs for Alzheimer’s and related dementias.

“In my more than 40 years working in this field, my excitement about the future has never been stronger,” said Howard Fillit, M.D., Founding Executive Director and Chief Science Officer of the ADDF. “These two days have been incredibly energizing and have shown us the remarkably wide range of work being done in the field.”

The conference featured four sessions during which researchers discussed novel approaches to underlying causes of Alzheimer’s, including neuroinflammation and degeneration, metabolic and mitochondrial dysfunction, and synaptic health. The sessions also included results from preclinical through phase 2 clinical studies.

The fifth session was devoted to novel biomarkers in Alzheimer’s disease. The ADDF has supported the development of biomarkers for Alzheimer’s and related dementias virtually since its inception, with an increased emphasis on those that are non-invasive and inexpensive over the past two years through its Diagnostics Accelerator program. Biomarkers were also featured in nearly every talk during the two-day conference, highlighting their importance in the clinical trial process and ultimately clinical care.

Conference highlights included:

In a session focused on neuroprotection, synaptic health and neurotransmitters, Ana Pereira, M.D., Assistant Professor of Neurology and Neuroscience at the Icahn School of Medicine in New York, presented results of a phase 2 clinical trial of the Glutamate Modulator Riluzole in Patients with Mild Alzheimer’s Disease.

Riluzole works by modulating levels of the neurotransmitter glutamate in the brain, which when dysregulated causes significant cerebral damage and accelerates cognitive decline.

The trial randomly assigned 42 patients with mild Alzheimer’s between the ages of 58 and 88 years to receive either riluzole or placebo for six months. Investigators used two types of functional brain imaging to assess metabolic changes in the brain, plus neuropsychological tests to assess changes in cognition.

Patients in the treatment arm had significantly less decline in cerebral metabolism, measured by FDG-PET scan in several brain regions, and investigators found a strong correlation between brain metabolism and cognitive performance. Investigators found no difference between treatment and placebo groups in their levels of N-acetylaspartate, a metabolite that is reduced in people with Alzheimer’s, but did observe changes in glutamate levels as a measure of target engagement through magnetic resonance spectroscopy. “We are very excited by these promising FDG-PET cerebral metabolic results, which correlate with cognitive changes and disease progression, supporting moving into phase 3 clinical trials where we can study a larger number of patients for a longer period,” said Dr. Pereira.

The ADDF has been a long-time supporter of Dr. Pereira’s work with riluzole, a repurposed drug that has been used for more than 20 years in patients with ALS, also known as Lou Gehrig’s disease. Riluzole is the only drug that has been shown to slow the course of ALS and its long-term safety has been well documented.

In a session on novel approaches for neuroinflammation, CJ Barnum, Ph.D. of INmune Bio presented Phase 1b Study in Patients with Neuroinflammation. Interim results from 6 of the 18 patients expected to enroll in this study show that treatment with a selective inhibitor of tumor necrosis factor (TNF) decreased inflammation in the language processing area of the brain by an average of 40%. The study measured a novel biomarker, White Matter Free Water, which shows edema within the white matter tissue of the brain. The trial is expected to complete by the end of 2020 with additional biomarker results to come.

In the neuroinflammation section, Jeffrey Stavenhagen, Ph.D., Chief Science Officer of Therini Bio, Inc., presented Preclinical Development of an Antibody Therapeutic and an Imaging Agent Targeting Fibrin-Mediated Neuroinflammation. Fibrin is an important blood protein that is responsible for normal blood clotting, but when it leaks into the brain, it can initiate damaging inflammation. Cerebral microbleeds and other vascular abnormalities associated with fibrin occur in about 45% of patients during the early stages of Alzheimer’s disease. With support from the ADDF, Therini Bio is developing a novel monoclonal antibody that selectively inhibits fibrin’s ability to cause inflammation while leaving its essential coagulation function intact. This is a very important target because this vascular problem occurs early in the disease and is hypothesized to be an independent predictor of cognitive decline. Therini Bio is moving forward with humanizing antibody candidates currently in preclinical models with plans to soon start clinical studies. 

In the day one keynote address, Gene Therapy for Neurodegeneration, Ronald Crystal, M.D., Chairman of Genetic Medicine at Weill Cornell Medicine in New York, discussed the promise and challenges of gene therapy for Alzheimer’s and other neurodegenerative diseases. This cutting-edge approach aims to replace or correct faulty genes that are at the root of neuron deterioration and death.

Since the ADDF began funding the Weill Cornell Medicine gene therapy project in 2004, Dr. Crystal and his team have initiated a gene therapy trial for Alzheimer’s disease in humans and have developed gene therapies for cardiovascular and other genetic diseases. Now they are using what they have learned as they turn their attention to stopping neurodegeneration.

The most important advance in gene therapy for neurodegenerative diseases, says Dr. Crystal, was the discovery and development of a family of benign viruses that can carry gene therapies across the blood-brain barrier and deliver them directly to the right target cells. “It’s like a message in a bottle, but with amazing precision,” says Dr. Crystal. “We can modify the adeno-associated viruses to be sure they land where we need them — in this case the brain’s neurons, where they drop off their message in the form of a therapeutic gene that can fix the underlying problem.”

In the day two keynote address, Current State for Blood Biomarkers in Alzheimer’s Disease, Henrik Zetterberg, M.D., Ph.D., Professor of Neurochemistry at the University of Gothenburg in Sweden discussed how new studies combining ultrasensitive measurement technologies with clearly defined patient populations are uncovering ways to reliably diagnose underlying Alzheimer’s pathology using blood tests. Promising tests are on the horizon to detect levels of three proteins signaling the disease: amyloid, NfL (neurofilament light peptide) and tau. Dr. Zetterberg’s research is one of the initiatives funded through the ADDF’s Diagnostics Accelerator, which aims to accelerate the development of reliable and affordable biomarker tests for Alzheimer’s.

In the program’s final session on novel biomarkers, Lampros Kourtis, Ph.D. of Circadic discussed Digital Biomarkers in Alzheimer’s Disease, which are advancing at a rapid pace as a deeper understanding of the biology of Alzheimer’s disease is matched by lightning-fast advances in technologies, including artificial intelligence, ambient sensors, and mobile and wearable devices.

These programs and devices, says Dr. Kourtis, offer a passive and unobtrusive way to gather data about motor functions, spoken and written language, physical activity, and many other domains. “People who go on to an Alzheimer’s diagnosis are likely to have changes in each of these areas,” says Dr. Kourtis. He cautions each biomarker alone has extremely limited ability to forecast or detect Alzheimer’s. “But combined these data can help us create composite scores, or digital phenotypes, that can tell with much greater specificity whether the changes an individual is experiencing are normal or predictive of an Alzheimer’s diagnosis.”

“I applaud the hard work and dedication of all of the researchers who joined us,” said Dr. Fillit. “Meetings like this are a vital part of the Alzheimer’s drug discovery and development process, giving some of the best and brightest minds in our field the opportunity to exchange ideas, share results and challenge each other to find new and innovative approaches to conquer this complicated disease of aging.”