For almost two decades, the Alzheimer's Drug Discovery Foundation (ADDF) has brought together scientists—representing academia, government and industry—with one clear focus in mind: accelerating the development of treatments for Alzheimer's disease and related dementias. On September 17 and 18, nearly 200 researchers gathered at our 19th International Conference on Alzheimer's Drug Discovery to share their updates on various approaches being pursued to tackle this incredibly complex disease.
We are at a pivotal point in time in Alzheimer's research—as demonstrated by the research presented this year. We learned more about gene therapy and alternative modalities for neurodegenerative diseases, development of biomarkers, the use of existing drugs for other illnesses that can be used to help patients with Alzheimer's, and brain aging and Alzheimer's—novel drug targets such as inflammation, mitochondria, and neuroprotection.
The ADDF is proud to host this meeting each year and support programs in pursuit of finding a cure. It is an opportunity to share our collective learnings and progress in advancing research and clinical trials. It speaks to the importance of collaboration in bringing us one step closer to achieving this goal. And, that is to support the science that will drive forward the development of therapies for the prevention and treatment of Alzheimer's.
The Need for New Biomarkers for Alzheimer's Disease
Biomarkers are critical tools used to diagnose patients, identify the right patients for clinical trials, monitor treatment response, and eventually to identify patients that will respond to specific drugs. In a keynote address, Rosa Canet-Aviles, PhD, Science Program Manager for Neuroscience at the Foundation for the National Institutes of Health (FNIH), discussed consortium efforts for developing biomarkers for drug development. She highlighted the importance of establishing public-private partnerships in addressing the challenges around prioritizing biomarker needs, focusing resources, and integrating efforts across stakeholders. The ADDF is currently supporting efforts through the FNIH Biomarker Consortium.
In presentation sessions, researchers highlighted several blood tests in early development for Alzheimer's disease with the goal of facilitating lower cost and more efficient screening of patients for Alzheimer's clinical trials. Blaine Roberts, MD, of the Florey Institute of Neuroscience and Mental Health, and Tim West, PhD, of C2N Diagnostics, focused on the development of two different blood tests to measure Abeta levels. Abeta is the peptide responsible for the neurotoxicity seen in Alzheimer's disease. Finding candidate molecules to reduce Abeta in clinical trials of Alzheimer's patients is a goal of researchers.
Diana Cha, PhD, of Brigham and Women's Hospital, described efforts to isolate brain-derived exosomes, tiny packets from the brain that are found in the blood that could serve as an Alzheimer's disease biomarker. The ADDF is actively supporting the development of these tests through the Diagnostics Accelerator, an initiative that advances the development of novel biomarkers from blood and other peripheral fluids and tissue to diagnose Alzheimer's disease and related dementias.
Jacob Hooker, PhD, of Massachusetts General Hospital, described the use of a novel positron emission tomography (PET) ligand, which can measure levels of enzymes, called histone deacetylases (HDAC) in the human brain. (A PET-ligand is a type of tracer that can bind to a specific molecule in the body and be imaged in a special type of scanner.) This allows for the visualization of HDAC levels in the brain, which indicates how much certain genes in the brain will be expressed. By using this PET tracer, Dr. Hooker was able to show how HDAC levels change with age and relate to the development of neurodegenerative diseases. This ligand could potentially inform how HDACs could be used as a drug target for Alzheimer's.
Promising Gene Therapy Approaches
Several presentations highlighted gene therapy and stem cell approaches for dementia. The ADDF is funding two different ways to target APOE4, the most significant genetic risk factor for Alzheimer's disease. Anastasia Khvorova, PhD, of the University of Massachusetts Medical School, and her collaborator Evgeny Rogaev, PhD, are developing RNAi constructs (also known as anti-sense oligonucleotides) to reduce APOE gene expression. Ronald Crystal, MD, of Weill Cornell Medicine, uses a different approach where APOE2 (the protective form of the gene) is delivered to the brain to counteract the negative effects of APOE4. Dr. Crystal recently received FDA approval to proceed into the first human clinical trials with APOE2 gene therapy. People with two copies of the APOE4 variant of the gene are up to 12 times more likely to develop Alzheimer's and to get it at younger ages.
Advancing Clinical Trials
Agitation is a common and persistent symptom in those with Alzheimer's disease and current therapies have modest efficacy and/or poor safety. Krista Lanctôt, PhD, Sunnybrook Research Institute, University of Toronto, presented study results on the safety and efficacy of nabilone in patients with moderate to severe Alzheimer's disease. Dr. Lanctôt reported that nabilone significantly improved agitation in a trial of 39 moderate-to-severe Alzheimer's patients. Improvements were observed with nabilone as early as two weeks. Some patients experienced sedation with nabilone, though 53 percent of the patients tolerated the highest dose (2 mg/day). As the pilot study showed positive results, a larger Phase 3 study is being planned. Nabilone is a synthetic derivative of cannabis marketed for nausea and vomiting associated with chemotherapy. This study is funded by the ADDF and the Alzheimer's Society of Canada.
Synapses, the junctions between nerve cells, are important for memory and cognition. Current treatments for Alzheimer's disease increase levels of acetylcholine, a neurotransmitter that carries signals across synapses. However, these treatments only modestly impact Alzheimer's symptoms. Paul Newhouse, MD, of Vanderbilt University Medical Center, reported preliminary results from his Phase 1 study of a novel drug compound VU319 that modulates M1 synaptic receptors, helping to "catch" those signals. Previous drugs targeting M1 produced improvement in cognitive performance and behavioral disturbances in Alzheimer's patients, but failed in Phase 3 trials due to intolerable (cholinergic) side effects. The five doses of VU319 tested so far have been well-tolerated. In late 2018, the second part of the Phase 1 trial is planned with the aim to start a Phase 2a VU319 study in people with mild cognitive impairment in the latter half of 2019. This trial will be a proof-of-concept double-blind placebo-controlled study to assess the ability of VU319 to modulate brain networks.
Giacomo Koch, MD, PhD, of Santa Lucia Foundation, presented preliminary findings from the DOPAD trial, which tests a dopaminergic therapy called rotigotine. Rotigotine is a transdermal patch prescribed for Parkinson's disease and restless leg syndrome. The trial in 94 mild Alzheimer's patients tested whether rotigotine improved cognitive function, including executive function, and activities of daily living after six months of treatment. Initial results will inform the design of a larger study for rotigotine as a potential cognitive enhancer for Alzheimer's.
For excerpts of a few highlights, we encourage you to visit NeurologyLive, which featured interviews of the researchers and medical experts at our meeting. Their expertise and perspectives will inform their viewers, who are healthcare professionals treating neurological diseases.
Howard Fillit, MD is the Founding Executive Director and Chief Science Officer at the ADDF.