19th International Conference on Alzheimer's Drug Discovery Highlights Multiple Approaches to Prevent and Treat Alzheimer's Disease

Nearly 200 academic and industry researchers gathered this week to share updates on preclinical and clinical-stage Alzheimer's disease research at the 19th International Conference on Alzheimer's Drug Discovery. The two-day conference, organized by the Alzheimer's Drug Discovery Foundation (ADDF), focused on gene therapy and alternative modalities for neurodegenerative diseases, progress in developing novel drugs to treat Alzheimer's disease (AD) and related dementias, as well as the need for new biomarkers.

"This is a pivotal time in Alzheimer's disease research and drug discovery," said Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF. "Progress in many areas of research, including the identification of new biomarkers, novel drugs and gene therapy, as well as the use of existing drugs for other illnesses, show promise as new approaches for the prevention and treatment of Alzheimer's disease."

Highlights from the conference included:

• In a keynote address, "NIH Biomarker Initiatives in Neuroscience—Consortium Efforts in the Development of Biomarkers for Drug Development," Rosa Canet-Aviles, Ph.D., Science Program Manager for Neuroscience at the Foundation for the National Institutes of Health (FNIH), discussed consortium efforts for developing biomarkers for drug development. Biomarkers are critical tools to diagnose patients, identify the right patients for clinical trials, monitor treatment response, and eventually identify patients that will respond to specific drugs. Dr. Canet-Aviles noted the challenges around prioritizing biomarker needs, focusing resources, and integrating efforts across stakeholders. She highlighted the importance of establishing public-private partnerships. ADDF is currently supporting efforts through the FNIH Biomarker Consortium.
• In the biomarker session that followed, speakers 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 Alzhiemer's clinical trials. Blaine Roberts, M.D., of the Florey Institute of Neuroscience and Mental Health, and Tim West, Ph.D., 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 vivo and in clinical trials of Alzheimer's patients is a goal of researchers.
• Diana Cha, Ph.D., 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, Ph.D., 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 radioligand that is used for diagnostic purposes via PET imaging.) This allows for the visualization of how brain gene transcription levels change with age and relate to the development of neurodegenerative diseases. This ligand could potentially be used as a biomarker to measure the efficacy of agents targeting brain atrophy.
• Several presentations highlighted gene therapy and stem cell approaches for dementia. The ADDF is funding two different approaches that target APOE4, the most significant genetic risk factor for Alzheimer's disease. Anastasia Khvorova, Ph.D., of the University of Massachusetts Medical School, and her collaborator Evgeny Rogaev, are developing RNAi constructs (also known as anti-sense oligonucleotides) to reduce APOE gene expression. Ronald Crystal, M.D., 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.
• In a session focused on clinical trials, Krista Lanctôt, Ph.D., Sunnybrook Research Institute, University of Toronto, presented study results on the safety and efficacy of nabilone in patients with moderate to severe AD. 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 THC marketed for nausea and vomiting associated with chemotherapy. Agitation is a common and persistent symptom in those with Alzheimer's disease and current pharmacotherapies have modest efficacy and/or poor safety. This study is funded by the ADDF and the Alzheimer's Society of Canada.
• Giacomo Koch, M.D., Ph.D., 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.
• 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, M.D., 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, a multiple-ascending dose study is planned to assess the safety and tolerability of seven consecutive-day dosing, 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.

"We have come a long way in our scientific understanding of Alzheimer's disease, particularly in the past 10 to 15 years," said Dr. Fillit. "This meeting highlights the support of ADDF, which has granted more than $115 million to fund more than 585 Alzheimer's drug discovery programs and clinical trials in 18 countries."