The Alzheimer’s Drug Discovery Foundation (ADDF) awarded three new grants in November and December, totaling nearly $2.5 million. The grants represent the ADDF’s commitment to advancing the most promising drugs to clinical trials, the final stages of drug development—two of the grants support clinical trials and the third funds testing required before beginning such trials.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, remarked: “These grants demonstrate the wide-ranging approaches we take to find effective drugs for Alzheimer’s disease. One drug, efavirenz, is approved for another condition but, at a lower dose, appears to benefit Alzheimer’s patients. VU046731, which the ADDF has funded for several years, takes a fresh approach to improve and preserve memory and slow the progression of the disease. The third drug, MW150, targets brain inflammation, a very promising area of Alzheimer’s treatment that we supported a decade before most funders. Thanks to those early investments, drugs tackling neuroinflammation are headed toward the clinic.”
Irina Pikuleva, PhD, Case Western Reserve University School of Medicine
Cholesterol-metabolizing Enzyme CYP46A1 as a New Therapeutic Target for Alzheimer's Disease
Cholesterol is produced and is abundant in the human brain. Preclinical studies suggest that eliminating excess cholesterol may decrease beta-amyloid proteins and improve cognition in Alzheimer’s patients. Dr. Pikuleva and her team discovered that very low doses of efavirenz, an FDA-approved anti-retroviral medication, increase the activity of the CYP46A1 enzyme responsible for cholesterol elimination in the brain. With ADDF funding, she plans to conduct a small Phase 1b/2a clinical trial to determine the optimal dose of efavirenz for treating Alzheimer’s and confirm its safety in older adults. If successful, Dr. Pikuleva plans larger confirmatory trials.
Paul Newhouse, MD, Vanderbilt University Medical Center
Phase 1 First-in-Human Multiple Ascending Dose Study of the Putative Cognitive Enhancer and M1 Positive Allosteric Modulator VU0467319
Synapses, the spaces between neurons, are important for memory and cognition. Current treatments for Alzheimer’s disease increase levels of acetylcholine, a neurotransmitter that carries signals across synapses. But these treatments only modestly impact Alzheimer’s symptoms. Dr. Newhouse and his colleague Dr. Jerri Rook have developed a drug that focuses on M1 synaptic receptors, which “catch” those signals. Previous drugs targeting M1 have had intolerable side effects. With previous support from the ADDF, Drs. Newhouse and Rook took an indirect approach to M1 and developed the drug VU0467319, which appears to improve cognitive symptoms and prevent losses in cognitive abilities without the negative side effects. With this new grant, the researchers plan to conduct a Phase 1 clinical trial of VU0467319 in Alzheimer’s patients to assess its safety and the optimal dose to achieve benefit. This program is supported through the ADDF’s partnership with the Harrington Discovery Institute.
Ottavio Arancio, MD, PhD, Columbia University
A Novel Isoform Selective Kinase Inhibitor Candidate with In Vivo Efficacy in Two Alzheimer's Models: Proposal for GLP Tox Package for Phase 1 IND
Kinases are enzymes that, in the brain, are involved in inflammatory responses. Reducing kinase activity can lessen brain inflammation and protect neurons from damage, thus slowing the progression of Alzheimer’s disease. Dr. Arancio together with Dr. Watterson—a well-known pharmacologist and our 2016 Goodes Prize recipient—have developed MW150, a drug that inhibits specific kinases and reduces toxic inflammation. With this funding, the team will complete the testing required by the FDA prior to beginning human clinical trials. Once the tests are done, Dr. Arancio will file an investigational new drug (IND) request with the FDA and, if approved, proceed to clinical trials.