Nearly 200 academic and industry researchers came together to share updates on preclinical and clinical-stage Alzheimer’s disease research at the 18th Annual Conference on Alzheimer's Drug Discovery. The two-day conference, organized by the Alzheimer’s Drug Discovery Foundation (ADDF), is the first and only to focus solely on non-amyloid drug programs in development.
“It’s encouraging to see how many promising new targets have reached clinical stages of development,” said Howard Fillit, MD, chief science officer of the ADDF. “Thanks to the hard work of these researchers, the field is finally shifting toward more innovative targets for treating Alzheimer’s and looking beyond amyloid-targeted approaches for answers.”
Data presented at the conference focused on targets across neuroinflammation, neuroprotection, neural regeneration, epigenetics, and more.
Pre-clinical finding highlights included:
- Challenges in Developing Microglia-Targeted Therapeutics: Stefan Lohmer, PhD, from the Italian research organization Axxam, found that microglia, classically defined as resting, are in fact not. “They are like sharks,” said Lohmer. “Always moving around, always monitoring the surrounding environment.” This better understanding of the brain’s immune cells is helping to pave the way for new therapeutic routes to this challenging target.
- Therapeutic Potential of Dual Leucine Zipper Kinase Inhibitors in Alzheimer's Disease: William J. Ray, Ph.D., from the Neurodegeneration Consortium at MD Anderson Cancer Center presented data on his neuroprotective drug IACS-8300. Dr. Ray noted that injury to axons is common in Alzheimer’s and other neurodegenerative diseases. And this axonal injury often leads to the death of neurons. Dual leucine zipper kinase (DLK) is involved in this process and inhibiting DLK appears to protect neurons from axonal degeneration. IACS-8300 blocks DLK and has a good safety profile in preclinical studies. Dr. Ray and his team are currently optimizing their drug for clinical use.
Clinical-stage highlights included:
- Safety and Anti-Inflammatory Actions of GC021109, Targeting the P2Y6 Receptor to Stimulate Microglia: As levels of amyloid increase in the brain they decrease in cerebrospinal fluid (CSF), indicating that these proteins aren’t being cleared from the brain by microglia. Philip Haydon, PhD, of Boston-based biotechnology company GliaCure, developed GC021109 to help microglia perform their clearance function more effectively. Dr. Haydon’s completed phase 1 clinical trial suggests that GC021109 changes the trajectory of a decades-long decline in amyloid in CSF in patients with mild Alzheimer’s after 28 days of treatment.
- NDX-1017, a Novel Regenerative Disease-Modifying Therapy for Alzheimer’s Disease: Leen Kawas, PhD, of M3 Biotechnology, expects to enter phase 1 clinical trials with her drug NDX-1017 in October 2017. The drug targets the receptor for hepatocyte growth factor, which appears to induce the growth and survival of neurons. Dr. Kawas presented preclinical data showing that NDX-1017 increased synapses, improved learning, and reversed spatial memory deficits.
- Results from a Pilot Clinical Trial of Allopregnanolone: A Regenerative Therapy for Alzheimer’s Disease: Roberta Diaz Brinton, PhD, from the University of Arizona, is conducting a phase 1b/2a pilot trial of allopregnanolone (allo), a neuro-steroid. In previous studies, she found that allo activates neural stem cell proliferation. Initial results from the pilot trial indicate that allo is safe and appears to prevent atrophy in the hippocampus compared to placebo, with patients responding to allo being overwhelmingly APOE4-positive. Surprisingly, Dr. Brinton found that the left and right sides of the hippocampus don’t react to the drug the same way, and male and female patients also responded differently. She plans to investigate these outcome further in future trials.
- Applying Radiochemical Approaches to Investigating Novel Targets for Neurodegenerative Disease: Neil Vasdev, PhD, of Massachusetts General Hospital and Harvard Medical School, gave the second day’s keynote. Dr. Vasdev is committed to helping his fellow Alzheimer’s researchers get their drugs into human trials as quickly as possible and ensuring the success of those trials through the development of brain imaging markers. He is currently developing positron-emission tomogrophy (PET) ligands for nearly a dozen different markers of Alzheimer’s disease.
PET scans and other tests accelerate Alzheimer’s drug development in two ways: they tell researchers whether their drugs are reaching the intended target and if they are having the desired effect. And they are in short supply. Many researchers at the conference described their need for better biomarkers to advance their drug programs. Steven Finkbeiner, MD, PhD, of the Gladstone Institutes and University of California, San Francisco, is working on drugs to stimulate autophagy, a process that clears proteins from neurons. Dr. Finkbeiner said: “It is difficult to develop good clinical markers of autophagy. We need better tools to understand these complex processes.”
Dr. Fillit ended the proceedings, saying: “Joining so many pioneering researchers—each committed to their unique path to treat Alzheimer’s—is why I look forward to this conference every year. The ADDF is committed to giving them all the resources they need to succeed.”
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