Trevor Twose, Ph.D., is CEO of Mithridion, which is developing M1/M4 subtype-selective muscarinic receptor agonists that result in decreased levels of Aß and restoration of cognitive deficits.
The M1 subtype, in particular, acts on cognition and memory and has disease-modifying potential, explained Dr. Twose. While proof of concept has been achieved for the ability of M1/M4 agonists to improve cognition, their ability to modify the course of AD has not yet been demonstrated.
Muscarinic receptors work through G-protein coupled receptors (GPCRs) to trigger the inositol phosphate (IP) pathway. Mithridion used xanomeline, a known muscarinic agonist, as the basis for a primary in vivo nonisotopic, time-resolved FRET assay designed to measure selective muscarinic M1 activity.
Subsequent lead optimization has led to the development of MI-10-022, a fourth-generation lead candidate that is selective for M1/M4 activity, is about seven times more potent than xanomeline, according to Mithridion data, efficiently crosses the blood-brain barrier, and is resistant to metabolism.
MI-10-022 is also a potential first-in-class monotherapy for schizophrenia, according to Dr. Twose. The compound has completed preclinical development and is ready to enter IND-enabling studies, including toxicology, analytical methods development, and optimization of production and large-scale manufacturing.
Biomarkers have been critical to the development of MI-10-022. “They let us answer the question of how well our experimental compounds engage the muscarinic M1 receptor in the hippocampus,” said Dr. Twose. They have also allowed the company to perform studies in the salivary glands of animals to measure simultaneously in the same animal the compound’s activity against the M1 and M3 subtypes to assess its comparative selectivity.
“Research is exploding in this area,” concluded Dr. Twose, with the emergence of AD-focused consortia including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) based at the University of California, San Francisco, and the more recently formed Dominantly Inherited Alzheimer Network (DIAN) consortium out of Wash.ington University in St. Louis.
By following individuals with the inherited form of AD who carry dominant mutations in the presenilin-1 gene, which are 100% penetrant for early-onset AD, it is possible to correlate CSF and imaging biomarkers with the onset of preclinical disease.
Professor Masters is a member of the core research team of AIBL, the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing. Launched in 2006, AIBL is a prospective longitudinal study that includes patients with AD, mild cognitive impairment (MCI, a precursor to AD), and healthy volunteers.
At the Singapore conference, Professor Masters described several goals for AIBL: to develop and confirm diagnostic biomarkers and psychometrics for objective monitoring of disease progression; to understand the role of lifestyle factors; and to inform the development of preventive and therapeutic strategies. For biomarker research overall, Professor Masters concluded that “PET scans are proving enormously valuable, and we are getting close to being able to see registration at the FDA level for ligands to detect amyloid.”
When that occurs, “testing for preclinical disease will be a reality.” In the future, PET scanning might be used more broadly as a screening tool downstream of a suspicious CSF or blood test.
The aim of AIBL is “to get a handle on the natural history of AD, including preclinical progression and [variability in the] rates of progression. The single major problem we have is confounding diseases—mainly vascular disease and small strokes in the brain,” with the effects of ischemia caused by stroke being difficult to distinguish from preclinical AD.