Stronger links between novel agents and their targets, more precise selection of patients, and better assessment of response are essential elements for Alzheimer’s disease (AD) clinical trials, said Alessandro Padovani, Professor of Neurology, University of Brescia, Italy, in his packed plenary session at AAT-ADPD.
Clinical trials have made a major contribution to recent advances in understanding the pathophysiology of AD and in demonstrating that earlier treatment is beneficial for prodromal patients. Professor Padovani expressed his optimism that new treatment discovery depends upon the continued efforts of AD researchers worldwide to:
- Provide a deep understanding of disease mechanisms
- Demonstrate strong linkage of targets to AD
- Improve translational measures, from preclinical to clinical
- Improve trial design (many failures over the past 20 years have resulted from poor study design)
- Generate promising potential investigational compounds to strongly linked targets
- Identification of patients most likely to respond to a given mechanism of action of an investigational drug
A great deal of progress has been made over the past decade
Over the past decade, the mechanisms behind the underlying pathophysiology of β-amyloid and tau in AD have become much more clearly defined. In addition, the detection of β‑amyloid and tau biomarkers in vivo — both imaging and in the CSF — has demonstrated that the pathological processes precede clinical symptoms by many years; and trial results suggest that early treatment is beneficial for prodromal AD patients.
Many new investigational compounds target beta-amyloid and tau pathobiology
Many new investigational compounds targeting different forms of β‑amyloid and tau pathobiology have been developed and are undergoing clinical trials. Professor Padovani explained how minor structural features in monoclonal antibodies can drive selectivity for β-amyloid aggregates and enhance agents’ ability to penetrate the blood-brain barrier.
In the development of these antibodies, he emphasized the importance of demonstrating that brain exposure is proportional to the dose, providing evidence of in vivo binding to β‑amyloid deposits, and showing a dose-dependent decrease in amyloid plaques with chronic treatment.
Collaboration between centres worldwide and the development of tools to enable comparisons of data from different centres are critical to maintain and accelerate the progress that has been made.
Professor Padovani highlighted in particular the Centiloid Project developed by the Global Alzheimer’s Association Interactive Network (GAAIN). Centiloid is a 100-point scale for β‑amyloid imaging that can be applied across tracers and methods: it has an average value of zero in high-certainty amyloid-negative subjects (young controls aged 45 years) and an average of 100 in typical AD patients.
More precision is needed to identify trial populations
The presence of amyloid pathology defines different baseline scores and trajectories for cognitive and functional decline in β‑amyloid positive and negative patients, Professor Padovani said. It is essential to be more precise in identifying trial populations.
Genetic data and biomarkers enable a more precise approach for identifying trial populations
Human genetic data to identify patients with the ApoE-e4 allele and biomarkers to identify patients with prodromal and mild AD are therefore being used to enable a more precise approach in interventional trials so specific pathways can be targeted in the disease process and in the appropriate people.
Compared to past trials, participating patients are now more likely to respond to the mechanism of action of the new investigational compound and include patients with earlier stages of AD. Most current Phase 3 clinical trials require confirmation that patients are positive for β‑amyloid pathology.
Finally, Professor Padovani emphasized the need to confirm the clinical proof of concept of any intervention by measuring its effect using tools such as the Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB).