Vincent Madelain, Principal Scientist at Servier discussed his work on pharmacokinetic properties of antisense oligonucleotides (ASOs). Servier conducts research across many therapeutic areas in the neuroscience. Madelain focused on the application of ASOs in the central nervous system (CNS). The company has a strong background in small molecule development but is looking to expand into biologics space. ASOs are highly versatile molecules that target and modify RNA transcripts to slow down or stop disease progression.
Like all drug candidates, evaluating the tolerability and safety profile of ASOs is key at every step of drug discovery and preclinical development. Madelain stresses integrating pharmacokinetic (PK) criteria early on in lead optimisation work. He stated that chemical modifications can improve ASOs’ PK profiles. These modifications include substituting PO with PS and altering sugars to enhance potency, affinity, and stability. He presented a case study demonstrating the improved half-life and stability of an optimised ASO candidate in mouse brain tissues compared to a competitor's product.
Madelain also addressed the challenges in translating preclinical findings to clinical settings. He presented the variability in drug distribution within the brain and the need for appropriate bioanalytical methods to measure ASO concentrations. He discussed the use of non-human primates for more accurate predictions and the implementation of PK modelling to refine and project human pharmacokinetics.
The overarching goal is to maximize the informativeness of studies while minimizing the use of animals, ensuring ethical and financial considerations are met.
