Good to see some PK/PD relating exposure to efficacy. It has been hypothesised efficacy in mice is driven by greater target residence, leading to free EC50=1.1nM compared to the in vitro mNa1.7 IC50=59.4nM. Whilst there is a clear difference in human dissociation half-life, this difference is less pronounced in mice. Moreover, the authors suggest their compound is 10-fold more potent than PF-05089771 which has mNa1.7 IC50=4.9nM. There is no head-to-head profiling of mouse in vivo efficacy or dissociation half-life. Pain models are very difficult to compare unless the study is done head to head. It will be important to consider the potential differences in target residence and not just in vitro IC50. It is not clear if DS-1971a is a better in vitro tool compared to PF-05089771. I couldn’t see the Nav1.9 selectivity (I assume it will be good based on the selectivity of DS-1971a for other subtypes but may be important as expressed in the same tissue).
28 Jul 2021 )