SMA is an inherited disease that leads to loss of motor function and ambulation 
and a reduced life expectancy. We have been working to develop orally 
administrated, systemically distributed small molecules to increase levels of 
functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested 
in clinical trials in healthy volunteers and SMA patients. It was safe and well 
tolerated and increased SMN protein levels up to 2-fold in patients. 
Nevertheless, its development was stopped as a precautionary measure because 
retinal toxicity was observed in cynomolgus monkeys after chronic daily oral 
dosing (39 weeks) at exposures in excess of those investigated in patients. 
Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that 
focused on thorough pharmacology, DMPK and safety characterization and 
optimization. This compound is undergoing pivotal clinical trials and is a 
promising medicine for the treatment of patients in all ages and stages with 
SMA.