AIMS: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and 
peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing 
modifier for the treatment of spinal muscular atrophy (SMA). The objectives of 
this entry-into-human study were to assess the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the 
strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male 
volunteers.
METHODS: Part 1 had a randomized, double-blind, adaptive design with 25 subjects 
receiving single ascending oral doses of risdiplam (ranging from 0.6-18.0 mg, 
n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate 
risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on 
the PK of risdiplam was also assessed using a two-period cross-over design 
(n = 8).
RESULTS: Risdiplam in the fasted or fed state was well tolerated. Risdiplam 
exhibited linear PK over the dose range with a multi-phasic decline with a mean 
terminal half-life of 40-69 h. Food had no relevant effect, and itraconazole had 
only a minor effect on plasma PK indicating a low fraction of risdiplam 
metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to 
approximately 41% (95% confidence interval 27-55%) of the estimated maximum 
increase in SMN2 mRNA.
CONCLUSIONS: Risdiplam was well tolerated and proof of mechanism was 
demonstrated by the intended shift in SMN2 splicing towards full-length SMN2 
mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA 
are now ongoing.