A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier

Abstract

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.

Fusion transcripts: Unexploited vulnerabilities in cancer?

“…Small molecules could also form ternary complexes with fusion pre‐mRNAs and RNA‐binding proteins, which may activate or inhibit alternative splicing (Figure e, bottom). For example, RG‐7916 is currently in Phase II clinical trials for various types of spinal muscular atrophy and it functions by modulating pre‐mRNA splicing of the survival motor neuron‐2 ( SMN2 ) gene (Poirier et al, ; Ratni et al, ; Sturm et al, ; and http://clinicaltrials.gov; NCT03779334). It was shown recently that binding of RG‐7916 analogues to SMN2 pre‐mRNA enhances the recruitment of two splicing activators (FUBP1 and KHSRP) and the formation of these ternary complexes contribute to its mechanism of action to enhance SMN2 splicing (J. Wang, Schultz, & Johnson, ).…”

RNA-Targeted Therapies and High-Throughput Screening Methods

“…Compared to RG7800, risdiplam showed enhanced potency and improved safety in preclinical studies [93]. The drug candidate was well tolerated in a Phase 1 clinical study and is being investigated in Phase 2/3 studies for all types of SMA [102]. Risdiplam is now under priority review for possible approval by the FDA.…”

Targeted Treatments for Inherited Neuromuscular Diseases of Childhood

“…10 Side effects reported throughout the studies included headache, abdominal pain, diarrhea, nasopharyngitis, influenza, dry mouth, erythema, and pyrexia. 10,11 Gene Therapy and Application to SMA…”