Type 1 spinal muscular atrophy (SMA) is a severe neuromuscular disease in which untreated infants fail to achieve major motor milestones and typically die before 2 years of age. SMA is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations of the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein. Risdiplam is a centrally and peripherally distributed oral SMN2 pre‑mRNA splicing modifier that increases the levels of functional SMN protein. Risdiplam (EVRYSDI™) has been approved by the FDA for the treatment of patients with SMA, aged 2 months and older.
FIREFISH (NCT02913482) is an ongoing, multicenter, open-label study of risdiplam in infants with Type 1 SMA and two SMN2 gene copies (inclusion criteria aged 1–7 months at enrollment). Part 1 (low-dose cohort, n=4; high-dose cohort, n=17) assesses the safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD) of different risdiplam dose levels (plus exploratory efficacy outcomes); pivotal Part 2 (n=41) assesses the safety and efficacy of risdiplam at the dose selected in Part 1.
To report safety, tolerability, PK/PD and exploratory efficacy data in infants from Part 1 who have received risdiplam treatment for ≥24 months.
There have been no treatment-related safety findings leading to withdrawal in any risdiplam trial (data-cut: 28th June 2019). Although FIREFISH Part 1 was not designed to assess efficacy, after 16 months of risdiplam treatment (data-cut: 2nd July 2019), 86% (18/21) of infants were alive, and no surviving infant required tracheostomy or reached permanent ventilation. Most infants showed improvement in motor function, with 82% (14/17) on the high dose scoring ≥40 on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Infants in Part 1 also achieved motor milestones not observed in the natural history of Type 1 SMA, including 53% (9/17) who were able to maintain head control and 41% (7/17) who were able to sit independently (as assessed by the Hammersmith Infant Neurological Examination, Module 2).
Safety, tolerability, PK/PD and exploratory efficacy data will be reported in infants from Part 1 who have received risdiplam for ≥24 months.
FIREFISH Parts 1 and 2 are ongoing globally and will provide important data on the efficacy and safety of risdiplam in Type 1 SMA.