FIREFISH Part 1: 24-month safety and exploratory outcomes of risdiplam in infants with Type 1 spinal muscular atrophy (SMA)

Topic:

Clinical Trials

Poster Number: 60

Author(s):

Basil T Darras MD, Giovanni Baranello , Odile Boespflug-Tanguy , John W Day , Nicolas Deconinck , Andrea Klein , Riccardo Masson , Eugenio Mercuri MD, PhD, Angela Dodman , Muna El-Khairi , Marianne Gerber MD, Ksenija Gorni MD, PhD, Heidemarie Kletzl , Renata S Scalco , Laurent Servais MD, PhD

Institutions:

1. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, 2. The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, 3. I-Motion - Hôpital Armand Trousseau, 4. Department of Neurology, Stanford University, 5. Neuromuscular Reference Center, UZ Gent, 6. University Children’s Hospital Basel, 7. The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, 8. Universita Cattolica del Sacro Cuore, 9. Pharma Development Neurology, F. Hoffmann-La Roche Ltd, 10. Roche Products Ltd, 11. Pharma Development, Safety, F. Hoffmann-La Roche Ltd, 12. PDMA Neuroscience and Rare Disease, F. Hoffmann-La Roche Ltd, 13. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, 14. Pharma Development Neurology, F. Hoffmann-La Roche Ltd, 15. MDUK Oxford Neuromuscular Centre

Background:
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.

Objective:
To report safety, tolerability, PK/PD and exploratory efficacy data in infants from Part 1 who have received risdiplam treatment for ≥24 months.

Results:
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.

Conclusion:
FIREFISH Parts 1 and 2 are ongoing globally and will provide important data on the efficacy and safety of risdiplam in Type 1 SMA.