FIREFISH Part 2: 24-month Efficacy and Safety of Risdiplam in Infants with Type 1 Spinal Muscular Atrophy (SMA)
Basil T. Darras1, Ricardo Masson2, Maria Mazurkiewicz-Bełdzińska3, Kristy Rose4, Hui Xiong5, Edmar Zanoteli6, Giovanni Baranello2,7, Dmitry Vlodavets8, Angela Dodman9, Muna El-Khairi10, Marianne Gerber11, Ksenija Gorni12, Heidemarie Kletzl13, Renata S. Scalco9, Laurent Servais14,15,16
1Department of Neurology, Boston Children’s Hospital, Harvard Medical School, 2Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 3Department of Developmental Neurology, Medical University of Gdańsk, 4Paediatric Gait Analysis Service of New South Wales, The Children’s Hospital at Westmead, 5Department of Pediatrics, Peking University First Hospital, 6Department of Neurology, Faculdade de Medicina, Universidade de São Paulo (FMUSP), 7The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, 8Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, 9Pharma Development Neurology, F. Hoffmann-La Roche Ltd, 10Roche Products Ltd, 11Pharma Development, Safety, F. Hoffmann-La Roche Ltd, 12PDMA Neuroscience and Rare Disease, F. Hoffmann-La Roche Ltd, 13Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, 14MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, 15Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, Department of Pediatrics, University Hospital Liège & University of Liège, 16I-Motion, Hôpital Armand Trousseau
Objective:

To determine the efficacy and safety of risdiplam in infants with Type 1 spinal muscular atrophy (SMA) after 24 months of treatment.

Background:

SMA is a severe, progressive neuromuscular disease 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.

Design/Methods:

FIREFISH (NCT02913482) is a multicenter, open-label, two-part study of risdiplam in infants with Type 1 SMA and two SMN2 gene copies (inclusion criteria 1–7 months at enrollment). Part 1 (N=21) assesses the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (N=41) assesses the efficacy and safety of the Part 1-selected dose of risdiplam.

Results:

The primary endpoint of Part 2 at 12 months was met (data-cut: 14th November 2019); 29% (P<0.0001, performance criterion=5%) of infants were able to sit without support for ≥5 seconds, as measured by the Bayley Scales of Infant and Toddler Development, Third Edition. This milestone was never achieved in natural history cohorts. After 12 months, risdiplam treatment also resulted in a significantly higher percentage of infants surviving, demonstrating improvements in motor function and achieving motor milestones compared with natural history cohorts. No treatment-related safety findings leading to withdrawal were reported in Part 2.

For the first time, we will present efficacy and safety data from infants in Part 2 who have received risdiplam treatment for 24 months.

Conclusions:
Part 2 is ongoing and will provide important data on the long-term efficacy and safety of risdiplam in infants with Type 1 SMA.