FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA)
Basil Darras1, Giovanni Baranello2, Odile Boespflug-Tanguy3, John Day4, Nicholas Deconinck5, Andrea Klein6, Ricardo Masson7, Maria Mazurkiewicz-Bełdzińska8, Eugenio Mercuri9, Kristy Rose10, Dmitry Vlodavets11, Hui Xiong12, Edmar Zanoteli13, Muna El-Khairi14, Marianne Gerber15, Ksenija Gorni16, Heidemarie Kletzl17, Laura Palfreeman14, Angela Dodman18, Laurent Servais19
1Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA, 2Dubowitz Neuromuscular Centre, University College London, London, UK; Developmental Neurology, Istituto Neurologico C Besta, Milan, Italy, 3IMotion Institut de Myologie AP-HP, Hôpital Armand Trousseau, Paris, France; Université Paris Cité, UMR 1141, NeuroDiderot, Paris, France, 4Department of Neurology, Stanford University, Palo Alto, CA, USA, 5Neuromuscular Center, UZ Gent, Ghent, Belgium; Centre de Référence des Maladies Neuromusculaires, Children’s University Hospital, ULB, Brussels, Belgium, 6Paediatric Neurology, Uni. Children’s Hospital Basel, Basel, Switzerland; Paediatric Neurology, Inselspital, University of Bern, Bern, Switzerland, 7Developmental Neurology, Istituto Neurologico C Besta, Milan, Italy, 8Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland, 9Pediatric Neurology Institute, Catholic University, Rome, Italy, 10Paediatric Gait Analysis Service of New South Wales, The Children’s Hospital at Westmead, Sydney, Australia, 11Children Neuromuscular Center, Pirogov Medical University, Moscow, Russia, 12Department of Pediatrics, Peking University First Hospital, Beijing, China, 13Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil, 14Roche Products Ltd, Welwyn Garden City, UK, 15Pharma Development, Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland, 16PDMA Neuro/Rare Disease, F. Hoffmann-La Roche Ltd, Basel, Switzerland, 17Pharmaceutical Research, Roche Innovation Center Basel, Basel, Switzerland, 18Pharma Development Neuro, F. Hoffmann-La Roche Ltd, Basel, Switzerland, 19MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK; Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, Department of Pediatrics, University of Liège, Liège, Belgium
Objective:

To determine the efficacy and safety of risdiplam in infants with Type 1 SMA after 36 months of treatment.

Background:

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 90 countries worldwide.

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 old at enrollment). FIREFISH Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam doses. Pivotal Part 2 assessed the safety and efficacy of risdiplam over 24 months at the dose selected from Part 1. Thereafter, infants entered a 3-year open-label extension phase and continue to receive risdiplam at the pivotal dose.

Results:

Pooled safety and efficacy data were available from 58 enrolled infants who received risdiplam treatment (Part 1 high-dose cohort, n=17; and Part 2, N=41). As of the cut-off date (23 November 2021), there were no treatment-related adverse events leading to withdrawal, no additional deaths since the clinical cut-off date of the primary analysis (14 November 2019), and no additional infants meeting the definition of permanent ventilation since Month 24. At Month 36, 84% of infants were alive and did not require permanent ventilation. In FIREFISH, infants have achieved motor milestones not observed in the natural history of Type 1 SMA. Overall, infants have maintained or improved their motor skills in terms of developmental milestones and motor function between Month 24 and Month 36.

Conclusions:

FIREFISH Parts 1 and 2 are ongoing globally and will provide further safety and efficacy data of risdiplam in Type 1 SMA.

10.1212/WNL.0000000000203624