Safety update: Risdiplam clinical trial program for spinal muscular atrophy (SMA)


Clinical Trials

Poster Number: 152


Claudia A. Chiriboga, MD MPH FAAN, Department of Neurology, Columbia University Medical Center, New York, NY, USA, Laurent Servais, MD, MDUK, Oxford, UK, Giovanni Baranello, MD, Great Ormond Street Hospital for Children, Basil Darras, MD, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, John Day, MD, PhD, Stanford University, Nicolas Deconinck, MD, Universitair Ziekenhuis Gent, Michelle A Farrar, MBBS FRACP PhD, Sydney Children’s Hospital Network and UNSW Medicine, UNSW Sydney, Sydney, Australia, Richard Finkel, MD, St. Jude Children's Research Hospital, Enrico Bertini, MD, Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambin Gesù C, Janbernd Kirschner, PhD, University Medical Center Freiburg, Riccardo Masson, MD, Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, Maria Mazurkiewicz-Bełdzińska, Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland, Dmitry Vlodavets, PhD MD, Veltischev Clinical Pediatric Research Institute, Moscow, Russia, Silvia Bader-Weder, Pharma Development, Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Marianne Gerber, MD, Pharma Development, Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Ksenija Gorni, MD PhD, Roche, Birgit Jaber, MSc, Pharma Development, Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Tammy McIver, Roche Products Ltd, Welwyn Garden City, UK, Gergely Papp, MD, Pharma Development, Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Renata S Scalco, MD PhD, Pharma Development Neurology, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Eugenio Mercuri, MD, PhD, Department of Paediatric Neurology and Nemo Clinical Centre, Catholic University

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA) in over 90 countries worldwide.
Safety data were obtained from FIREFISH (NCT02913482) in infants with Type 1 SMA (inclusion criteria [IC] aged 1–7 months at enrollment), SUNFISH (NCT02908685) in patients with Types 2/3 SMA (IC aged 2–25 years at enrollment) and JEWELFISH (NCT03032172) in patients with SMA who have previously received other disease-modifying therapies (IC aged 6 months–60 years at enrollment); clinical cut-off dates (CCODs): 23 Nov 2021, 6 Sep 2021 and 31 Jan 2022, respectively. Data were pooled and analyzed per SMA type. Data from RAINBOWFISH (NCT03779334; IC birth–6 weeks of age at first dose; CCOD 1 Jul 2021) were collected from presymptomatic patients and presented separately.

These analyses aim to determine the longer-term safety profile of risdiplam in patients with SMA who have participated in risdiplam clinical trials.

A total of 465 symptomatic patients (overall exposure: 1,292 patient-years [PY]) and 18 presymptomatic patients were included in the analyses. At the CCODs, most treatment-related adverse events (AEs) were mild and none led to treatment withdrawal in any of the clinical trials (N=483). In presymptomatic patients, the most common AEs per 100PY were vomiting (48.24), teething and pyrexia (41.35 each), nasal congestion (34.46), and diarrhea and viral infection (27.57 each). The overall rate of AEs in symptomatic patients decreased over time with continued treatment. In symptomatic patients, serious AEs (SAEs) were more frequent in the Type 1 SMA pool compared with the Types 2/3 pool. The rate of SAEs declined in the Type 1 SMA pool but remained stable in the Types 2/3 pool. No SAEs were observed in presymptomatic patients. The MedDRA standard organ classes with the highest number of AEs were infections and gastrointestinal (GI) AEs. A rapid decline in the rate of GI AEs was seen during the first 4 weeks of treatment in symptomatic patients; with no trend in the rate of infection AEs in the first 6 months.

Data across studies suggest that risdiplam has a favorable safety profile. The FIREFISH, SUNFISH, JEWELFISH (open-label extension) and RAINBOWFISH studies are currently ongoing; updated safety data will be published annually until patients have completed 5 years of treatment.