2023 American Academy of Neurology Abstract Website

Claudia Chiriboga¹, Claudio Bruno², Tina Duong³, Dirk Fischer⁴, Janbernd Kirschner⁵, Mariacristina Scoto⁶, Eugenio Mercuri⁷, Marianne Gerber⁸, Ksenija Gorni⁹, Heidemarie Kletzl¹⁰, Imogen Carruthers¹¹, Carmen Martin¹¹, Teresa Gidaro¹², Francesco Muntoni⁶
¹Department of Neurology, Columbia Irving Medical Center, ²Translational and Experimental Myology Centre, Istituto Giannina Gaslini, ³Department of Neurology, Stanford University, ⁴Division of Neuropediatrics, University Children’s Hospital Basel, ⁵Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, University of Freiburg, ⁶The 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, ⁷Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Fondazione Policlinico Gemelli IRCCS, ⁸Pharma Development, Safety, ⁹PDMA Neuroscience and Rare Disease, F. Hoffmann-La Roche Ltd, ¹⁰Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, ¹¹Roche Products Ltd, ¹²Pharma Development Neurology, Hoffmann-La Roche Ltd

Objective:

To determine the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of risdiplam in non-treatment-naïve patients with SMA.

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:

JEWELFISH (NCT03032172) is a multicenter, open-label study of daily risdiplam in non-treatment-naïve patients with SMA (inclusion criteria aged 6 months–60 years at enrollment) who were previously enrolled in the MOONFISH study (RG7800) or previously treated with nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®).

Results:

The enrolled population (N=174) included a broad range of age (1–60 years), SMA type (1–3), SMN2 copy number (1–4) and motor function (non-sitters/sitters/walkers). Of the 174 patients enrolled, thirteen patients were previously enrolled in MOONFISH (three patients were treatment-naïve as they had received placebo and never switched to RG7800), 76 received nusinersen, 70 received olesoxime, and 14 received onasemnogene abeparvovec. One patient withdrew from the study at baseline. Risdiplam treatment led to a >2-fold increase in SMN protein versus baseline within 4 weeks, irrespective of previous treatment. No drug-related safety findings leading to withdrawal were reported for any patient. The safety profile of risdiplam was consistent with the safety profile in treatment-naïve patients treated with risdiplam in the FIREFISH (NCT02913482) and SUNFISH (NCT02908685) studies. Based on the exploratory efficacy analysis, an overall stabilization of motor function was observed following 24 months of risdiplam treatment in patients 2–60 years as assessed by the 32-item Motor Function Measure and Revised Upper Limb Module scales (data-cut: 31 January 2022).

Conclusions:

JEWELFISH is ongoing at sites across Europe and the USA and is providing important data on the safety, PD and exploratory efficacy of risdiplam in a broad population of non-treatment-naïve patients with SMA.