Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study
Claudia A. Chiriboga, Claudio Bruno, Tina Duong, Dirk Fischer, Eugenio Mercuri, Janbernd Kirschner, Anna Kostera‐Pruszczyk, Birgit Jaber, Ksenija Gorni, Heidemarie Kletzl, Imogen Carruthers, Carmen Martín, Francis Warren, R. Scalco, Kathryn R. Wagner, Francesco Muntoni, the JEWELFISH Study Group, Nicolas Deconinck, Irina Balikova, Inge Joniau, Valentine Tahon, Sylvia Wittevrongel, Nathalie Goemans, Cathérine Cassiman, Lies Prové, Lisa Vancampenhout, M. van den Hauwe, Annelies Van Impe, C. Cancès, Vincent Soler, Lauriane Maillard De La Morandais, Delphine Vovan, Pascal Cintas, Françoise Auriol, Marianne Mus, Gwennaelle Alphonsa, Valerie Bellio, Olaia Gil Mato, Florence Flamein, Cécile Evrard, Amina Ziouche, Ikram Bouacha-Allou, Philippe Debruyne, Gilles Derlyn, Sabine Defoort, Florian Leroy, Loïc Danjoux, Isabelle Desguerre, Dominique Brémond‐Gignac, Maxence Rateuax, E. Deladrière, Carole Vuillerot, Quentin Veillerot, Bénédicte Sibille-Dabadi, Aurélie Barrière, Marie Tinat, Manel Saidi, Stéphanie Fontaine, Camille De Montferrand, Laure Le-Goff, Aurélie Portefaix, Ulrike Walther Louvier, Pierre-André Duval, Pascale Caradec, Souad Touati, Alberto Zamora Herranz, Janbernd Kirschner, Jan Bollig, Fanni Molnár, Sibylle Emilie Vogt, Astrid Pechmann, David Schorling, Sabine Wider, Heike Kölbel, Ulrike Schara, Frederik Braun, Andrea Gangfuß, Tim Hagenacker, Anja Eckstein, Dirk Dekowski, Michael Oeverhaus, M Stoehr, Bárbara Andres, Karin Smuda, Enrico Bertini, Adele D’Amico, Sergio Petroni, Paola Valente, Anna Maria Bonetti, Adelina Carlesi, Irene Mizzoni, Claudio Bruno, Marina Pedemonte, Noemi Brolatti, Enrico Priolo, Giuseppe Rao, Lorenza Sposetti, Simone Morando, Giacomo P. Comi, Silvia Osnaghi
Abstract
INTRODUCTION: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. METHODS: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. RESULTS: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. CONCLUSIONS: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.