JEWELFISH: Safety and pharmacodynamic data in non-naïve patients with spinal muscular atrophy (SMA) receiving treatment with risdiplam

Clinical Trials
62
Claudia Chiriboga MD, MPH, Claudio Bruno , Tina Duong MPT, PhD, Dirk Fischer , Janbernd Kirschner , Eugenio Mercuri MD, PhD, Marianne Gerber MD, Ksenija Gorni MD, PhD, Heidemarie Kletzl , Tammy McIver , Renata S Scalco , Francis Warren , Mariacristina Scoto
1. Columbia University Medical Center, 2. Translational and Experimental Myology Centre, Istituto Giannina Gaslini, 3. Department of Neurology, Stanford University School of Medicine, 4. Division of Neuropediatrics, University Children's Hospital Basel, University of Basel, 5. Clinic for Neuropediatrics and Muscle Disease, University Medical Center Freiburg, Freiburg, Germany, 6. Universita Cattolica del Sacro Cuore, 7. Pharma Development, Safety, F. Hoffmann-La Roche Ltd, 8. PDMA Neuroscience and Rare Disease, F. Hoffmann-La Roche Ltd, 9. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, 10. Roche Products Ltd, 11. Pharma Development Neurology, F. Hoffmann-La Roche Ltd, 12. Roche Products Ltd, 13. The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre

Background:
Spinal muscular atrophy (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 functional SMN protein levels. Risdiplam (EVRYSDI™) has been approved by the FDA for the treatment of patients with SMA, aged 2 months and older.

JEWELFISH (NCT03032172) is an ongoing, multicenter, open-label study evaluating the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics relationship of daily oral risdiplam in non-naïve patients (previously treated with other SMA therapies) with SMA (inclusion criteria 6 months–60 years at enrollment). JEWELFISH participants previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec-xioi (ZOLGENSMA®).

Objective:
To report updated safety and PD data from the JEWELFISH study.

Results:
We previously presented safety data from 173 patients with SMA (data-cut: 31st January 2020) who received risdiplam for up to 32.8 months (patients previously received RG7800 [n=13], nusinersen [n=76], onasemnogene abeparvovec [n=14] or olesoxime [n=70]). No treatment-related safety findings leading to withdrawal were reported. The overall adverse event profile of risdiplam treatment in non-naïve patients was consistent with that of treatment-naïve patients. Previously presented JEWELFISH PD data showed a ≥2-fold increase in median SMN protein levels versus baseline (data-cut: 1st June 2020), which was consistent with PD data from the SUNFISH study (NCT02908685) in treatment-naïve patients with Type 2/3 SMA. We will report updated safety and PD data from the JEWELFISH study.

Conclusion:
JEWELFISH is ongoing in sites across Europe and the US and will provide important data on the safety and PD of risdiplam in non-naïve patients with SMA.