Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy

Abstract

Objective Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU. Methods Subjects included patients with SMA aged 2 months–60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age‐appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD‐OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2–6 months depending on study and assessment. SD‐OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study. Results A total of 245 patients receiving risdiplam were assessed. Comprehensive, high‐quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD‐OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam‐induced toxicity and resolved with ongoing treatment. Interpretation Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

“…No serious adverse events related to the drug was reported. No ophthalmological findings attributable to Risdiplam exposure were reported [ 270 ] as in preclinical studies with cynomolgus monkeys. Retinal toxicity was observed in these monkeys consisting of photoreceptor degeneration and microcystoid macular degeneration (MMD) in the central retina after 5–6 months of daily treatment [ 242 ].…”

Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy

“…Ratni et al determined that risdiplam was safe, well tolerated, and increased SMN protein levels up to twofold in patients [73]. Its development was abruptly halted as a precautionary measure due to retinal toxicity being observed in cynomolgus monkeys; the dosage in these animals significantly exceeded that of patients [89]. Fortunately, patient trials have proceeded more smoothly.…”

“…The clinical trials SUNFISH (NCT02908685) and JEWELFISH (NCT03032172), which follow the effectiveness of risdiplam in Type 2 and Type 3 SMA patients, have not yet reported efficacy. Although the FDA approved risdiplam in August 2020 [73,74,91], full safety analysis has not been completed [89,92]. Furthermore, since risdiplam is not sequence specific, the potential off-target effect is also a long-term concern.…”

Terapie genowe i genetyczne w chorobach nerwowo- mięśniowych wieku dziecięcego

“…Aktualnie prowadzone są także ba-dania dla niemowląt przedobjawowych (RAINBOWFISH) i dla grupy pacjentów, którzy wcześniej byli leczeni innymi preparatami (JEWELFISH). Wyniki ostatnich badań wskazują, iż risdiplam nie jest toksyczny dla siatkówki u pacjentów z SMA i w trakcie leczenia nie są wymagane specjalne kontrole okulistyczne [19] (inaczej niż sugerowano po badaniach przeprowadzonych na zwierzętach).…”