Abstract
ObjectiveEvaluation 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.MethodsSubjects 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.ResultsA 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.InterpretationExtensive 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.
Highlights
Overview of spinal muscular atrophy (SMA)Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder
Patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as reflected in the United States Prescribing Information for risdiplam
13 patients withdrew from the study prior to the clinical cut-off date (CCOD) 28 June 2019
Summary
Overview of SMASpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. The most common form is caused by a homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene on chromosome 5q, which encodes SMN,[1,2] an essential protein for normal development and functional homeostasis.[3] Most individuals carry a second gene, SMN2, that produces small amounts of functional SMN protein.[4] SMA is characterized by the progressive loss of spinal motor neurons leading to muscle weakness.[2] Without therapeutic intervention, it is the leading genetic cause of mortality in infants and young children, with an incidence of 1 in 10,000 live births.[5]. SMA manifests in various degrees of severity defined by age of onset and highest motor milestone achieved;[2] there are three main subtypes: Type 1 (patients never sit independently), Type 2 (patients can sit but not walk), and Type 3 (patients achieve independent walking).[6] All subtypes have common clinical signs, including hypotonia, muscle weakness and atrophy, and impaired mobility.[7]
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