O.41Sunfish part 1: 18-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with type 2 or 3 spinal muscular atrophy

Baranello, Giovanni; Kirschner, Janbernd; Servais, Laurent; Goemans, Nathalie; Pera, Maria Carmela; Tichý, M.; Yeung, Wai Yin; Kletzl, Heidemarie; Gerber, Marianne; Czech, Christian; Annoussamy, M.; Cleary, Yumi; Gorni, Ksenija

doi:10.1016/j.nmd.2019.06.595

Cited by 8 publications

(12 citation statements)

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“…The inability of the HFMSE to capture some small functional changes in patients with Type 2 and 3 SMA was demonstrated in a natural history study which showed that pulmonary and motor function outcome measures remained relatively stable over 12 months, requiring longitudinal observational studies to extend beyond 12 months 14 . More recently, in two double‐blind, placebo‐controlled studies, the Motor Function Measure (MFM), 15,16 and RULM 16 captured a significant difference between treated and untreated patients, while the HFMSE failed to do this.…”

Section: Introductionmentioning

confidence: 99%

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Annoussamy

Seferian

Daron

et al. 2020

Ann Clin Transl Neurol

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Objective To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. Methods Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease‐modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo®), quantitative magnetic resonance imaging (fat fraction [FFT2] mapping and contractile cross‐sectional area [C‐CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. Results MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C‐CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. Interpretation These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months.

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Section: Introductionmentioning

confidence: 99%

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Annoussamy

Seferian

Daron

et al. 2020

Ann Clin Transl Neurol

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“…The study consists of a dose‐finding Part 1 and a confirmatory Part 2 at the dose selected in Part 1. In total, 51 patients were enrolled in Part 1 15 . Patients receiving placebo were switched to active treatment at the dose tested in their respective cohort after a minimum 12‐week, placebo‐controlled treatment period.…”

Section: Methodsmentioning

confidence: 99%

“…This molecule increases the production of functional SMN protein in the central nervous system and throughout the body 13 . Risdiplam has a favorable safety profile and positive efficacy results in infants, children, and adults, supporting its use in SMA 14‐16 …”

Section: Introductionmentioning

confidence: 99%

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

Sergott

Amorelli

Baranello

et al. 2020

Ann Clin Transl Neurol

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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.

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“…30 In addition, improvement in motor functioning has been suggested for treated individuals with Type 2 and Type 3 SMA ranging in age from 2 to 25 years old in a multicenter, double-blind, placebo-controlled study (SUNFISH, NCT02908685). 31 As of June 2020, risdiplam remains under priority review with the FDA.…”

Section: Gene Therapy In Spinal Muscular Atrophy 2 Understanding Spimentioning

confidence: 99%

Overview of Gene Therapy in Spinal Muscular Atrophy and Duchenne Muscular Dystrophy

Abreu

Waldrop

2020

Preprint

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Both 5q-linked spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by loss-of-function mutations. SMA is an autosomal recessive disorder affecting motor neurons that is typically caused by homozygous whole-gene deletions of SMN1. DMD is an X-linked recessive muscle disease most often due to exon deletions, but also duplications and smaller sized variants within the DMD gene. Gene replacement therapy offers the opportunity to correct the underlying genetic defect by the introduction of a functional gene. We review the transformative work from clinical trials to United States Food and Drug Administration approval of onasemnogene abeparvovec-xioi in SMA and its application in clinical practice and the early results of microdystrophin delivery in DMD. We also review the introduction of antisense oligonucleotides to alter pre-mRNA splicing to promote exon inclusion (as in nusinersen in SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular therapeutics. There are multiple promising novel genetically mediated therapies on the horizon, which in aggregate point towards a hopeful future for individuals with SMA and DMD.

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O.41Sunfish part 1: 18-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with type 2 or 3 spinal muscular atrophy

Cited by 8 publications

References 0 publications

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

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

Overview of Gene Therapy in Spinal Muscular Atrophy and Duchenne Muscular Dystrophy

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