Evrysdi (risdiplam) at its approved and therapeutic dose does not lead to eye damage in children or adults with spinal muscular atrophy (SMA), data from extensive ophthalmologic monitoring of patients in its clinical trials — prompted by earlier safety findings in monkeys — show.
These data support the therapy’s favorable safety profile, and suggest that physicians do not need to monitor people using Evrysdi specifically for eye damage, the researchers noted — in agreement with its prescribing information in the U.S.
Findings were reported in the study, “Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy,” published in the journal Annals of Clinical and Translational Neurology.
In August, Evrysdi became the first oral and at-home treatment for adults and children, ages 2 months and older, with all SMA types in the U.S., followed shortly by an identical approval in Brazil. Similar approval requests are currently being reviewed by health authorities in Canada, China, Switzerland, and in Europe, where the application is under accelerated assessment.
Marketed by the Roche subsidiary Genentech, Evrysdi is a small molecule that works by increasing the levels of SMN, the protein whose production is impaired in SMA patients, leading to progressive muscle weakness and wasting.
Promising findings in cellular and mouse models of the disease, as well as in non-human primates, supported Evrysdi’s advance into clinical trials. However, irreversible damage in the retina — a thin layer lining the back of the eye that sends vision signals to the brain — was observed in non-human primates after 20 weeks of treatment with two of the three doses tested.
Importantly, the lowest of these two primate doses corresponded to exposures more than twice that achieved with Evrysdi at the therapeutic doses tested in human trials (including the now recommended dose).
Still, these findings prompted extensive ophthalmologic exams of SMA patients in the first three Evrysdi trials — the Phase 2/3 FIREFISH (NCT02913482) and SUNFISH (NCT02908685) studies, and the Phase 2 JEWELFISH trial (NCT03032172) — to ensure no occurrence of retinal toxicity.
Patients with a history of ophthalmologic disease and those using medications known or suspected to cause retinal toxicity within the year before entering a trial were not eligible for these trials.
Participants underwent a battery of eye exams, assessing retinal structure and visual function, at baseline (study entry) and every two to six months depending on study and assessment.
Predefined criteria were used to classify changes from baseline as abnormal or potentially meaningful; only those evident at the patient’s last available assessment were considered.
“Findings were reviewed by a central reader who provided recommendations for additional assessments in consultation with the site ophthalmologist, if required,” the researchers wrote. Ophthalmologic adverse events during the trials were also assessed.
As of June 28, 2019 (clinical cutoff date), a total of 245 Evrysdi-treated patients (all treated at Evrysdi’s now approved dose) had ophthalmologic assessments going out at least two months, and most for longer periods. Fifteen patients were assessed for two-and-a-half years, 52 for two years, 143 for one year, and 233 for six months.
Results showed that 207 (84.5%) of these people had ophthalmologic changes at their last assessment, but most were related to test variability (particularly in imaging angles due to head and neck weakness) or were not considered clinically meaningful.
Less than 15% of these patients experienced ophthalmologic adverse events during the studies, which were mild to moderate in intensity, “not suggestive of [Evrysdi]‐induced toxicity and resolved with ongoing treatment,” the researchers wrote. No eye-related event led to study withdrawal.
Overall, there were no clinically significant changes in retinal structure or visual function in Evrysdi-treated patients.
In a June interview with SMA News Today, the pediatric neurologist Laurent Servais — who was involved in the FIREFISH and SUNFISH trials — noted that the worrisome preclinical safety findings “led to incredibly extensive ophthalmological follow-up.
“The beauty is that now we are pretty sure there is nothing in terms of ophthalmology safety issues in these patients after two years of treatment,” and not by lack of proper assessment. “We spent an incredible amount of time and energy to do it,” said Servais, a professor of pediatric neuromuscular diseases at the MDUK Oxford Neuromuscular Centre.
“Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that [Evrysdi] does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose,” the researchers wrote.
Roche is currently “monitoring longer-term ophthalmologic safety of [Evrysdi] in the open‐label extension parts of the ongoing clinical studies,” they added.
An open-label Evrysdi trial, called RAINBOWFISH (NCT03779334), is still enrolling newborns up to 6 weeks old with a genetic diagnosis of SMA but no evidence of symptoms (presymptomatic) in several countries, including the U.S. More information can be found here.
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