MDA 2023: Evrysdi may work better than Spinraza for SMA type 1

Lindsey Shapiro PhD avatar

by Lindsey Shapiro PhD |

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The Muscular Dystrophy Association's acronym is shown against a backdrop of polka dots for this MDA Clinical & Scientific Conference illustration.

Evrysdi (risdiplam) may be associated with longer survival and greater motor improvements than Spinraza (nusinersen) in children with spinal muscular atrophy (SMA) type 1, according to an indirect comparison of clinical trial data.

Sponsored by Roche — which markets Evrysdi — the analysis “leverages the longest follow-up currently available from two robust clinical trial sources,” according to researchers.

Still, the treatments were not directly compared in a single trial. Despite efforts to adjust for differences that could affect prognosis, this type of analysis can still be biased by unknown factors. The findings thus require further confirmation, the team noted.

The analysis was discussed at the Muscular Dystrophy Association’s MDA Clinical & Scientific Conference, held March 19-22, in a poster titled, “Long-term comparative efficacy and safety of risdiplam versus nusinersen in children with Type 1 spinal muscular atrophy.”

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Evrysdi and Biogen’s Spinraza are two approved disease-modifying therapies designed to slow the progressive loss of motor function that marks SMA.

The two work through a similar mechanism. But while Evrysdi is taken orally once a day, Spinraza is injected directly into the spinal canal once every four months.

Both target the SMN2 gene — which works as a backup to the SMN1 gene affected in SMA — with the goal of boosting the production of the SMN protein. It’s the deficiency of SMN that causes the neuromuscular disease.

Despite their established efficacy and safety in SMA, no head-to-head trials have been conducted to directly compare these two treatments in individuals with the disease.

“Indirect comparisons are therefore needed to provide information on the relative efficacy and safety of these treatments to inform healthcare decision-making,” the researchers wrote.

To address that, investigators performed a comparison of data from Spinraza’s clinical trials — the Phase 3 ENDEAR trial (NCT02193074) and its open-label extension SHINE (NCT02594124) — to available data from the open-label Phase 2/3 FIREFISH study (NCT02913482) of Evrysdi.

The analysis included data from 139 infants with SMA type 1. Of them, 81 had enrolled in the ENDEAR/SHINE trials, and had about 3.5 years of follow-up, and 58 were from FIREFISH, with about three years of available follow-up.

A type of analysis called matching-adjusted indirect comparison was used to compare safety and efficacy findings from the trials, while adjusting for cross-trial differences that could influence a patient’s prognosis.

In this study, researchers specifically adjusted the data for age at treatment initiation, time living with SMA, and baseline motor function at the start of treatment. During this process, the 81 Spinraza-treated patients were matched to 41 Evrysdi-treated patients.

Participants in the two groups had a mean age of 5.4 months at the time of their first dose and had been living with SMA for 13.2 weeks, or a little over three months.

Results from the analysis indicated that survival among type 1 SMA infants may be significantly prolonged with Evrysdi relative to Spinraza, amounting to a 78% lower death rate. Similarly, the estimated risk of death or need for permanent ventilation was 81% lower in the Evrysdi group.

The analysis also favored Evrysdi in terms of the likelihood that children would reach certain motor milestones, as assessed by the Hammersmith Infant Neurological Exam (HINE-2). Patients on Evrysdi experienced a 45% higher rate of milestone achievement than those given Spinraza.

Indirect comparisons are … needed to provide information on the relative efficacy and safety of these treatments to inform healthcare decision-making.

Evrysdi-treated children also appeared to be more likely to experience earlier motor function improvements, as assessed with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND).

Importantly, motor assessments differed between the two trials. Children in FIREFISH had more CHOP-INTEND assessments, while those in ENDEAR had earlier and more frequent HINE-2 measurements. According to the researchers, these differences “may bias results in favor of Spinraza.”

To address that potential bias, an analysis was performed to adjust for differences in the timing of motor assessment. The analysis still favored Evrysdi on both scales.

Serious adverse events after starting treatment were 57% less frequent in the Evrysdi group, with the analysis suggesting that patients treated with Evrysdi may have a longer time to experience any serious side effect compared with those on Spinraza.

While results from the analysis overall suggest that type 1 SMA patients given Evrysdi “may see greater improvements compared with infants treated with [Spinraza],” the researchers note that an indirect trial comparison “may still be biased by unreported or unknown factors.”

For example, because Evrysdi was approved after Spinraza, it is possible that respiratory care standards were better at the time of the FIREFISH study and contributed to better outcomes.

“Additional data sources should be consulted to expand on these findings,” the researchers wrote.

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