Evrysdi safe for patients moving from other SMA therapies: Trial
Two years of JEWELFISH findings support safety in switch to oral treatment
Switching to oral Evrysdi (risdiplam) from another disease therapy is safe for spinal muscular atrophy (SMA) patients, with side effects similar to those observed in clinical trials involving patients new to treatment, according to a two-year analysis from the JEWELFISH clinical trial.
Exploratory efficacy analyses also suggest that the therapy stabilized motor function in these patients, regardless of which treatment they had taken previously.
The study, “JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam,” was published in the Journal of Neurology. It was sponsored by Roche, which markets Evrysdi.
JEWELFISH study focused on safety, side effects with switch to Evrysdi
Approved SMA therapies work in different ways to increase levels of the SMN protein, a lack of which is the cause of disease symptoms, as a way of slowing its progression.
Evrysdi, the most recently approved of SMA’s three disease-modifying treatments, is a once daily oral therapy. Spinraza (nusinersen) is injected into the spinal canal once every four months, and Zolgensma (onasemnogene abeparvovec-xioi) is a one-time infusion gene therapy.
Throughout their lives, patients may switch between treatments or use therapies in combination in order to maximize benefits and minimize side effects. But data are limited on the safety and efficacy of these changes in treatment regimens.
The open-label Phase 2 JEWELFISH trial (NCT03032172) was designed primarily to assess the safety of starting treatment with Evrysdi after using a different disease-specific therapy.
It enrolled 174 people with SMA types 1-3, ages 1-60, who previously had received Spinraza (76 patients) or Zolgensma (14 patients), or the investigative therapies RG7800 (10 patients, three others on a placebo) and olesoxime (71 patients) given in clinical trials. Neither RG7800 nor olesoxime are still in clinical development.
153 SMA patients finished two years of daily treatment
In JEWELFISH, all were treated daily with Evrysdi for two years, after which they could join its ongoing, open-label extension phase, where they are continuing treatment for up to three more years. The trial is expected to conclude in late December.
The current study covered two-year findings from JEWELFISH participants. Overall, 153 of its patients completed two years of treatment as of Jan. 31, 2022, when data collection stopped for this study.
Consistent with previous interim trial reports, Evrysdi at two years of use was seen to be generally well-tolerated regardless of prior treatment. Common side effects, mostly “mild to moderate in intensity,” were fever (24%), upper respiratory tract infection (21%), and headache (18%), the researchers reported.
Rates of these adverse events and serious adverse events declined after the first six months of treatment. Adverse event rates dropped by around 50% between the first and second year, they noted.
Additional analyses showed that the safety profile of Evrysdi was consistent with that observed in earlier clinical trials involving treatment-naïve patients, including the FIREFISH trial (NCT02913482) in infants with SMA type 1, and the SUNFISH trial (NCT02908685) that enrolled children and young adults with SMA types 2 and 3.
Evrysdi’s use also led to a median two times increase in SMN protein blood levels that were sustained over two years, regardless of which therapy patients had been on before.
Changes in motor function were evaluated in an exploratory manner for patients ages 2-60 using a battery of tests, including the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module.
Exploratory motor skill tests showed stabilization with Evrysdi’s use
As previously reported, motor function across these measures was generally stabilized over two years of treatment, including in a group of adult patients ages 25 to 60.
Researchers noted that while direct comparisons cannot be made, such stabilization is a stark contrast to the disease’s natural history, or its progression without treatment. Natural SMA history reports show “a considerable decline in measures of motor function” over two years, the scientists wrote.
Among 13 evaluated type 3 patients who were able to walk at the study’s start, all maintained that ability at the two-year analysis. Among those with available data, the distance they could walk in six minutes also increased during that time, again contrary to what’s expected in SMA’s natural course.
Six patients younger than age 2 at study entry all were classified as “motor milestone responders,” meaning that more motor milestones showed improvements than worsening after two years of treatment compared with the study’s start.
Since JEWELFISH mainly looked at the treatment’s safety and pharmacology, the researchers emphasized that these motor findings were exploratory and should be interpreted with caution.
Overall, data reported in this study “provide further evidence that [Evrysdi] can be safely received by patients who have previously been treated with [Spinraza] or [Zolgensma],” the researchers wrote.
Follow-up evaluations in the trial’s ongoing extension will offer additional insights into the treatment’s long-term safety, they concluded.
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