AAN 2023: Evrysdi effective in already treated SMA patients in trial
Treatment with Evrysdi (risdiplam) in spinal muscular atrophy (SMA) patients who previously received other therapies was found to safely stabilize motor function and lead to slight improvements in arm function, new clinical trial data show.
These results occurred “irrespective of previous treatment,” the researchers wrote, adding that “no drug-related safety findings leading to withdrawal were reported for any patient.”
The findings were presented last week at the American Academy of Neurology (AAN) 2023 Annual Meeting, in a poster titled, “JEWELFISH: 24-month Safety, Pharmacodynamic and Exploratory Efficacy Data in Non-Treatment-Naïve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam.” The work was funded by by Roche, which markets Evrysdi.
“Based on the exploratory efficacy analysis, an overall stabilization of motor function was observed following 24 months of [Evrysdi] treatment in patients” who have “a broad range of age (1-60 years) [and] SMA type,” the team wrote in a trial abstract presented at AAN.
Broadest patient population studied to date in SMA trial
SMA is caused by reduced levels of the SMN protein, which lead to the progressive loss of nerve cells that control voluntary movement. There are three available treatments, all of which work to boost levels of this protein.
In addition to the daily oral medication Evrysdi are the one-time gene therapy Zolgensma (onasemnogene abeparvovec-xioi), and Spinraza (nusinersen), which is administered by injection into the spine every four months.
All of these medications have proven effective at slowing the progression of SMA in clinical trials, though studies to date have mainly focused on young children in the early stages of SMA.
There are less data on the use of these treatments in the broader population of people living with the disease — including in older patients and among those with more advanced disease. Data on what happens when patients combine or switch between these medicines also are limited.
To address this knowledge gap, Roche is sponsoring a Phase 2 trial called JEWELFISH (NCT03032172). It’s evaluating the safety and efficacy of Evrysdi in SMA patients who previously received other treatments.
The study enrolled 174 people with SMA types 1, 2, or 3 who had previously been treated with Spinraza or Zolgensma, or with experimental SMA therapies no longer in development (RG7800 or olesoxime). The main reasons for entering into JEWELFISH were hopes of additional benefit for patients previously on Zolgensma, and tolerability concerns for those on prior Spinraza.
At the start of the study, a majority of patients (57%) were able to sit up but could not walk. A total of 34% could not sit up, and 9% were able to walk.
This group of patients represents “the broadest population ever studied in an SMA trial,” the researchers noted. In this poster, they presented two-year results from JEWELFISH.
Over this study period, about 10% of patients discontinued the trial, mainly for reasons such as not wanting to travel, or choosing to switch to commercial Evrysdi or another treatment. None of the patients stopped due to treatment-related side effects, and just one discontinued due to Evrysdi not being effective.
Most safety-related findings in the study were reflective of patients’ underlying SMA, and they became notably less common over the course of the study period.
Evrysdi found to increase SMN protein levels in most patients
Trial results showed that treatment with Evrysdi led to a sustained increase in levels of SMN protein, by more than twofold for the majority of patients. The effect was similar regardless of which other SMA treatment patients had previously received.
Scores on the Motor Function Measure 32 (MFM-32), which as its name implies assesses motor function, were generally stable over the course of the trial. Specifically, after two years on Evrysdi, the average MFM-32 score decreased by 0.17 points.
To put this number in context, the researchers also presented data from a natural history study that followed untreated SMA patients, ages 6 to 30. Over the course of two years without treatment, MFM-32 scores decreased by 2.66 points for these patients.
While the researchers cautioned that it’s impossible to make a direct comparison between the two groups, they said the data illustrate that motor function was generally stable for SMA patients on Evrysdi in JEWELFISH, whereas without treatment motor function would be expected to gradually worsen.
An overall stabilization of motor function was observed following 24 months of [Evrysdi] treatment in patients … [who have] a broad range of age (1-60 years) [and] SMA type.
Scores on another measure of motor function, the Hammersmith Functional Motor Scale Expanded (HFMSE), also were stable over the study period, with an average decrease of 0.11 points over two years. Average scores on the Revised Upper Limb Module (RULM), a measure of arm and hand function, showed a slight but statistically significant improvement of 0.71 points after two years on Evrysdi.
A sub-analysis of adult SMA patients — those 25 or older at the study’s start — consistently showed stabilized motor function, with minimal change in MFM-32, HFMSE, and RULM scores after two years on Evrysdi.
None of the patients who were able to walk at the start of the study lost this ability after two years on Evrysdi. In fact, the average distance patients could walk in six minutes tended to increase over the study period, which the researchers noted markedly contrasts with the usual course of SMA.
The scientists also highlighted data for six babies younger than age 2 at the study’s start. Three had previously been treated with Spinraza, and three had received Zolgensma. At the study’s start, only one of the babies given Spinraza and two of those on Zolgensma could sit up unassisted. After two years on Evrysdi in the JEWELFISH trial, all six children could sit unassisted.
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