Evrysdi safely boosts SMN levels in previously treated patients: Trial

Lindsey Shapiro PhD avatar

by Lindsey Shapiro PhD |

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A year of treatment with Evrysdi (risdiplam) was safe and boosted levels of SMN — the protein that’s deficient in spinal muscular atrophy (SMA) — among previously treated patients, according to published Phase 2 trial data.

The safety profile was deemed similar to that observed in trials testing Evrysdi in patients who hadn’t previously received other therapies.

These interim findings from the JEWELFISH Phase 2 trial (NCT03032172), which have been previously reported, have now been published in Neurology and Therapy. The study was titled, “Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study.”

Evrysdi is an approved oral therapy that works to boost the SMN protein lacking in patients with the main types of SMA. It was developed by Roche and its subsidiary Genentech in collaboration with the SMA Foundation and PTC Therapeutics.

JEWELFISH is evaluating Evrysdi’s safety, tolerability, and pharmacokinetics (movement through the body) in children and adults with SMA types 1-3 who’d previously received other therapies.

A total of 174 participants (median age, 14) were enrolled — 15 with SMA type 1, 108 with SMA type 2, and 51 with type 3. About a third of the patients weren’t able to sit (34%); 57% could sit, but not walk; and 9% could walk. Around half (53%) required some ventilation support.

Among those older than 2, about two-thirds (63%) had a score of less than 10 on the Hammersmith Functional Motor Scale Expanded (HFMSE), reflecting limited motor function. Most (83%) had scoliosis, an abnormal curvature of the spine.

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Evrysdi’s motor benefits sustained for 2 years in SUNFISH study

Results of Evrysdi on previously treated patients

Regarding previous treatments, 76 patients had previously taken Spinraza (nusinersen) and 14 had used Zolgensma (onasemnogene abeparvovec), both of which are currently approved for SMA. Another 71 had used olesoxime, an investigational treatment in Genentech’s pipeline that’s no longer in clinical development. The remaining 13 had enrolled in a previous clinical trial testing the investigational therapy RG7800; three of them had been assigned to a placebo.

While JEWELFISH was designed to evaluate the effects of Evrysdi after two years, the recently published study concerns an interim analysis conducted as of January 29, 2021 when patients had been using it for a mean of 17 months, or almost 1.5 years.

Results showed Evrysdi was associated with a sustained, twofold increase in SMN protein levels in the blood after four weeks, regardless of which therapies had previously been used, patients’ age, or body weight.

Those who had fewer copies of the SMN2 gene had lower SMN levels in the blood at the study’s start and throughout the trial. SMN2 is the “backup” SMN-producing gene that Evrysdi targets to boost SMN production. Still, these patients saw SMN increases after four weeks that were sustained with a year of Evrysdi.

Side effects of Evrysdi

The most common side effects were upper respiratory tract infection (17%), fever (17%), headache (16%), nausea (12%) and diarrhea (11%). Pneumonia was the most common serious side effect, occurring in four people.

No side effects related to the treatment required dose modifications or interruptions. One treatment-related serious side effect — an irregularly fast heartbeat affecting the heart’s upper chambers (supraventricular tachycardia) — resolved without any treatment change.

The frequency of side effects was more than 50% higher in the first six months after starting treatment than from six to 12 months, which is comparable to previous findings.

The oral, at-home dosing of Evrysdi “reduced the need to travel to hospitals to receive treatment, which decreased the burden on patients and caregivers,” the researchers said.

It’s also a viable treatment option for patients with advanced scoliosis, which makes delivering medications directly into the spinal canal (intrathecally) more challenging. About a third of the patients in JEWELFISH who were previously on Spinraza expressed concerns about its mode of administration.

Exploratory efficacy analyses have indicated Evrysdi led to stabilizations in multiple measures of motor function, a contrast to the progressive motor declines usually observed in SMA. Unpublished two-year findings, reported by Genentech last year, were generally consistent with interim reports.

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