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Treatment with Evrysdi (risdiplam) is safe and increases the levels of SMN — the missing protein in spinal muscular atrophy (SMA) — in children and adults who previously received other SMA-targeted therapies, according to updated data from the JEWELFISH clinical trial.
These findings were presented recently in a poster titled “JEWELFISH: Safety and pharmacodynamic data in non-naïve patients with spinal muscular atrophy (SMA) receiving treatment with risdiplam,” at the 2021 MDA Virtual Clinical and Scientific Conference, held March 15–18.
The data were presented by Claudia A. Chiriboga, MD, a pediatric neurologist who is following JEWELFISH participants at the Columbia University Irving Medical Center trial site.
Evrysdi — developed by Roche and its subsidiary Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is an oral, flavored liquid therapy designed to boost the production of functional SMN protein, which is impaired in SMA patients.
In August, it was approved in the U.S. as the first oral and at-home treatment for adults and children, 2 months and older, with all types of SMA; similar decisions soon followed in Brazil, Chile, Ukraine, South Korea, Georgia, and Russia.
Evrysdi also may be close to approval in the European Union, following a positive recommendation by an arm of the European Medicines Agency, and is under regulatory review in 30 other countries.
The approvals were based on positive safety and effectiveness data from the ongoing Phase 2/3 FIREFISH (NCT02913482) and SUNFISH (NCT02908685) trials, which are evaluating Evrysdi in a total of 221 patients, 1 month to 25 years old, with SMA types 1, 2, and 3, and who received no prior disease-modifying therapy.
The fully-enrolled, Phase 2 JEWELFISH trial (NCT03032172) is assessing Evrysdi’s safety, tolerability, pharmacokinetics (movement into, through, and out of the body), and pharmacodynamics (effects on the body) in SMA patients, ages 6 months to 60 years, who were treated previously with other SMA-targeting therapies. Patients are given Evrysdi once a day.
The study enrolled 174 patients with great diversity in terms of age, SMA type, motor function, and previous treatment.
Participants’ mean age was 14 years, and 62% had SMA type 2, 29% were diagnosed with type 3 disease, and 9% had type 1, the most severe form. One-third (34%) were unable to sit, 57% were sitters, and 9% were able to walk. Most (80%) participants had scoliosis, a sideways curvature of the spine.
A total of 84 patients were treated previously with Genentech’s investigational compounds (such as olesoxime and RG7800, the predecessor to Evrysdi), 76 with Biogen’s Spinraza — the first approved SMA-targeted therapy — and 14 with Novartis’ one-time, gene therapy Zolgensma.
The most commonly reported reason to begin Evrysdi treatment was challenges with treatment administration directly into the spinal canal for the Spinraza group and hopes of additional benefit for the Zolgensma group.
Lack of previous treatment efficacy was the main reason to initiate Evrysdi in 18% of Spinraza-treated patients, and 14% in Zolgensma-treated patients.
One patient withdrew from the study before receiving Evrysdi, meaning that the treated population included 173 participants.
As of July 31, treatment duration ranged from less than a month to more than three years, and most (55%) participants had received Evrysdi for more than six months to a year.
Those who previously received Zolgensma had the shortest treatment duration (mean of 6.4 months), while those previously given RG7800 were treated with Evrysdi the longest (mean of 29.9 months).
Most (85%) participants experienced an adverse event (side effect) and 16% had an Evrysdi-related event, including one serious side effect (abnormally fast heartbeat), which was resolved with ongoing treatment. No Evrysdi-associated side effects led to treatment discontinuation.
The therapy’s safety profile was generally consistent with that reported in other Evrysdi trials of patients not previously treated with an SMA disease-modifying therapy.
The most common adverse events included upper respiratory tract infections (16%), fever (14%), headache (13%), diarrhea (9%), nausea (9%), and common cold and rash (8% each).
In addition, Evrysdi “led to rapid and sustained increases in SMN protein levels in all non-naïve patients,” the researchers noted in the poster.
Importantly, SMN levels were increased by at least twofold among participants previously treated with Spinraza or Zolgensma, highlighting the therapy’s potential to boost SMN production even after other approved SMA therapies. This raise in SMN levels was consistent with data from both FIREFISH and SUNFISH trials.
JEWELFISH data for exploratory efficacy goals will be presented after all patients have been treated for a minimum of one year, the researchers noted.
The therapy’s clinical program also includes the Phase 2 RAINBOWFISH study (NCT03779334), which is currently enrolling newborns up to 6 weeks old with a genetic diagnosis of SMA, but no evidence of symptoms at several sites across nine countries, including the U.S.
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