#CureSMA2021 – Evrysdi Linked to Improved Motor Function in 2 Trials

Evrysdi (risdiplam) continues to be linked to motor function improvements in a broad range of people with spinal muscular atrophy (SMA), according to recent data from two ongoing Phase 2 clinical trials.

These data were presented at the 2021 Virtual SMA Research & Clinical Care Meeting.

Presymptomatic babies treated with Evrysdi for at least a year reached many of the same motor skill milestones as healthy children, the data show, while people between the ages of 1 and 60, who had received prior treatment, more than doubled their amount of SMN protein — one of a group of proteins called the SMN complex, important for the maintenance of specialized nerve cells called motor neurons. The data also showed no changes in Evrysdi’s safety profile.

“It is incredible to see that pre-symptomatic SMA infants are able to achieve developmental milestones consistent with healthy children,” Stuart W. Peltz, PhD, CEO of PTC Therapeutics, said in a press release.

Evrysdi is an oral, flavored liquid therapy designed to boost the production of functional SMN protein, which nerves need to survive and grow properly, and is impaired in SMA. It was developed by Roche and its subsidiary Genentech, in collaboration with PTC Therapeutics and the SMA Foundation. The medication has been approved in the U.S. as the first oral and at-home treatment for patients, 2 months and older, with any SMA type. It also has been approved in the European Union, Canada, Brazil, Chile, South Korea, Georgia, and Russia.

Two ongoing trials — JEWELFISH (NCT03032172) and RAINBOWFISH (NCT03779334) — are evaluating the therapy’s safety, tolerability, pharmacokinetics, and pharmacodynamics in different patient groups. Of note, pharmacokinetics refers to how the medication enters, transits, and exits the body, while pharmacodynamics looks at Evrysdi’s effects on the body.

JEWELFISH involves 174 people between the ages of 6 months and 60 years, with SMA types 1, 2, or 3, and between one and four copies of the SMN2 gene, which determines SMA severity.

Participants in this study all previously used other SMA therapies and now receive Evrysdi once per day.

Among them, 84 were treated previously with Genentech’s investigational compounds, such as olesoxime and RG7800, the predecessor to Evrysdi. Another 76 previously received Biogen’s Spinraza, the first approved SMA-targeted therapy. The final 14 previously were given Novartis’ one-time gene therapy Zolgensma. One patient withdrew from the study before receiving Evrysdi, meaning that the treated population included 173 participants.

SMN levels in patients taking Evrysdi more than doubled — a change which both occurred quickly and was sustained, the trial investigators said. The team also noted stabilization in motor function, as measured by the MFM-32, a scale that measures motor function abilities in people with neuromuscular disease.

Evrysdi’s safety profile remained consistent with past results. The most common side effects, called adverse events, were upper respiratory tract infections (17%), fever (17%), and headache (16%), followed by nausea (12%), diarrhea (11%), common cold (10%), and vomiting (8%).

More severe side effects, known as serious adverse events, were less likely, but included pneumonia (2%), lower respiratory tract infection (2%), upper respiratory tract infection (2%), and respiratory failure (2%).

No treatment-related side effects or other safety concerns caused patients using Evrysdi to withdraw from the JEWELFISH study.

“These data from JEWELFISH add to the growing body of evidence supporting the use of Evrysdi in patients from 1 to 60 years of age,” Levi Garraway, MD, PhD, Genentech’s chief medical officer, said in a separate press release.

“Importantly,” added Claudia Chiriboga, MD, one of the trial’s investigators, “the data also suggest a stabilization of motor function in trial participants.”

“As a progressive disease, untreated patients with SMA typically show a decline in motor function over time,” said Chiriboga, a professor of neurology and pediatrics at Columbia University Medical Center, in New York.

While JEWELFISH’s participants spanned a wide range of ages, the patients being evaluated in the open-label RAINBOWFISH study include up to 25 pre-symptomatic infants genetically diagnosed with SMA.

The study continues to enroll infants from newborn to 6 weeks old at their first dose, regardless of how many copies of the SMN2 gene they have. Notably, recruitment will close once 10 infants carrying two copies of the “backup” gene SMN2 — meaning they are likely to develop SMA type 1 — and normal muscle response are enrolled.

Infants participating in the study receive Evrysdi for two years, followed by a three-year extension trial.

This trial’s main goal is the proportion of infants who are able to sit without support for at least five seconds after one year of treatment, as assessed through the Bayley Scales of Infant and Toddler Development-III Gross Motor Scale. This goal will be evaluated specifically in the 10 infants with two SMN2 copies and normal muscle response.

Preliminary data showed that five infants treated for one year all managed to sit unsupported, roll, and crawl. Four could stand and walk independently. In addition, four scored the maximum 64 points on the CHOP-INTEND scale of motor function, while one scored 63.

Two of these five babies had two copies of SMN2, while the other three had more than two copies.

Results concerning the proportion of participants able to sit unassisted for five seconds will be reported once all patients reach one year of treatment, the investigators said.

“The early findings from RAINBOWFISH in presymptomatic babies under two months old are very encouraging,” Garraway said.

The primary completion date for the JEWELFISH study is January 31, 2022, while June 21, 2023 is listed as the primary completion date for RAINBOWFISH.