Editor’s note: The SMA News Today team is providing in-depth coverage of the 2021 Virtual SMA Research & Clinical Care Meeting, held June 9–11. Go here to read stories from the conference. 

Evrysdi (risdiplam) appeared both safe and effective when used after other therapies to treat five patients with spinal muscular atrophy (SMA), a small study showed.

The results suggest that this therapeutic approach — of using Evrysdi as a second-line or secondary treatment — deserves greater investigation, according to researchers from the University of Arkansas for Medical Sciences.

Kapil Arya, an associate professor at the university, and Paul Drake, MD, a resident physician, discussed these data in an oral presentation at the 2021 Virtual SMA Research & Clinical Care Meeting. The presentation was titled “Clinical Efficacy and Safety of Risdiplam Use as Combination Therapy in Spinal Muscular Atrophy (SMA) Patients Post Onasemnogene-Abeparvovec-xioi (Onasemnogene) and/or Nusinersen Use.

Marketed by Genentech, Everysdi corrects the underlying cause of SMA — a low amount of survival motor neuron (SMN) protein — by helping the SMN2 gene produce functional SMN2 protein. Nerve cells need that protein to grow properly and to survive.

Everysdi was approved in the U.S. in August 2020 as a therapy for SMA. No clear rules yet exist for combining Everysdi with other SMA medications, and moreover, data on how effective that strategy might be are lacking.

“There is no clear criteria for combination therapy,” Drake said in the presentation, referring to the use of Everysdi subsequent to two other approved SMA treatments, Spinraza (nusinersen) or Zolgensma (onasemnogene abeparvovec-xioi).

“Data on the clinical efficacy and/or safety of risdiplam in such circumstances is lacking,” he said.

To learn more, Drake and Arya, and their colleagues, examined the effects of administering Everysdi in five children with SMA who had previously taken Spinraza and/or Zolgensma.

Specifically, one patient received Evrysdi after having used Spinraza, while two started the therapy after initially using Zolgensma. Two patients began Evrysdi after using both Spinraza and Zolgensma. All five had two copies of SMN2.

The children all had been gradually improving or were stable on their earlier medications and switched to Evrysdi at a median age of 33 months, or nearly three years. The range was 15 months to 5 years. A median of 25 months, or just over two years, passed between the time of each patient’s initial treatment and the use of Evrysdi, although the time at which each began their first line of therapy varied widely.

Study participants experienced a variety of improvements. All showed overall functional improvement, as measured by a median 6-point increase in their Children’s Hospital of Philadelphia infant Test of Neuromuscular Disorders (CHOP INTEND) scores.

Furthermore, “all patients’ families reported continued subjective improvements in motor milestones,” Arya said.

Families reported their children had more energy and stamina, which allowed them to move with greater freedom and to better engage in physical therapy. Most also were better able to perform activities involved in daily living, and improvements in vocalization also were reported.

All patients needed ventilatory support prior to receiving Evrysdi — ranging from non-invasive ventilation while sleeping to being completely ventilator dependent — and their need for such support declined modestly after switching treatment.

Importantly, however, none of the study participants experienced respiratory failure (also called respiratory decompensation) after having moved to Evrysdi treatment.

“This is a very good clinical outcome,” Arya noted.

Finally, none of the patients reported major adverse side effects and none discontinued Evrysdi treatment. Overall, Evrysdi use “was well tolerated in our cohort (used sequentially), with no major adverse effects reported,” Arya said.

Nonetheless, the researcher noted that “further studies are needed to determine which combination or sequence would be safe and most efficacious for children with this disease.”

One issue with this study — and of similar studies in general — is the difficulty of determining the degree to which one medication influences an outcome versus another. Which improvements in function can be attributed to Evrysdi, for instance, as opposed to an earlier treatment with either Zolgensma or Spinraza? This was one of the questions made after the presentation.

“That is a difficult question to answer,” said Arya, “and definitely there has been discussion [surrounding] seeing improvement at four months post-risdiplam use, but is that really improvement from risdiplam, or is that improvement from SMN1 gene therapy given 12 months back? Very difficult to tease that out.”

Arya explained, however, that the improvement seen upon treatment with Evrysdi in this study followed a state in which patients had “plateaued in their improvement” up to that point.

“So presumably,” he concluded, “it is the effect of risdiplam.”

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