Science News: Treatment for Spinal Muscular Atrophy Using Onasemnogene Abeparvovec

Submitted by: Justin Willer, MD
Edited by: Eman Tawfik, MD

Can Ebru Bekircan-Kurt, Megan A Waldrop, Anne M Connolly, Jerry R Mendell. Treatment for spinal muscular atrophy using onasemnogene abeparvovec. touchREVIEWS in Neurology 2022;18(2): 133-41.

Summary: The article summarizes the development, safety, and efficacy of intravenously administered drugs using the Adeno-associated virus vector for spinal muscular atrophy (SMA) type 1 and intrathecal administration for SMA type 2.

The article discusses several clinical trials. The SART trial was groundbreaking. Based on its positive results, the FDA approved onasemnogene abeparvovec gene therapy for SMA on May 24, 2019. The STRIVE trial included patients aged 6 months or less with 1 or 2 copies of SMN2. Endpoints were independent sitting for > 30 seconds per Bayley-II at 18 months and survival at 14 months. Thirteen patients in the treatment group achieved sitting > 30 seconds versus none in the control group, and 18 patients did not use ventilatory support. On the other hand, The STRONG trial was performed to address the drug use in SMA-2. Patients were between 6 and 12 months and able to sit unassisted for 10 seconds, but were not able to walk or stand. Patients were given prophylactic prednisolone (1 mg/kg/day) 24 hours prior to intrathecal delivery that was maintained for about 30 days. The STEER trial has now started in patients with SMN type 2.

The review also briefly discusses two additional pharmacologic agents, nusinersen and risdiplam, which are clinically approved as alternative treatments. Nusinersen is administrated intrathecally, and was approved by the FDA under the brand name Spinraza®. In the ENDEAR trial, it was found that significantly higher percentage of infants treated with nusinersen had a motor milestone response.

Risdiplam is the only orally administered medication for SMA, and is approved by the FDA under the name Evrysdi®. It is a pre-mRNA splicing modifier that increase production of the SMN protein. Its efficacy results from its unique SMN2 pre-mRNA binding sites: a 5’ splice site in intron 7 and exonic splicing enhancer in exon 7. This increases levels of full-length SMN mRNA and protein. The authors conclude that risdiplam is an important alternative to nusinersen in patients with SMA type 1 for patients who cannot receive first line gene therapy (those with AAV antibodies).

Comments: This is an excellent article on the pathophysiology of SMA, the underlying genetic defects, and the basis for treatment with a review of the available agents.