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Repeat doses of intrathecal nusinersen safe in infantile-onset SMA

Elvira Manzano
29 May 2018

Repeat doses of the intrathecal antisense oligonucleotide nusinersen in children with infantile-onset spinal muscular atrophy (SMA) continue to demonstrate safety, according to early data from the phase III SHINE extension study, bringing considerable hope to the SMA community.

Infantile-onset SMA is the most common genetic cause of infant mortality, typically resulting in death at age 2. Most children with SMA will be paralysed from head to toe and can only move their eyes. “If we can diagnose and treat [these children] early, hopefully, we can improve their outcomes,” said lead author Dr Diana Castro from the University of Texas Southwestern Medical Center, Dallas, Texas, US.

The ongoing SHINE study included 89 children who were transitioned from the original phase 3 ENDEAR trial.  ENDEAR was a success that the trial was stopped early for all children to receive nusinersen therapy. Those who received nusinersen in the ENDEAR trial and the new SHINE trial had continued improvements in motor function (on Section 2 of the Hammersmith Infant Neurological Examination [HINE-2]), such as sitting and head control, and event-free survival (EFS) time, which measured death or permanent ventilation. [AAN 2018, abstract 003)

The mean change in HINE-2 total score from the initiation of nusinersen treatment to last observed visit was 5.8 in those treated with nusinersen in both trials vs 1.1 in those treated with the sham procedure in ENDEAR and then nusinersen in SHINE. Twenty-eight percent achieved full head control and 15 percent achieved independent sitting in those treated with nusinersen throughout the trials.

Mean EFS time was significantly greater in children who received nusinersen in both trials than in those who underwent a sham procedure in ENDEAR and were switched to nusinersen in SHINE (73 weeks vs 23 weeks, respectively). Of note, new improvements in motor function were seen in those who switched to nusinersen.

Patients with infantile-onset SMA historically start to have deterioration of the upper respiratory function and require ventilation support at age 3 to 4 months. In the SHINE study, 58 percent of those transitioned from ENDEAR were alive without permanent ventilation as of June 30, 2017, the cut-off date for the analysis.

Eighty-three children had experienced some types of adverse events (AEs), but there were no treatment-related serious AEs. The most commonly reported AEs were pyrexia and upper respiratory tract infection, said Castro. “I work a lot with patients with SMA, it makes me happy to see that this medication continues to be safe,” she said.

The new analysis is a “reassurance” that the nusinersen therapy continues to work, commented Dr Natalia S Rost, chair of the AAN 2018 scientific committee and director of the Acute Stroke Service at Massachusetts General Hospital in Boston, Massachusetts, US.  However, she said more questions remain including how safe nusinersen is in the long term and what are the complications across a broad range of SMA populations.

Nusinersen is administered via injection into the cerebrospinal fluid and the first drug approved by the US FDA for the treatment of SMA. Treatment is initiated with four loading doses and maintenance dose is administered every 4 months thereafter.

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