Thomas Crawford, MD, Pediatric Neurologist at Johns Hopkins, discusses the results from the DEVOTE study using a higher dose of nusinersen to treat patients with spinal muscular atrophy (SMA).
SMA is a group of genetic neuromuscular disorders that affect the motor neurons. The loss of motor neurons causes progressive muscle weakness and loss of movement due to atrophy. Many types of SMA mainly affect the muscles involved in walking, sitting, arm movement, and head control. Breathing and swallowing may also become difficult as the disease progresses. SMA type 1, 2, 3, and 4 are caused by genetic changes in the SMN1 gene. Extra copies of the nearby related gene, SMN2, modify the severity of SMA. There are other rarer types of SMA caused by changes in different genes.
Nusinersen is an antisense oligonucleotide designed to alter the splicing of the SMN2 gene. This alteration helps to increase the production of fully functional SMN protein. The therapy was originally approved in 2016 for the treatment of SMA.
DEVOTE Clinical Trial
The DEVOTE clinical trial is an escalating dose, randomized, controlled study testing the safety and efficacy of a higher dose regimen (50mg/28mg) of nusinersen in treatment-naïve participants with infantile-onset and later-onset SMA enrolled in DEVOTE Part B and participants who transitioned from the currently approved 12mg/12mg regimen in DEVOTE Part C.
It was observed that the higher dose regimen of 50mg/28mg led to greater reductions in plasma Nfl at earlier points. This indicates a more rapid slowing of neurodegeneration. In treatment-naïve infantile-onset participants, the higher dose proved statistically significant improvement for 6-month change in CHOP-INTEND score from baseline, which was the primary endpoint. Additionally, this group trended in favor of the higher dose over the 12mg/12mg groups from DEVOTE and sham groups. Finally, improvements to HFMSE and RULM scores were shown in a cohort ages 4-65 years who transitioned to the higher dose regimen following several years on the 12mg/12mg regimen. The higher dose regimen was also observed to be well tolerated with no new safety signals.
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