The ENDEAR and CHERISH Trials in SMA

Tim Hagenacker, MD: The ENDEAR trial is a milestone publication and treatment in SMA [spinal muscular atrophy] because within that publication, SMA type 1 patients were treated with a primary outcome parameter of death or permanent mechanical ventilation. We see that important contrast between the number of patients who reached the primary end point who were treated with nusinersen versus patients who received placebo. This was a really important trial.

Nusinersen was typically well tolerated. There were no severe adverse events. After the approval, some cases of hydrocephalus occurred, which treaters have to be aware of, especially during infancy and childhood. Typically, it is a well-tolerated and efficacious treatment option.

James Wymer, MD, FAAN: There were several trials that were done to look at the effectiveness of nusinersen. The CHERISH trial was a phase 3 trial that involved some later-onset disease patients. Those were patients between 2 and 12 years old. From 2 to 12 years of age, they were randomized 2 to 1 to placebo and/or monitored through the disease, looking at the Hammersmith Functional Motor Scale as primary end points. The Hammersmith looks at activities of daily living. Again, that assess activities like rolling over or sitting up. As patients got more involved, because the Hammersmith is involved primarily with proximal function, they had the right Revised Upper Limb Module that was also looked at.

The Limb Module is asking that same question. It’s a functional scale. Can you pick up a coin? Can you raise something up? That’s focused more on the arm, though. They used several functional end points to measure improvement, and they did find statistically significant changes in both of those. The changes were significant enough that when they reached this prespecified interim analysis, the data were so good that the study had to be discontinued. When they completed the analysis and looked at it, and did the final analysis of that interim, the FDA agreed that the study should be discontinued because drug needed to be FDA approved. Between the ENDEAR and CHERISH trials, there were 2 studies showing strong evidence of efficacy, and nusinersen was approved in December 2016.

Well the Hammersmith Functional Motor Scale Expanded, or HFMSE, and the right Upper Limb Module are both functional scales looking at what one can do in terms of activities of daily living, as well as functional use of the arms. Three points are considered to be significant for both of those. When these scales are developed, they ask a series of questions. With those questions, in the case of the right Upper Limb Module, there are 19 questions they ask, and you score them either 0, 1, or 2. One of them is scored on a 0-to-1 scale. You ask those questions and get a score from 0 to 37: 37 is normal, while 0 is at the lower end of the scale

Anytime you see about a 3-point improvement, that’s a significant improvement in quality of life as reported by a patient. Nusinersen showed benefits in both those scales in all the analysis that was done.