Crystal Proud, MD: I'd like to transition and discuss another medication that has been FDA approved for the treatment of spinal muscular atrophy [SMA].
Nusinersen was the first meditation approved for this diagnosis. It acts in a different mechanism. We know that Zolgensma [onasemnogene abeparvovec-xioi] delivers the SMN1 transgene and that our patients with SMA have a missing or mutated SMN1 gene. Nusinersen acts on the SMN2 gene. The SMN2 gene is a faulty gene, only producing full-length protein about 10% of the time, and nusinersen's mechanism of action is to address the alternative splicing such that more full-length protein is being produced.
It's administered intrathecally in a loading dose phase and then continued administrations through maintenance dose phase. Its FDA approval was supported by the ENDEAR clinical trial. John, can you remind us of the significance of the ENDEAR clinical program and the phenotype of SMA that was being evaluated there?
John Brandsema, MD: There are many ways that you could approach the concept of significance with this study because this really was trailblazing, a huge landmark moment in our neuromuscular history. Firstly, just thinking about the logistics of the fact that this was a placebo-controlled study of intrathecal administration, so they had to be separate teams, 1 of which was doing a placebo procedure of sham spinal injection of the medication versus the two-thirds who were being actively treated with medication.
They then planned an interim analysis when about 80 of the infants had gone through 6 months of treatment. In most studies, interim analysis is an opportunity to look for any safety signals that might have been unanticipated and start to look at whether there is a hint of efficacy so that you can say, “Let's finish the protocol the way that we originally set it up.” In this study, the data were so strikingly different between the interventional arm and the placebo arm that it was halted early because it was such a striking difference.
There was 40% of the treated group defined as motor responders, having gained the number of points on the Hammersmith infant scale that they were using to measure the patients. When they went to the final analysis, this even went up to 50% of the patients being defined as responders. That's a huge gain of function to be defined as a responder, even if you stabilize or decline less quickly, these are all therapeutic effects in neuromuscular disorders.
We're setting the bar very high for being an intervention with these treatments because they are making a totally different experience of the disease than would be expected in the natural history. The other thing about the ENDEAR study was that these treatments seem to be well-tolerated. The importance of monitoring platelets and coagulation parameters and urine protein, both from the perspective of thrombocytopenia and the perspective of renal injury that has been seen in some medications in this category, is important to recognize.
In the trial, there was also difference between the groups in respiratory infection rate, which seemed to get smaller as they went to the final analysis and may have been related to the treated group being slightly more severe at baseline. Some who have looked at the data think that. In general, this is a well-tolerated medication. We now know this from clinical experience too. The overall hazard ratios that they looked at in the study in terms of death or needing permanent ventilation and the motor gains that are seen in the cohort are really remarkable and led to the label being in place so quickly after the trial was initiated.