James Wymer, MD, FAAN: Earlier this year, a group out of Germany published a long-term observational study of about 14 months of patients aged 16 to 55 years old. There were about 139 patients who were enrolled, and they actually analyzed 124 of those. They looked at these patients over the course of 6, 12, and 14 months, as they were treating. This was observational. The patients received their medication through their insurance, the standard way. This was an analysis just looking to see if there was improvement with the nusinersen.
Again, were people were between the ages of 16 and 55 years. They saw at 6 months, using the Hammersmith Functional Motor Scale, that there was about a 28% improvement. At 10 months, 35% of the patients showed clinically meaningful improvement. At 14 months, it was about 40%.
It’s important to remember that those numbers show improvement. As you go further in the clinical trial, the number of people that continue in the clinical trial gets smaller. You get some tricks, in terms of the statistics. But the bottom line on this is that spinal muscular atrophy [SMA] is gradually progressive.
We know this from the natural history. As we get older, functioning is going to gradually decline more, and now we’ve got a treatment on which, in this observational study, a high percentage of patients either stabilized or showed some modest improvement. That is a huge benefit. It may not have cured their disease, but it prevented the decline. That’s the take-home message from that study.
The trial used the FDA-approved dosing. They had the standard loading dose and then went to the standard maintenance dosing afterward. What I didn’t comment on is that they looked at several parameters. The Hammersmith Scale was the primary parameter. The 6-minute-walk test for those who were ambulatory was 1 of the secondary end points, as was the right Upper Limb Module I mentioned before. They also looked at cost. All those end points showed some partial improvement. This was all using standard, real-world dosing that would be through FDA approval.
The most important part and the key factor in this is that spinal muscular atrophy is known to have a gradually progressive course. This validated what we have been seeing clinically. When we treat patients with nusinersen, we get the reports from the patients that they’re stabilizing. But we don’t have the data that back that up. There have been a couple of scattered reports of single sites based on what they have been seeing. Most of them have been reporting stabilization with this, but they’ll do it on 10, 20, or maybe 30 patients.
When you start getting over 100 or more, the data become valid. When it’s a small sample, there could be errors or site problems. You have problems with small sample sizes. By going to the larger numbers, you get rid of a lot of those errors. The strength in this is the sample size, for 1. No. 2, there wasn’t a decline. There was stabilization in treatment of SMA.
Tim Hagenacker, MD: In the pivotal trials, only infants and children were treated with nusinersen, but the approval also includes adult patients. Before we had performed that real-world evidence trial within the adult patients, there was a lack of data. That was the reason nusinersen wasn’t reimbursed in every country worldwide. We decided to perform a trial to test the drug within the adult population, and we found that it is also efficacious and safe, as we found in the CHERISH and the ENDEAR trials. For a primary outcome parameter, we chose the same as in the CHERISH trial: the Hammersmith Scale. In the secondary outcome parameters, we chose the Revised Upper Limb Module. For the patients who are ambulatory, the 6-minute-walk test was administered.
In every case, we found a significant improvement of motor function. Especially in the SMA type 3 patients, we also found that with increasing treatment time, an increasing number of patients reached a clinically meaningful improvement of motor function. This does not exclude the SMA type 2 patients. They didn’t have the same amount of motor function increase, but they stabilized. This is also an important treatment goal in the very severely affected patients.
This study is important because it completes the data we also have on infants and children. The important message is that patients cannot be too old to get on treatment, because we don’t find a correlation with patient age. Some of our best improvers in the study were patients who were above 50 years old. It is important that treatment is initiated as early as possible to get the best effects on motor function. On the other hand, patients cannot be too old to get on treatment.