ENDEAR Study, Patient Factors, and Drug Approval Criteria

Peter L. Salgo, MD: When you say remarkable efficacy, what are we looking at? Because there are 2 kinds of significance. There’s the statistical significance, in which a P value is good but not so much in a clinical sense. Then there’s clinical significance, which means I gave this drug, and this patient got clinically better. Do people confined to wheelchairs walk? Do people without breathing, without assistance, now breathe on their own? What do you see?

John Brandsema, MD: Translating the research-type data, where you’re looking at functional scales in numbers, to real-life experience is always challenging. What you have to remember, in the natural history of this disease, is that if you were to diagnose an infant who is symptomatic, you’re looking at somebody who’s barely going to be moving within a couple of years of that diagnosis and on full respiratory support with noninvasive or invasive ventilation and full feeding support. In the ENDEAR study, there was 1 outcome measure that was either death or being on more than 16 hours a day of ventilatory support. There was a relative risk reduction, just to give you a sense of the severity of what they were looking at in that trial.

But just in practical terms, what we’re talking about is babies who were predicted not to be able to move within a couple of years of their life are gaining skills like sitting independently and standing, and some are even walking if they’re treated early enough with this intervention. In the NURTURE study, which are the presymptomatic open-label data, they’ve shared that several of those patients achieved walking at this point. It’s a really transformed experience of this disorder.

Peter L. Salgo, MD: That is knock-me-over-with-a-feather good. I mean, you’re smiling.

Sika Dunyoh: Yeah.

Peter L. Salgo, MD: You haven’t been smiling for a while.

Sika Dunyoh: Yeah. I mean, I have chills just thinking about it.

Peter L. Salgo, MD: Is it amazing?

Sika Dunyoh: There is so much hope and promise for the families affected by SMA [spinal muscular atrophy]. It’s incredible.

Peter L. Salgo, MD: What patient factors are involved? Who gets this drug? Who doesn’t get this drug?

John Brandsema, MD: Going back to what I said a little earlier in the conversation, it was a challenge for us to decide about using this medication in groups that were different from the original research trial. One of the most challenging groups are patients who are born very symptomatic, so those who have had in utero start of their symptoms—what we used to call type 0 SMA—but who need significant support at birth. Another group are those who have been living with SMA for a long period of time and already have very severely progressed functional impairment. Those groups were more challenging to know what a realistic expectation of using the medication would be. I can say that anecdotally, at our center, we have seen meaningful differences in patients who are receiving that therapy in terms of some of their different clinical aspects of their symptomatology of SMA. But it’s less easy to measure than in the group that was in the research trial, and so our real-world experience is looking at trying to figure out how to best quantify what that is for the patient and what kind of impact the treatment is having.

Peter L. Salgo, MD: He likes this drug. She likes this drug. Parents like this drug. Not only are there data—lab data, study data—to show that it’s statistically significant, but it’s also clinically significant. Ring, ring, ring. A patient says, “I want the drug.” And you say?

Maria Lopes, MD, MS: We say, “You do get the drug. You have to meet certain criteria.”

Peter L. Salgo, MD: What criteria?

Maria Lopes, MD, MS: The criteria are types 1, 2, and 3, and that you have the 5q-SMA homozygous—compound heterozygous.

Peter L. Salgo, MD: That means that you’ve got to have the genetic makeup for which this drug will work.

Maria Lopes, MD, MS: Exactly.

Peter L. Salgo, MD: Without that, there’s no point, right?

Maria Lopes, MD, MS: Exactly.

Peter L. Salgo, MD: Even you agree with that.

John Brandsema, MD: Yeah, I completely agree with her.

Peter L. Salgo, MD: OK, so we’re on the same page. What else?

Maria Lopes, MD, MS: Then the final requirement is usually that early is better. We usually have a cutoff of age 15 at the initiation of therapy. Obviously, if you’re doing well, you’re going to progress and you’re going to continue on the therapy. But the tough part is perhaps those who have lost significant function. We don’t even address that. We leave it up to the shared decision-making part, which I imagine would be a very difficult conversation. But those are the 3 things, and you’re usually in the hands of a specialist, which we want it to be.

Peter L. Salgo, MD: That makes sense. They’ve got to be in the hands of somebody who knows this disease and knows what to do with these drugs, and it’s an Lp(a) [lipoprotein]—delivered drug. But I was fascinated by part of your answer, which is that we leave it up to the clinician. We leave it up to some degree to the caregivers.