Current Series: Understanding Spinal Muscular Atrophy


Nancy L. Kuntz, MD: These 2 clinical trials and treatment modalities are relating to increasing production of SMN protein through modulating SMN2 gene. There have been other approaches. Liz, I know that you have some experience as well with the trials using gene transfer for treatment of SMA [spinal muscular atrophy].

Elizabeth Kichula, MD, PhD: Yes. So the current therapy that’s being developed is AVXS-101, or onasemnogene. It’s quite exciting. The application is currently being reviewed by the FDA, and we anticipate an answer shortly. This is a gene transfer strategy using the adeno-associated virus 9 [AAV9], which is one that’s commonly being used in current gene therapy trials. And so the adeno-associated virus doesn’t cause any human illness at all, and really they’ve taken out all the parts of the viral genomes that would replicate and really replaced it with a normal functioning copy of the SMN gene.

It is a virus that doesn’t integrate its DNA into the human genome, so we shouldn’t run into issues that arose in earlier clinical trials from decades ago, where there was an increased cancer risk with certain gene therapies. Rather, the viral caps just sit there in the cell but can continually express SMN. The choice of the virus is a really important thing when you’re talking about gene therapies because every virus has particular cells that it likes to infect. And so AAV9 was picked in particular because it likes those neurons and astrocytes, although it’s important to note that it will kind of go throughout the body as well. And in particular, liver and muscle and other tissues will also get certain levels of viral expression moving forward.

So really, the initial studies have looked at both its safety and efficacy with a phase 1 trial that was published back in the New England Journal of Medicine in 2017. The initial study was of 15 patients. The first 3 patients received a lower dose really to look for basic safety. And the next 12 received a higher dose, where it was clear that there was better efficacy as well. And so a lot of the outcomes that they looked at had significant overlap with things that you’ve already heard about. So the CHOP INTENT had significant improvement and really improved quite rapidly over the first several months following infusion. In addition, none of the patients required any full-time ventilatory support. None of the patients died during the trial. All these things that in the untreated SMA type 1 population we would have anticipated to see during that.

Nancy L. Kuntz, MD: Absolutely.

Elizabeth Kichula, MD, PhD: They’ve also looked a lot at some of the feeding and the bulbar involvement and speech, and we’re also seeing that those outcomes are also really continuing to improve. And 2 out of the 12 who were treated in the high-dose group have walked independently. So a very drastic change from where we would otherwise anticipate these patients to be.

On the basis of that, they really have moved forward. There’s a larger phase 3 clinical trial, also of type 1 patients, that’s being done. And it’s important for me to backtrack a little bit and note that in these phase 1 patients, they are giving the medication intravenously. So the virus completely crossed the blood-brain barrier. We don’t run into those issues that we get with nusinersen, so it is a onetime intravenous injection. Then the virus has to just sit there and will continue to express the protein.

They’re also doing a study in older patients, in type 2 patients, where they’re administering the drug intrathecally to really maximize getting more of the medication, more of the virus, to the motor neurons where it’s most necessary. It’s an exciting area, and we’re anticipating where things will go. It definitely has some benefits, including the fact that it’s onetime infusion, although it does require a lot of safety monitoring afterward, particularly looking for any liver toxicity, which is the main thing to monitor for in the period after infusion.

Claudia A. Chiriboga, MD, MPH: Even though it is administered intravenously and it diffuses throughout the body, it remains only in nonreplicating cells. So rapid replicating cells will lose that vector genome. But it does stay in lots, for quite a bit of time from what I understand, because that doesn’t replicate as quickly. What was the mean age of treatment of these babies?

Elizabeth Kichula, MD, PhD: Was about 3½ months.

Claudia A. Chiriboga, MD, MPH: So quite young, yes.

Nancy L. Kuntz, MD: But there is a trial ongoing with older children, is that correct?

Elizabeth Kichula, MD, PhD: Yes.

Nancy L. Kuntz, MD: But it’s too early.

Elizabeth Kichula, MD, PhD: Only preliminary data have been released at this point.