Collins, Thomas R.

doi: 10.1097/01.NT.0000520852.35562.83

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In a new gene therapy trial, infants with spinal muscular atrophy survived longer without adverse events and achieved developmental milestones. Independent experts said the therapy should be studied and compared with the recently-approved drug, nusinersen.

BOSTON All 15 infants treated with gene therapy for spinal muscular atrophy type 1 (SMA-1) survived past the age at which 75 percent of untreated infants typically die or need at least 16 hours a day of ventilation support, according to results of an open-label phase 1 trial reported here in April at the AAN Annual Meeting.

The event-free survival of the infants to at least 13.6 months shows the promise of the proprietary gene therapy known as AVXS-101, for Avexis, the Illinois-based manufacturer that funded the study.

The drug uses an adeno-associated virus 9 AAV9 to deliver a fully functioning survival motor neuron gene to the patient's cells.

Researchers also found that all nine infants born at least 20 months before the January data cut-off reached the 20-months' time point. All of the patients in the trial are alive, and only one has required 16 or more hours per day of ventilator support at 28.8 months, according to the researchers.

The United States Food and Drug Administration (FDA) granted the drug breakthrough therapy status, which will mean faster review, in July.

Jerry R. Mendell, MD, FAAN, the principal investigator of the current study, said SMA-1 is nearly always fatal for children. Dr. Mendell, who conducted the first gene therapy studies on the treatment and developed the neuromuscular gene therapy program at Nationwide Children's Hospital in Columbus, OH, noted that a 2014 study in Neurology, conducted to establish the natural history against which potential therapies could be measured, found that only 25 percent of children with SMA-1 survive without permanent ventilation beyond 13.5 months. And only 8 percent of untreated infants live beyond 20 months.

In the current study, 12 of the 15 children were given the high dose of the drug. All of these infants have reached at least one milestone, and most have achieved several milestones, such as bringing their hands to their mouths, head control, and sitting. Two children stand and walk independently, and eight can talk.

These are milestones that are essentially never achieved in untreated children, said Dr. Mendell, who reported he has no financial interest in the drug.

None of them ever learn to talk and as they approach their death march, they can no longer feed except by G-tube and they basically live in a vegetative state, he said. And all that has changed dramatically.

Dr. Mendell emphasized the importance of early treatment. The two best patients in our clinical trial were those who were treated very early, and they very rapidly reversed their course; they are now walking, he said. Many of the patients in the trial were treated early because they have a family history [for SMA] and were recognized prenatally. That is what facilitated the study and also what will make a difference in the long run.

He added: I'm hoping the results of this study will allow for newborn-screening for this disease. That will provide a pathway for early treatment.

Last year, the FDA approved the new SMA drug nusinersen, an antisense oligonucleotide therapy, which uses targeted RNA binding to boost production of a protein in which SMA patients are deficient. Dr. Mendell said it's possible that the two drugs could work well together, although this hasn't been evaluated yet.

What we all wonder about on the gene therapy side and on the oligonucleotide side is whether these treatments could be complementary, he said. We'll know the answer to that because some of our patients have requested opportunity to move to nusinersen.

He noted that is an option for patients after their two-year enrollment commitment is reached.

In a review of the abstract, Brent L. Fogel, MD, PhD, FAAN, associate professor of neurology and human genetics at the University of California, Los Angeles, said the results sound promising, and he agreed that the therapy should be compared with nusinersen.

Given the recent success of the FDA-approved antisense oligonucleotide therapies which increase production of SMN protein by altering the splicing of the endogenous SMN2 gene, rather than replacing the damaged SMN1 gene it would be important to compare the risk and benefit between the two approaches to determine the optimal treatment for patients with SMA, who previously had none at all, he said.

He said that other clinical questions remain, as well. It would be of key interest to know what cells the virus is targeting, the resulting gene expression initially and whether that is maintained, and if any side effects are observed as the patients are followed over time, Dr. Fogel said. This would have implications for similar future therapies in other neurogenetic disorders.

Kathryn J. Swoboda, MD, director of the neurogenetics program at the Massachusetts General Hospital for Children, who was a site leader in the multi-center trial on nusinersen, noted that the evidence of gene therapy's efficacy is limited in scope, at least for now.

It's a viral-derived vector, she said, referring to the AAV-9 used in the gene therapy trial. It's a common virus that people are ultimately exposed to so they produce antibodies with time. So the proof that it works is only in babies right now, she said

If you take a young baby with SMA, those are where the phenomenal results are. Even if you took a 9-month-old or an 8-month-old or a 7-month-old with a severe form of disease, it didn't do much, because by then they've already had devastating loss of motor neurons. So we don't know how this would be tolerated in older patients and adults, and we don't have the capacity to make enough virus to deliver it to those patients at this point, and so it's going to take some additional time to do those studies.

The approval of nusinersen could complicate the future of trials on gene therapy, she said.

You've already got an approved drug and how do you design those trials? Do you say they can't get a drug we know might help them? And what if the therapy for gene therapy doesn't work? A back-up plan to start the approved therapy later could mean it might to be too late to respond, she said.

I think there's a lot to think about from an ethical perspective.

News of new therapies for the disease has drawn tremendous demand for SMA treatment from around the world, she said.

We've gotten calls from parents of newborns, prenatal cases, all the way up to 70-year-old patients who want something because it's a progressive disease, she said. And even though it's slowly progressive after a certain point, you're still losing something continuously over time.... They don't even care if it's a major improvement. They just want to stay where they are.

Nonetheless, the path forward is not clear, she said.

Does this cure? Do we have a cure yet? No. We have a really promising set of therapies that are so above anything we've seen for neurodegeneration that it's tremendously exciting. But it doesn't mean that it makes it easy to figure out how to do this.

. AAN Annual Meeting Abstract CT.003: Mendell J, Al-Zaidy SA, Shell R, et al. AVXS-101 phase 1 gene therapy clinical trial in SMA type 1: Event free survival and achievement of developmental milestones. http://bit.ly/genetherapy-abstract.

. AAN Annual Meeting Abstract CCI.002: Kuntz N, Farwell W, Zhong ZJ, et al, on behalf of the ENDEAR Study Group. Nusinersen in infants diagnosed with spinal muscular atrophy (SMA): Study design and initial interim efficacy and safety findings from the phase 3 international ENDEAR study. http://bit.ly/nusinersen-abstract

. Sign up for the video link to the plenary here: http://aan.informz.net/AAN/pages/17_AMOD_Form.

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News from the AAN Annual Meeting: Gene Therapy Found to Benefit Infants with SMA Type 1 in Open-Label Trial - LWW Journals