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BOSTON -- Early results from a small phase I trial of a gene therapy for spinal muscular atrophy (SMA) were promising, with many children hitting milestones not typically seen in the condition, researchers said here.

In the latest update from the trial of AVXS-101, all 12 young patients were able to bring their hand to their mouth, 11 had good head control, 11 could sit without assistance, and nine could roll over, Jerry Mendell, MD, of the Center for Gene Therapy at Nationwide Children's Hospital in Columbus, Ohio, reported during the clinical trials plenary session at the .

Two patients crawled, stood, and walked independently, and eight could actually speak, Mendell reported, adding that the latter is "one of the remarkable things you see in this trial, which you never see in SMA."

Claudia Chiriboga, MD, MPH, of Columbia University Medical Center in New York City, who was not involved in the study, said the early data are "very encouraging, showing a robust response in respiratory, nutritional, and motor function."

But she cautioned that the findings are only "proof of concept" -- albeit "deserving of a larger study."

"As with nusinersen," Chiriboga said, "early treatment, before onset of significant respiratory or feeding impairments, was associated with better outcomes."

SMA has received much attention at this year's meeting, as nusinersen (Spinraza) was approved late last year. As an antisense oligonucleotide, that drug has a different mechanism of action from AVXS-101, which is a gene therapy delivered via AAV9 viral vectors.

Mendell noted that SMA Type 1 is a fatal disease, with only 8% of children surviving or remaining free of permanent ventilation at the age of 20 months.

For the study, the researchers conducted a single-site, open-label, dose-escalation IV infusion of AAV9 virus carrying the SMA gene. Patients had to be diagnosed with SMA before age 6 months, had to have bi-allelic SMN1 gene mutations, and have two copies of SMN2.

The primary endpoint was safety and tolerability, while the secondary endpoints were time to death or a surrogate of time to 16-hour ventilation continuously for at least 2 weeks.

Mendell discussed two cohorts: The first enrolled three patients who were dosed with 6.7E13 vg/kg of the viral vector, in which two patients survived event-free for over 30 months. One patient required respiratory support around that age.

Seeing good safety, the researchers launched a second cohort of 12 patients, who were dosed with 2E14 vg/kg of the viral vector.

Mendell reported that the first patient has survived event-free for over 30 months, and nine have reached event-free survival at 20 months. Every patient achieved event-free survival at 13.6 months.

In terms of nutritional support, respiratory support, and bulbar muscle function, six of the seven children who did not require feeding at study entry continued without nutritional support; seven of the 10 who did not require BiPAP support at study entry continued without any BiPAP; and no children hospitalized for respiratory illnesses required a tracheostomy or prolonged invasive ventilation.

Nearly all the children (11 of the 12) are feeding orally, including six who are feeding exclusively by mouth, Mendell said. Additionally, eight of 12 are able to speak.

"It's very gratifying when you see that eight of these kids are actually speaking," Mendell said.

In terms of safety, the team saw no new adverse events since the initial report last October. At that time, there were five treatment-related adverse events, two of which were classified as serious based on FDA criteria for asymptomatic elevated liver function enzymes.

Of the 251 non-treatment-related adverse events, 10 were classified as serious, as they were infections that required hospitalization -- but all patients recovered without incident, Mendell said, concluding that the overall safety profile looks good and that the drug is generally well tolerated.

"The safety record here is impeccable," he added.

In a motor milestone achievement assessment of cohort 2 that was adjudicated by an independent external reviewer in January 2017, the researchers saw that all patients were able to bring their hand to their mouth, 11 had good head control, nine could roll over, and 11 can sit without assistance -- nine of them can sit more than 5 seconds, seven can sit more than 10 seconds, and five could sit more than 30 seconds.

Those numbers have since increased, Mendell said. In data collected since that time, 10 children can now sit for at least 5 seconds, nine for at least 10 seconds, and eight for 30 seconds or more.

In addition, two patients crawled, stood, and walked independently. Mendell noted that the published natural history shows no SMA Type 1 patients achieving any motor milestones.

During the plenary, Mendell played a video of one 18-month old patient walking independently, carrying a bag, and reaching up to press an elevator button at the hospital -- a clip that was met with enthusiastic applause from physicians attending the plenary session.

"When you examine him, it just about takes your breath away," Mendell said.

But questions remain about how long a single infusion of AVXS-101 will last, and whether patients can receive additional infusions if necessary.

"It's an interesting question in the gene therapy world, and we're still trying to understand that," Mendell said. "Much depends on how long the promoter will continue to function. If that promoter shuts down using this serotype, we do have the potential for readministering the virus. ... We could also administer a different serotype. There's great potential here, and we're very optimistic."

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