SMA Type 1 Infants Treated With Zolgensma Achieving Milestones, Data Show

Infants with spinal muscular atrophy (SMA)  type 1 who received a single infusion of Zolgensma continue to achieve developmental milestones and show improvements in motor function, according to interim data from the Phase 3 STR1VE-EU trial. 

Importantly, these improvements were also seen in infants with more severe forms of the disease compared with those enrolled in previous, completed trials of Zolgensma, including the Phase 1 START (NCT02122952) and the Phase 3 STR1VE-US (NCT03306277) trials.

“In STR1VE-EU, patients achieved rapid improvements in motor function following treatment with Zolgensma, and most have already achieved motor milestones not observed in the natural history of SMA Type 1,” Eugenio Mercuri, MD, PhD, professor at the department of pediatric neurology at Catholic University in Italy, said in a press release.

“These interim results are especially encouraging considering STR1VE-EU includes some patients with a more severe phenotype [disease characteristics] than in the START and STR1VE-US studies, further supporting the gene therapy’s positive benefit/risk profile, even in this more fragile population,” Mercuri said.

Interim data from STR1VE-EU (NCT03461289), which also is now completed, was presented during a Clinical Trial Poster Session at the World Muscle Society (WMS) Virtual Congress, held online Sept. 28 to Oct. 2.

Zolgensma, formerly known as AVXS-101, is a one-time gene therapy originally developed by AveXis (recently renamed Novartis Gene Therapies), now part of Novartis, to treat all types of SMA. It was approved by the U.S. Food and Drug Administration in May 2019 as a single intravenous (into-the-vein) infusion treatment for newborns and toddlers up to age 2. More recently, it was approved in Japan for the same indication.

In Europe, the therapy has been approved conditionally to treat infants and young children with SMA and a clinical diagnosis of type 1, or for those having up to three copies of the SMN2 “backup” gene.

STR1VE-EU was one of the Phase 3 trials that assessed the safety and efficacy of Zolgensma. This trial involved 33 infants with SMA type 1 who were younger than 6 months at the time of treatment. All of the infants involved in the study had at least one copy of the SMN2 gene, and carried mutations in both copies of the SMN1 gene.

At the start of the study, nearly all (93.9%) infants were able to swallow thin liquids, just under a third required feeding (30.3%), and about one-quarter needed ventilatory support (27.3%).

Unlike previous trials of Zolgensma, STR1VE-EU allowed patients with more severe forms of the disease — including those requiring respiratory and feeding support, or with lower CHOP-INTEND scores — to enter the study. Of note, CHOP-INTEND is a rating scale used to assess motor function in patients with SMA type 1; lower scores indicate greater motor impairments.

This interim analysis covered data gathered until December 31, 2019. At this point, infants had been followed for an average period of 10.6 months, with ages ranging from 6.9 to 18.6 months.

Nearly all (97%) patients survived event-free, including 30 infants (93.8%) who could have reached 10.5 months of age event-free, and 18 infants (56.3%) who could have reached 13.6 months of age event-free.

Remaining event-free means that these infants did not require a tracheostomy or respiratory support lasting more than 16 hours every day for at least 14 consecutive days. Of note, a tracheostomy is a surgical procedure in which a surgeon creates an opening in the windpipe for mechanical ventilation.

These percentages are much higher compared with those reported by natural history studies, which estimate that 50% of infants with SMA type 1 live event-free until reaching 10.5 months of age, and that only 25% live event-free until reaching 13.6 months of age.

A total of 21 (65.6%) infants participating in the study also achieved motor milestones that were never observed in untreated children with the disease, including being able to sit by themselves for at least 10 seconds, control their head movements, and roll from back to sides. One also was able stand, crawl, and walk with help.

CHOP INTEND scores also increased gradually over the course of the study. An average increase of 5.9 points was observed in the first month following treatment. Six months after receiving Zolgensma, the infants’ CHOP INTEND scores had increased by an average of 13.3 points.

Compared with untreated children with SMA type 1, who rarely attain a CHOP INTEND score greater than 40 — which corresponding to near-normal motor function — 65.6% (21 total) of the infants participating in STR1VE-EU attained and maintained these scores, with 37.5% (12 children) even reaching scores greater than 50.

Most children (91.7%) who did not require respiratory support at the start of the study remained either ventilation-free or only received ventilation support for acute reasons during the trial. Approximately two-thirds of the infants (66.7%) also maintained the ability to feed orally without additional support, a strong indicator of disease stabilization.

One child discontinued the study due to respiratory distress and brain injury resulting from oxygen deprivation, which proved fatal. However, none of these events nor the patient death were found to be related to the use of Zolgensma.

Six children experienced serious adverse events that were found to be related to the therapy. Most infants (87.9%) also experienced elevations in the levels of liver enzymes, an indicator of liver damage and inflammation. However, all cases were easily resolved by treating children with the steroid prednisolone.

Zolgensma’s safety profile in STR1VE-EU was consistent with previous observations, with no new safety concerns identified.

“These strong interim results from the STR1VE-EU clinical trial continue to demonstrate consistent and significant therapeutic benefit in patients with SMA Type 1, the most common form of the disease, adding to the robust body of clinical evidence for Zolgensma,” said Shephard Mpofu, MD, senior vice president and chief medical officer of Novartis Gene Therapies.

“With more than 600 patients now treated, including some more than five years post-treatment and more than five years old, these data further reinforce the transformative benefit a one-time dose of Zolgensma has on SMA patients,” Mpofu added.