Major Developmental Milestones Met in Infants, Zolgensma Data Show

New data about Zolgensma, the one-time gene therapy for children with spinal muscular atrophy (SMA), demonstrate age-appropriate development when used pre-symptomatically, and rapid, meaningful efficacy in symptomatic children, even those with severe disease before treatment, according to two Phase 3 clinical trials.

The therapy, developed by Novartis, uses a harmless virus to deliver a functional copy of SMN1, the gene mutated gene in SMA. A lack of this gene results in the rapid loss of motor neurons, affecting muscle function, breathing, and swallowing.

Some people carry extra copies of a “backup” SMN2 gene. Those with two copies are likely to have a more severe form, SMA type 1, whereas patients with three copies are expected to develop the less severe SMA type 2.

In more than 90% of untreated cases, those with SMA type 1 need permanent ventilation by the age of 2 years and many do not survive. For those with SMA type 2, if left untreated, more than 30% will not survive beyond age 25.

Zolgensma was approved in 2019 in the U.S. for newborns and toddlers up to age 2. In Europe, it was approved conditionally for those weighing up to 21 kilograms (about 46 pounds), with a diagnosis of SMA type 1, or those still without symptoms who carry up to three copies of the SMN2 gene.

According to Novartis, more than 1,200 SMA patients have been treated with Zolgensma so far, either in clinical trials, managed access programs, or in a commercial setting.

The two-year SPR1NT trial (NCT03505099) is evaluating the therapy’s efficacy and safety in pre-symptomatic infants with SMA up to 6 weeks old. Of these, 14 carry two SMN2 copies, and 15 have three copies.

Data from the SPR1NT two-copy group is now complete. The results showed that all patients (100%) met the primary goal of sitting independently for at least 30 seconds, and 11 (79%) who were within the World Health Organization (WHO) window of typical development.

All participants achieved the secondary outcome of survival without any ventilatory support compared to 26% of those in the Pediatric Neuromuscular Clinical Research (PNCR) natural history group.

Most patients could stand independently (79%) and walk alone (64%), and most met these milestones within the WHO window of normal development. No patient required nutritional support for the study duration, and 13 of 14 maintained an age-appropriate weight for up to 18 months of age.

All two-copy participants achieved or maintained a Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score of 58.4 or greater. That tool assesses motor skills in infants using a scale from zero to 64 with higher scores reflecting better motor function. In contrast, according to the natural history, untreated SMA type 1 patients rarely achieve a CHOP INTEND score of 40.6 or more.

An assessment of fine motor skills showed all treated patients had similar scores to those without SMA at the same age, and the majority (64%) had overall motor performance scores similar to healthy same-age peers.

All participants experienced at least one adverse event (AE, a side effect) after the single dose, of which 10 (71%) were considered related to treatment. In contrast, there were no serious AE (SAEs) associated with Zolgensma, and five who reported SAEs were not related to treatment and were resolved.

“When treated with Zolgensma prior to the onset of symptoms, not only did all patients survive but were thriving — breathing and eating on their own and sitting independently, with many standing and walking,” Shephard Mpofu, MD, chief medical officer at Novartis, said in a press release. “When you consider these newborns would go on to develop severe symptoms of SMA Type 1, a devastating, progressive disease that robs children of the ability to talk, eat, sit up and even breathe, findings from the SPR1NT trial are nothing short of extraordinary.”

The SPR1NT trial investigating the three-copy group is ongoing.

STR1VE-EU trial

The now-completed STR1VE-EU trial (NCT03461289) assessed the safety and effectiveness of Zolgensma in 33 infants with SMA type 1 who were younger than 6 months and had two copies of the SMN2 gene.

STR1VE-EU was distinct from other Zolgensma trials because it included 33 symptomatic patients with variable degrees of disease severity. Before treatment (baseline), the mean CHOP INTEND score was 28, with nine participants (27%) requiring ventilatory support, nine (27%) needing feeding support, and five (15%) requiring both.

Of the 33 patients initially enrolled, 32 completed the study, and 27 (82%) met developmental milestones not seen in SMA type 1 natural history. Sitting independently for 10 seconds or more — the trial’s primary goal — was achieved by 14 (44%). Head control was seen in 30 (77%) participants, rolling from back to sides in 19 (58%), and 16 sat without support for 30 seconds or more, including all those who met the primary goal.

Two patients also stood with assistance, another crawled, pulled to stand, and walked without assistance, all by the age of 18 months.

The trial’s secondary efficacy outcome of survival without permanent ventilatory support at 14 months was met by 32 patients (97%) versus a quarter of those in the PNCR natural history group. Most (73%) achieved a CHOP INTEND score of 40 points or more, 14 (42%) a score of 50 or more, and three (9%) demonstrated scores of 58 points or more.

Thirteen did not require any ventilatory support at 18 months compared with none in the PNCR group. Of the nine needing ventilatory help before treatment, two achieved independence. The majority (67%) of those who did not require ventilation at baseline remained free from this support by the study’s completion.

An “ability to thrive” in these symptomatic patients, which included swallowing, feeding, and age-appropriate weight maintenance, was met by 23 patients, of which seven (30%) achieved this criterion at 18 months of age (versus none in the PNCR study) and 20 (87%) were fed exclusively by mouth and remained support-free. Of the nine participants who needed feeding, four did not need this support by 18 months. Age-appropriate weight maintenance was reported in 65%.

Regarding safety, all 32 reported at least one AE, of whom six experienced an SAE. All reported AEs were consistent with the known safety profile, and no new safety issues were identified. The child that discontinued the study had breathing distress and brain injury due to oxygen deprivation, which proved fatal. Based on autopsy findings, that death was unrelated to Zolgensma.

“STR1VE-EU included some patients with more severe SMA at baseline, yet the study demonstrated consistent and significant therapeutic benefit for symptomatic children with SMA Type 1,” said Eugenio Mercuri, MD, PhD, Department of Pediatric Neurology at the Catholic University in Italy. “This is a remarkable outcome that adds to the robust body of clinical evidence for Zolgensma showing that even among patients with more severe disease, Zolgensma was highly effective and demonstrated a consistent safety profile,” he said.

The STR1VE-EU data is being presented at the 2021 European Academy for Neurology (EAN) Virtual Congress.

“With more than 1,200 children now treated, these data presented at EAN further reinforce the life-changing benefit of a one-time treatment of Zolgensma,” added Mpofu.