#MDA2021 – Zolgensma Safe and Effective in Toddlers, Real-world Data Suggest

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Editor’s note: The SMA News Today team is providing in-depth coverage of the 2021 MDA Virtual Clinical and Scientific Conference, March 15–18. Go here to read the latest stories from the conference.


Zolgensma — given alone, after, or in combination with another spinal muscular atrophy (SMA) disease-modifying therapy — leads to clinically meaningful motor improvements in children older than six months, according to early real-world data from the RESTORE registry.

Reported side effects were also consistent with Zolgensma’s previously described safety profile.

These findings support the gene therapy’s favorable benefit-risk profile in a patient population older than that included in Zolgensma’s clinical trials.

These preliminary results, along with other early RESTORE findings supporting the benefits of newborn screening, were presented in two posters at the 2021 MDA Virtual Clinical and Scientific Conference, held March 15–18.

Zolgensma, Novartis’s one-time gene therapy, is given directly into the bloodstream and uses a modified and harmless virus to deliver a functional copy of the SMA mutated gene to cells.

It is available for use in children up to age 2 in the U.S. and other countries, and in those with almost all SMA types who weigh up to 21 kilograms (about 46 pounds) in Europe, which could cover children up to age 5.

Despite this approved age range, clinical trial evidence of Zolgensma’s safety and effectiveness mostly involves infants up to 6 months old, highlighting the need for real-world data on Zolgensma’s use in older SMA patients.

In the poster “Routine Practices in Use of Onasemnogene Abeparvovec in Older Patients with Spinal Muscular Atrophy: Early Findings from RESTORE,” researchers described the characteristics, safety data, and clinical outcomes of children given Zolgensma at ages 6 months and older, and participating in the RESTORE registry (NCT04174157).

Launched by AveXis (a Novartis subsidiary, now known as Novartis Gene Therapies), the ongoing RESTORE is a multinational, observational study meant to follow more than 500 SMA patients for up to 15 years.

While any patient not enrolled in a clinical trial of an investigational SMA therapies can join the registry at any of its 47 current clinical sites, the company is focused on enrolling those treated with Zolgensma, whether given in a clinical trial or commercially.

Registries like this one are a way of gaining real-world data that will help researchers better understand the effects of routine care and practice in SMA patients, and ultimately inform and improve treatment decisions.

A total of 70 patients in RESTORE, as of data cutoff on Dec. 7, 2020, were given Zolgensma when they were 6 months of age or older. Nearly half (34 or 48.5%) were up to 1 year of age, while six (8.5%) were older than age 2.

Most (64%) had SMA type 1, a severe form of the disease and the group most commonly included in the therapy’s trials.

Zolgensma was the only treatment given to 22 (31%) of these patients. For 28 (40%) others, Zolgensma’s use was initiated after a switch from Biogen’s Spinraza or Roche’s Evrysdi — two other SMA-targeting therapies.

Sixteen (23%) children were given Zolgensma while continuing treatment with Spinraza or Evrysdi, and four (6%) previously untreated patients started on Spinraza or Evrysdi after receiving the gene therapy.

Data covering 23 patients with two or more CHOP INTEND scale evaluations, tests of motor skill ability given to registry children up to age 2, showed that all but one (95.7%) improved or maintained their score over the study period.

Notably, 15 (65.2%) achieved a score increase of at least four points, which is considered clinically meaningful. Included in this group was six of 10 children treated as toddlers, between ages 1 and 2.

Reported adverse events were consistent with the previously described safety profile for the therapy, with most occurring in the first months after treatment. No new safety concerns were identified over long-term follow-up, the researchers reported.

Adverse events were successfully managed with timely detection, including common liver abnormalities and rare occurrences of a serious blood disorder.

“Based on the available data to date, the benefit-risk profile of [Zolgensma] remains favorable,” including in this older patient population, the researchers wrote.

In the second poster “Newborn Screening for Spinal Muscular Atrophy in the United States: Early Findings from the RESTORE Registry,” the researchers analyzed RESTORE data to compare the outcomes of newborn/prenatal genetic screening against clinical diagnosis based on symptoms in SMA type 1 infants in the U.S.

While newborn screening is thought to allow early diagnosis and treatment — which is critical for better clinical outcomes — real-world data supporting this are lacking.

“Moreover, there are no direct comparative data for patients with SMA type 1 treated pre-symptomatically [before the development of symptoms] versus after symptom onset,” the researchers wrote.

As of Dec. 7, 28 babies had been diagnosed through newborn or prenatal screening, and 56 were diagnosed based on clinical symptoms.

The team compared the groups’ mean age at diagnosis, age at first treatment, time from diagnosis to treatment, the proportion receiving single therapy versus more than one treatment, and changes in motor function.

They found that, compared with clinically diagnosed patients, those identified via newborn or prenatal screening were diagnosed at a significantly earlier age (0.8 versus 3.5 months) and treated significantly earlier in life (1.7 versus 4.4 months).

Mean time from diagnosis to treatment was 0.9 months for both groups.

A significantly greater proportion of clinically diagnosed patients received more than one SMA therapy, compared with those diagnosed through early genetic screening (71.4% vs. 28.6%). For both groups, Zolgensma was the most common single therapy.

Data from 22 patients with two or more CHOP INTEND assessments showed that clinically meaningful motor improvements were more often achieved by patients identified by newborn or prenatal screening (88.9%) than by those diagnosed based on symptoms (68.2%).

The mean change in CHOP INTEND scores was also slightly greater in the genetic screening group. Notably, neither of these group differences in CHOP INTEND scores reached statistical significance.

These results provide “real-world evidence that NBS [newborn screening] for SMA is associated with significantly earlier diagnosis and intervention, although some NBS patients may not have received presymptomatic treatment,” the researchers wrote.

“Our study may stimulate discussion and suggest new lines of inquiry regarding barriers to NBS implementation and reasons for delay between diagnosis and treatment,” they added.

Researchers noted, however, that these analyses of early RESTORE data were limited by the small number of patients, the short and variable duration of follow-up, and variable completeness of data and potential inconsistency in CHOP INTEND evaluations across study sites.