A single infusion of Zolgensma (onasemnogene abeparvovec-xioi) continues to lead to meaningful and sustained benefits in children with spinal muscular atrophy (SMA) treated in infancy, according to data from several clinical trials.
Zolgensma, formerly known as AVXS-101, is a gene therapy originally developed by AveXis, now part of Novartis, to treat all types of SMA. It was approved by the U.S. Food and Drug Administration (FDA) in 2019 as a one-time intravenous (IV) infusion treatment for newborns and toddlers up to age 2.
Clinical studies assessing the therapy’s safety, tolerability, and effectiveness in SMA patients include STR1VE (NCT03306277), SPR1NT (NCT03505099), START (NCT02122952) and its long-term extension study (NCT03421977).
STR1VE-US trial results
STR1VE, now complete in the U.S., was an open-label, Phase 3 trial evaluating the safety and efficacy of a single intravenous infusion of Zolgensma in 22 symptomatic infants with SMA type 1 under 6 months of age with one or two copies of the SMN2 “backup” gene. (SMN2 allows for the production of a shorter and less stable SMN protein.)
The study’s co-primary endpoints determined the percentage of babies able to sit independently for 30 seconds or longer at 18 months of age, and those with event-free survival — defined as not needing permanent ventilation to breath — at 14 months of age.
The trial also assessed changes in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score, a measure of motor function.
Preliminary findings from STR1VE showed one use of Zolgensma, given as an IV infusion, improved infants’ motor function and prolonged their survival beyond that of type 1 babies followed in a natural history (no treatment) study.
Final data from STR1VE-US, which ended in November 2019, showed that 2o of its 22 type 1 children (91%) achieved event-free survival at 14 months, and more than half (59%, 13 of 22) met the second co-primary endpoint of being able to sit independently for at least 30 seconds at 18 months of age.
Fifteen (68.2%) had no need for non-invasive ventilatory support at any point during the study, and 18 (81.8%) were able to breath without ventilatory support at 18 months of age.
Zolgensma treatment also led a rapid and sustained improvement in overall motor function, as assessed by CHOP-INTEND scores, compared to type 1’s natural history. In the 22 children, these scores increased by an average of 6.9 points at one month post-infusion, 11.7 points at three months, and by 14.6 points in 20 patients at six months.
STR1VE was also the first study to introduce the stringent composite measure of “ability to thrive,” the proportion of infants able to maintain a healthy body weight and not require nutritional support.
Of the 22 babies enrolled, nine (40.9%) showed the “ability to thrive” at 18 months of age, Novartis reported in a press release.
Novartis, in its release, went on detail the ability to thrive further. It stated that 19 children (86.4%) did not need a feeding tube for their nutritional requirements, 14 (63.6%) maintained a good weight, and 12 (54.5%) were able to tolerate thin liquids. These milestones were likely achieved by the study’s end, but ages or time frames were not mentioned.
At least one adverse event was reported in all 22 children, 12 of which were considered to be related to Zolgensma. All were considered manageable and consistent with the therapy’s profile.
These findings were recently presented at a virtual Clinical Trial Session conducted by the Muscular Dystrophy Association (MDA), scheduled following the cancellation of the 2020 MDA Annual Conference due to COVID-19 pandemic.
SPR1NT interim data
Novartis also announced new interim data in the ongoing SPR1NT trial, assessing the safety and efficacy of Zolgensma in 29 pre-symptomatic babies (up to 6 weeks old) with SMA and two (14 patients) or three (15 patients) copies of the SMN2 gene. (A higher number of SMN2 copies is associated with lower disease severity.)
At a data collection stop date of Dec. 31, eight infants with two SMN2 copies were able to sit independently for at least 30 seconds, and seven did so within the window of normal development defined by the World Health Organization (WHO).
Those still to reach these milestones have not yet surpassed the normal age window of attainment, Novartis said.
All 14 babies with two SMN2 copies have achieved or maintained a CHOP INTEND score higher or equal to 50, with 13 patients achieving a score higher or equal to 58. In SMA’s natural (untreated) history, type 1 patients rarely achieve a CHOP INTEND score equal to or greater than 40.
In the 15 infants carrying three SMN2 gene copies, four were able to stand unaided for at least three seconds as of late December, and three were able to walk independently. These milestones were all achieved within the range of normal child development.
Treated children in SPR1NT yet to reach these milestones, regardless of SMN2 copy number, are still with the normal age window for developing these skills, Novartis reported.
Almost all patients were alive and free of ventilatory support, and able to be fed orally without support, it added.
Again, at least one adverse event after dosing was reported in all children, with 17 considered treatment-related.
“SMA is a disease that robs babies of the ability to talk, eat, sit up and even breathe. In complete contrast to the natural course of the disease, patients who received Zolgensma soon after birth before the onset of symptoms are achieving age-appropriate motor milestone development — an extraordinary outcome for SMA patients,” Olga Santiago, chief medical officer for AveXis, said in the release.
“These SPR1NT data demonstrate the truly transformational impact a one-time dose of gene therapy can have, and further underscore the importance of newborn screening and early intervention to alter the course of the disease,” Santiago added.
START long-term extension trial
The long-term study of SMA type 1 children first treated in START, a two-year Phase 1 trial that concluded in 2017, is continuing to evaluate the safety, tolerability, and efficacy of Zolgensma.
New data covered 10 of the 12 original trial children treated with the higher, optimal dose of the gene therapy, who agreed to continue being examined in the extension study that runs through December 2033.
These children, treated with one dose of Zolgensma before age 6 months, are now either 5 years old or nearing that age (mean age, 4.8). No motor skills or abilities gained have been lost over five years since that single treatment (mean of 4.5 years), and none have required permanent ventilation, Novartis reported.
Two children in the extension trial are now able to stand with assistance. They are among four of the 10 who, since the gene therapy infusion, have not chosen to also use Spinraza (nusinersen, by Biogen), the first approved and targeted SMA treatment that works on SMN2 to allow production of a more viable SMN protein in cells. The other six are currently using Spinraza.
“The bar for treatment efficacy in SMA Type 1 patients has been raised beyond event-free survival and motor milestone achievement, and the expectation is now that these patients maintain the ability to thrive, an unprecedented and challenging endpoint,” Lisa Deschamps, chief business officer at AveXis, said in the release.
“Further, with hundreds of patients now treated, including some more than five years post-treatment and more than five years old, these new data further reinforce the profound benefit a one-time dose of Zolgensma has on SMA patients,” Deschamps added.
Cumulative safety data from the 335 patients given Zolgensma in clinical trials and other programs show adverse events in nearly all, but most are not serious and found not related to treatment. Most common of these events include fever, upper respiratory tract infection, constipation, scoliosis, and nasopharyngitis (a childhood cold).
Adverse events deemed related to Zolgensma were manageable, and the therapy’s overall safety profile remains favorable.
Posters detailing the findings of SPR1NT, the long-term extension study of START, and the cumulative safety data are expected to be published online by the MDA soon.
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