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Zolgensma continues to safely and effectively prevent motor function decline for at least five years, allowing the achievement and maintenance of developmental milestones in children with spinal muscular atrophy (SMA), according to data from long-term clinical trials.

The results support the gene therapy’s sustained benefit more than five years following dosing, with no new safety concerns identified.

These findings, “Long-term follow-up (LTFU) of Onasemnogene Abeparvovec Gene Therapy in Spinal Muscular Therapy (SMA),” were presented by Jerry R. Mendell, MD, a principal investigator across Zolgensma’s clinical program, in an oral presentation at the 2021 MDA Virtual Clinical and Scientific Conference, held online March 15-18.

Mendell is a practicing neurologist and researcher at Nationwide Children’s Hospital in Columbus, Ohio.

Marketed by Novartis, Zolgensma is a one-time gene therapy that uses a modified and harmless virus to deliver a functional copy of SMN1, the mutated gene in SMA, to cells. It is approved in several countries for the treatment of infants and young children with all or almost all SMA types. In the U.S., Zolgensma was approved in 2019 to treat all types of SMA in newborns and toddlers up to age 2.

The regulatory approvals were based on data from the Phase 1 START (NCT02122952) and the Phase 3 STR1VE-US (NCT03306277) trials, which tested a single intravenous (into-the-vein) infusion of Zolgensma in SMA type 1 infants up to 6 months old.

The results showed that the therapy led to rapid improvements in infants’ motor function, allowing them to achieve several developmental milestones over time, including being able to sit independently, crawl, and walk unaided — which are rarely or never attained in untreated children with type 1 disease.

Patients, with ages ranging from shortly after birth up to five years, who participated in these and other Zolgensma trials, have the option to enter one of two long-term studies — LT-001 (NCT03421977) and LT-002 (NCT04042025). Both are following the children, and assessing the therapy’s safety and effectiveness, for up to 15 years.

According to Mendel, the researchers are not questioning whether Zolgensma is effective. Rather, these trials ask: “Is it a persistent tool for treating patients with SMA? How long will it last?”

Launched in May 2014, LT-001 was designed exclusively for START participants. It involves annual in-person visits for five years, and then annual telephone visits for the remaining 10 years.

In LT-002, started in February 2020, participants of other Zolgensma studies will have in-person visits bi-annually over the first two years and then annually from the third to the fifth year of follow-up. The annual visits thereafter will be conducted by telephone.

After completing START, 13 children chose to enter LT-001, during which seven of them (54%) were simultaneously receiving Spinraza — the first disease-modifying therapy approved for SMA.

As of June 11, 2020, the mean age of the 10 children who received the therapeutic dose was 5.2 years, with the oldest patient being age 6.1.  All were alive and free of permanent ventilation about five years after dosing. Six (60%) of them also did not require regular, daily ventilatory support. The mean time since dosing was five years.

Data from the last annual visits, in December 2019, showed that no previously achieved motor milestones were lost, and that two children (20%) gained the ability to stand with assistance, while not receiving Spinraza at any point.

Mendell also noted that the participants with the least disability at the study’s start were the ones performing the best over the long term.

The results from LT-002 involved 31 children in all — 23 from the so-called IV group, who received an intravenous infusion of Zolgensma, and eight who were given the therapy directly into the cerebrospinal fluid, which bathes the brain and spinal cord. This was called the IT group. The children in the IV group had a mean age of 2.3 years, and a mean time since dosing of two years. Meanwhile, those in the IT group had a mean age of 4.3 years, and a mean time since dosing of 2.4 years.

As of November 2020, two children in the IV group and 4 children in the IT group also were receiving Spinraza or Evrysdi, the most recently approved SMA disease-modifying therapy.

Four children in the IV group (17%) achieved a total of 11 new milestones, such as sitting without support, which was attained by all four patients. Notably, three of them were not on any other SMA therapy.

Data from LT-001 showed that Zolgensma promotes “sustained, durable responses for up to 5.6 years and for the LT-002 there is response that is sustained for up to 2.7 years,” Mendell said.

“This answers a fundamental question for gene therapy, about persistence and acquiring new milestones,” he said.

In LT-001, most of the reported serious adverse events (side effects) were “associated with underlying disease,” Mendell said. In LT-002, one child in the IV group experienced an unusual serious side effect (Salmonella infection) and another in the IT group had two serious adverse events likely related to gene therapy, he noted.

There were no serious adverse events leading to study discontinuation or death, and no reports of Zolgensma-related serious adverse events in either study.

“In both LT-001 and LT-002, there is no evidence of new emerging safety signals,” Mendell said, adding that “the serious adverse events in these trials have been minimal and the gene therapy has been very well-tolerated.”

In addition, “the younger the patients are, the better they do … [and] the fewer side effects they have,” the neurologist noted.

Long-term data “suggest that [Zolgensma] shows a favorable benefit-risk profile, and continues to demonstrate durable efficacy,” the researchers wrote.

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