The gene therapy Zolgensma (onasemnogene abeparvovec-xioi) has been newly approved to treat patients with spinal muscular atrophy (SMA) through intravenous (IV) delivery, meaning systemically. However, Novartis is also waiting on a more sweeping label, one allowing both intravenous and intrathecal (IT) delivery — that which is given via the spinal canal.
But why is the same therapy given in two different ways?
SMA is caused by a defective SMN1 gene, which decreases the amount of needed SMN protein in motor neurons — specialized cells that control muscle contraction — leading to symptoms that include progressive muscle weakness. Zolgensma is a gene therapy that works by providing SMA patients with a functional copy of SMN1, which increases the levels of this key protein.
The team at AveXis, the company that first developed Zolgensma and was purchased by Novartis in 2018, designed two delivery routes for its therapy. The two options address the different needs that come with particular SMA forms: infants with type 1 — its most severe and common type — receive Zolgensma via IV injection, while older patients with type 2 and type 3 are treated by IT infusion.
Such distinction is based on early observations in animal models of the disease and in people. The scientists found that high levels of SMN protein are required very early in life in peripheral tissues, but this need drops after a few months, David Lennon, president of AveXis, said in a recent phone interview with SMA News Today.
“Our approach in using IV early in infants is to try to replicate the biological situation by giving high levels of SMN expression throughout the body,” Lennon said. In turn, older patients receive Zolgensma via the more targeted IT infusion to deliver SMN “where it’s needed most, which is in the motor neurons of the spine.”
“We believe that [IV delivery] is appropriate for younger children and [IT delivery] is appropriate for older children,” Lennon added.
In an earlier interview with SMA News Today, Brian Kaspar, chief scientific officer at AveXis, who has been involved in Zolgensma’s development since its preclinical studies, expressed a similar view: “We believe that targeting motor neurons is the central component of [type 2] disease, and there is little systemic or peripheral involvement.”
These two routes have been assessed in Zolgensma’s clinical trials.
IV delivery has been used in the pivotal Phase 1 trial (NCT02122952) in type 1 infants, up to 6 months old, showing disease symptoms when dosed, and in its long-term extension study called START (NCT03421977). It’s also the method used in the SPR1NT Phase 3 trial (NCT03505099) in presymptomatic babies, up to 6 weeks of age, with types 1-3 (which is now enrolling), and in the STR1VE (NCT03306277) Phase 3 study, also in type 1 infants up to 6 months old.
In turn, IT infusion is being explored at two dose levels in the STRONG Phase 1 trial (NCT03381729) in type 2 patients up to 5 years old. This study is still recruiting children for a higher dose C group; contact information is here.
Zolgensma uses a modified viral vector called AAV9. Immune reactions against AAVs typically develop at around age 2, but infants may have antibodies from their mothers. However, the latest results from the SPR1NT study showed that only one of four patients tested had antibody levels high enough to result in trial exclusion.
In turn, the low rates of AAV9 antibodies in the STRONG trial have not led to any study exclusion. In line with these findings, Jerry Mendell, MD, a principal investigator across Zolgensma’s clinical program, told SMA News Today that having less therapy reaching the systemic circulation lessens the risk for immune reaction and contributes to IT delivery being safer.
As a more targeted approach, enabling a lower dose to be used, IT delivery of Zolgensma also could be less costly, Mendell added.
The U.S. Food and Drug Administration approved Zolgensma as a potential single-dose IV treatment for pre-symptomatic newborns through 2-year-olds with any type of SMA in its May 24 decision.