How Zolgensma Works and Trials Underway in Range of SMA Patients

Zolgensma (onasemnogene abeparvovec-xioi), the newly approved gene therapy to treat SMA in infants and children under 2 years old, works by delivering directly to motor neurons a healthy copy of the SMN1 gene that is damaged by mutations in these patients and unable to make an essential protein.

Carried on a virus engineered to be harmless — an adeno-associated virus subtype known as AAV9 — that is infused into the bloodstream or injected into the spinal canal, the therapy enters the central nervous system to deliver a working gene to those specialized motor nerve cells that control muscle contraction.

An adeno-associated virus, or AAV, was chosen due to its ability to cross blood vessels and get into muscles. The specific type used, AAV9, came out of preclinical work that showed it targeted brain and spinal cord cells “at unprecedented levels, in ways we had never seen before,” Brian Kaspar, chief scientific officer at AveXis, said in a February interview with SMA News Today.

AveXis developed this therapy and, largely due to its success, was acquired in 2018 by Novartis, which will market it.

Motor neurons are primarily found in the spinal cord and the brainstem, which is connected to the spinal cord, and depend on the SMN protein produced by SMN1 for their health and survival. They send signals from across the central nervous system that tell skeletal muscles to contract, or tense, making voluntary movement possible.

Zolgensma “has the ability to produce either normal or even greater-than-normal levels of the SMN1 gene that is so required for all of these patients” Kaspar said, and to do so “immediately and continuously.”

Its continuously working nature is a reason why the therapy is considered by its developers to be a one-time treatment, especially in patients treated at diagnosis or in early disease stages. Their thinking is supported by data from a Phase 1 study (NCT02122952) that opened in 2014 and has seen not one of its 15 type 1 patients, treated as infants, need a second intravenous injection since, some for up to five years.

The combination of effectiveness and durability is also why Novartis, with AveXis, is testing Zolgensma in other types of SMA, with a variety of clinical trials underway or planned.

Studies now in progress are:

• the STR1VE Phase 3 study (NCT03306277) of intravenous delivery in type 1 infants up to 6 months old; it’s fully enrolled and its data also influenced the FDA’s approval decision.
• STR1VE-EU (NCT03461289), the Phase 3 European equivalent of STR1VE that is now enrolling infants up to 6 months old at sites across the continent.
• the soon-to-open Phase 3 STRIVE-AP trial  (NCT03837184), an equivalent study in three Asian Pacific countries; enrollment information is available here.
• the SPR1NT Phase 3 study (NCT03505099) in 44 pre-symptomatic infants, up to 6 weeks old, with multiple SMN2 copies, that is recruiting across the U.S. and elsewhere.
• the Phase 1 STRONG trial (NCT03381729) in SMA type 2 children, 6 months to 5 years old and able to sit independently for 10 or more seconds; it’s fully enrolled. This study will administer Zolgensma using intrathecal (spinal cord) injection.

A separate trial for SMA patients with types 1 to 3 and up to 18 years old, called REACH, is reported to be planned for patients not eligible for these studies. When it gets underway, it too will use intrathecal injection to administer Zolgensma.

All ongoing trials are open-label, meaning there is no placebo group and all enrolled are treated.

STRONG uses a single intrathecal (IT) injection because its developers consider this more targeted route preferable for older patients, while systemic IV infusions are thought better in treating infants. IT administration also enables a lower viral dose, lessening the risk of an immune response against the AAV9 vector.

As of April 24, 151 patients have been treated with Zolgensma across SMA types 1 and 2, Novartis and AveXis reported in a recent investor update. Each is now part of the “largest single treatment population for any gene therapy that’s been investigated so far in the world,” David Lennon, AveXis president, said in an earlier update.