Zolgensma, previously known as AVXS-101, is the proprietary gene therapy candidate from AveXis and Novartis designed to treat spinal muscular atrophy (SMA). Zolgensma is now approved by the U.S. Food and Drug Administration (FDA) to treat all SMA types in newborns through toddlers up to age 2. Clinical trials for the therapy’s use in other patients are ongoing.

How Zolgensma works

SMA is caused by a mutation in the SMN1 gene, which encodes for a protein that motor neurons — the nerve cells that control muscle contraction — need to survive. The mutation prevents this gene from producing any functional SMN protein.

Zolgensma is a gene therapy designed to deliver a functional copy of the SMN1 gene to motor neurons in SMA patients.

Zolgensma comprises the shell of a genetically engineered virus, the adeno-associated virus (AAV) 9, called a capsid, which delivers a normal copy of the SMN1 gene to the target motor neurons. Once the SMN1 gene (called a transgene because it comes from an external source) reaches patients’ cells, it supplements those cells’ own production of SMN protein.

The SMN1 transgene in Zolgensma consists of double-stranded DNA, meaning that it takes the same form as natural genes and can be activated more quickly, producing faster, more efficient therapy. Zolgensma also includes the genetic instructions to activate the transgene so that SMN protein production is continuous and sustainable.

Zolgensma in clinical trials

A Phase 1 open-label clinical trial (NCT02122952) called START evaluated the safety, tolerability, and efficacy of Zolgensma in 15 infants, ages up to 6 months, with SMA type 1. It assessed the effects of an injection of Zolgensma, given at a low or high dose through a vein in the arm or leg.

At the study cutoff, all the children were at least 20 months old and none required permanent mechanical ventilation. In comparison, only 8 percent of patients in a historical group survived to the same age without permanent mechanical ventilation. Seven children in the high-dose group were completely independent of ventilatory assistance. A total of 11 patients had achieved and retained the ability to swallow independently, and four were able to feed orally.

Among the 12 infants who received the high dose of Zolgensma, 11 were able to achieve head control. Nine were able to roll at least 180 degrees from the back to both the left and the right. The results showed 11 of the children were able to sit unaided for at least five seconds, 10 for at least 10 seconds, and nine for at least 30 seconds, something normally never seen in babies with SMA type 1.

Overall motor skills were assessed using the CHOP-INTEND score, which is based on a questionnaire that contains 16 items scored 0 to 4. The total score ranges from 0 to 64; the higher it is, the better the motor skills.

In the group that had received the high dose of Zolgensma, the CHOP-INTEND score increased by 9.8 points at one month following treatment, and by 15.4 points at three months. Of the 12 patients, 11 attained and sustained a score of more than 40 points. At the study cutoff, the children had a mean increase of 24.6 points. The three patients who had received the low dose had a mean increase of 7.7 points.

At a follow-up analysis at 24 months post-treatment, all 15 patients were still alive and did not require permanent ventilation. Two more children in the high-dose group (11 of 12) were able to sit unaided for 30 seconds or more. A total of 11 patients in this group reached a CHOP-INTEND score equal to or greater than 40, while 10 achieved scores of 50 or higher.

The 15 patients are now enrolled in a long-term follow-up study (NCT03421977) in which they are monitored annually as per standard of care for up to 15 years.

An ongoing Phase 3 trial, called STR1VE (NCT03306277), includes 20 infants with SMA type 1, and aims at further assessing the treatment’s effectiveness and safety. Preliminary results showed that in six babies who had received Zolgensma, the mean CHOP-INTEND score increased by an average of 7.8 points one month after treatment. Two months later, three of these patients had improved 17.3 points. 

A similar trial in Europe, called STR1VE-EU (NCT03461289) is ongoing; an Asia-Pacific version (NCT03837184) is not yet recruiting.

Another clinical trial is testing different doses of Zolgensma in children with SMA type 2, in which symptoms usually appear between 7 and 18 months. This Phase 1 trial, called STRONG (NCT03381729), is assessing the safety and tolerability of Zolgensma in 27 children, up to age 5. It is testing two different doses of Zolgensma, with each patient receiving a single dose of treatment injected into the spinal canal. Patients will be divided into two groups (younger or older than 2) at the time of dosing. 

A Phase 3 clinical trial (NCT03505099) called SPR1NT is currently recruiting infants with SMA type 1, type 2, or type 3,  6 weeks or younger, who do not yet show any symptoms. 

A planned study, called REACH, is an “all comers” trial that will include patients with SMA types 1-3, ages 6 months to 18 years, who are not eligible for other studies. 

At the 2019 American Academy of Neurology (AAN) conference, AveXis presented interim data from the STRONG, SPR1NT, and STR1VE clinical trials. The STRONG study showed motor function improvements in patients with SMA type 2 after a single intrathecal (into the spinal cord) injection of Zolgensma. In the SPR1NT trial, SMA patients with 2 or 3 copies of the SMN2 gene, who were pre-symptomatic, showed increased motor function and milestone achievements. The STR1VE trial continued to show improved results in CHOP-INTEND scores, and 13 of the 15 infants had reached 13.6 months of age without the need for permanent ventilation.

Other information

The FDA designated Zolgensma a breakthrough therapy in July 2016.

AveXis filed a request for FDA approval for intravenous infusion delivery in infants with SMA type 1, ages up to 9 months, in October 2018. The FDA accepted the application in December 2018, and granted it priority review.

On May 24, 2019, AveXis and Novartis received FDA approval for Zolgensma to treat SMA patients below age 2 through a single intravenous infusion. This approval makes Zolgensma the second disease-modifying treatment, and the first gene therapy treatment, for SMA to be approved by the FDA. 

The European Medicines Agency (EMA) granted Zolgensma access to its priority medicines (PRIME) program as a potential treatment for SMA type 1 in January 2017.

Zolgensma treatment can increase serum aminotransferase (a liver enzyme) levels to a degree that is considered a serious adverse event. This can, however, be controlled with prednisolone.

AveXis was acquired by Novartis in 2018 based on Zolgensma’s success in clinical trials.


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