Zolgensma, previously knowns as AVXS-101, is the proprietary gene therapy candidate from AveXis designed to treat spinal muscular atrophy (SMA).

How Zolgensma works

SMA is caused by a mutation in the SMN1 gene, which encodes for a protein that motor neurons — 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) evaluated the safety, tolerability, and efficacy of Zolgensma in 15 infants up to 6 months old 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 patients were at least 20 months old and did not require permanent mechanical ventilation. Only 8 percent of patients in a historical group survived this age without permanent mechanical ventilation. Seven patients in the high-dose group were completely independent of ventilatory assistance. Eleven patients had achieved and retained the ability to swallow independently, and four were able to feed orally.

Eleven of the 12 infants who received the high dose of Zolgensma 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, and 11 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 and by 15.4 at three months after treatment. Eleven of 12 patients attained and sustained a score of more than 40 points. At the study cutoff, patients 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 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. Eleven patients in this group reached a CHOP-INTEND score equal to or greater than 40. Ten patients achieved scores 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 to further assess the effectiveness and safety of the treatment. 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 currently recruiting.

A Phase 1 trial called STRONG (NCT03381729) will assess the safety and tolerability of Zolgensma in 27 children with SMA type 2, up to age 5. The trial will test two different doses of Zolgensma. Each patient will receive a single dose of treatment injected into the spinal cord. Patients will be divided into two groups, younger or older than 2 at the time of dosing. According to AveXis, the trial is now fully enrolled. 

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

Another “all comers” trial, called REACH, will include patients with SMA types 1-3, ages 6 months to 18 years, who are not eligible for other studies. The trial is set to begin in 2019.

Other information

The U.S. Food and Drug Administration (FDA) designated Zolgensma a Breakthrough Therapy in July 2016.

In October 2018, AveXis filed a request for FDA approval of Zolgensma for intravenous delivery in infants with SMA type 1, ages up to 9 months. The FDA accepted the application in December 2018 and granted priority review for Zolgensma. A final FDA decision is expected in May 2019.

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

Zolgensma injection 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 treatment.


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