Clinical Insights: Zolgensma for Spinal Muscular Atrophy


Zolgensma is the first gene therapy indicated for the treatment of children with spinal muscular atrophy.

On May 24, 2019, the FDA approved onasemnogene abeparvovec-xioi (Zolgensma), the first gene therapy indicated for children with spinal muscular atrophy (SMA), a rare genetic disease that affects the motor nerve cells in the spinal cord.1 With its approval, Zolgensma became the most expensive drug in the world, priced at more than $2 million per patient.

Here are several key therapeutic areas with Zolgensma that every pharmacist should know:


Zolgensma is indicated for the treatment of pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

Limitation of Use2

The safety and efficacy of repeat administration of Zolgensma have not been evaluated. Additionally, the use of Zolgensma in patients with advanced SMA (eg, complete paralysis of limbs, permanent ventilator dependence) has not been evaluated.

Zolgensma is only approved for SMA type 1. The safety and efficacy for SMA types 2-4 have not been evaluated.

Mechanism of Action2

Zolgensma is a recombinant AAV9-based gene therapy that is designed to deliver a copy of the gene that encodes the human SMN protein. The SMA disease is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression; therefore, Zolgensma functions to ultimately replace the missing SMN protein.

Access and Site of Administration3

Zolgensma will primarily be administered in the hospital outpatient setting. Unlike other gene therapy products currently on the market, Zolgensma will not be restricted to certain hospital sites. Despite this, it is expected that there will be a limited number of hospitals that will be administering soon after product launch, with a number of hospitals working on protocols to provide the drug in the future.

The manufacturer has partnered with 2 specialty pharmacies, Accredo and Orsini Pharmaceutical Services, to dispense Zolgensma. Accredo is reportedly offering a pay-over-time option to allow payers to defer the $2 million dollar cost over a 5-year period.


The recommended dose of Zolgensma is 1.1 × 1014 vector genomes per kilogram of body weight. There are 22 kits commercially available that contain 1 or more 5.5 mL vials and/or 8.3 mL vials.

It is given as a 1-time, 60-minute infusion. Clinical study data suggest that administering Zolgensma as soon as possible following diagnosis may result in improved outcomes versus delaying treatment.


The efficacy of Zolgensma was assessed in 2 clinical trials. All patients experienced onset of clinical symptoms consistent with SMA before 6 months of age and had a confirmed diagnosis. Efficacy was established on the basis of survival, achievement of developmental motor milestones, and scores on CHOP-INTEND, which is an assessment of motor skills in patients with infantile-onset SMA. Survival was defined as time from birth to either death or permanent ventilation.

The first study was an open-label, single-arm clinical trial that enrolled 21 patients with infantile-onset SMA. The mean age at the time of treatment was 3.9 months.

As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (ie, event-free survival) and were continuing in the trial, 1 patient died at age 7.8 months due to disease progression, and another patient withdrew from the study. Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support and only approximately 25% of these patients would be expected to survive beyond 14 months of age.

The open-label, single-arm, ascending-dose clinical trial enrolled 15 patients with infantile-onset SMA, 3 in a low-dose cohort, and 12 in a high-dose cohort. By 24 months post Zolgensma infusion, 1 patient in the low-dose cohort met the endpoint of permanent ventilation and all 12 patients in the high-dose cohort were alive without permanent ventilation.


The most common adverse reactions of Zolgensma reported in clinical trials were elevated

aminotransferases and vomiting. The drug has a boxed warning for acute serious liver injury.

In clinical studies, there were 2 reported patient deaths. The first patient died from respiratory failure; however, an investigation found it was unrelated to the gene therapy. The second death was deemed possibly related to treatment by the investigator.

Cost Considerations

Zolgensma is given as a 1-time infusion listed at $2.125 million.

The only other product available for SMA is nusinersen (Spinraza), which was approved in December 2016 to treat SMA in pediatric and adult patients. It is administered intrathecally via 4 year 1 doses and then every 4 months thereafter. Spinraza costs $750,000 for year 1 and approximately $375,000 per year thereafter.4

In April 2019, the Institute for Clinical and Economic Review (ICER) released a report assessing the comparative clinical efficacy and value of Spinraza and Zolgensma. They acknowledged that both products dramatically improve the lives of children with SMA. They voted unanimously that Spinraza is priced in such a way that it represents a low long-term value for money.

For Zolgensma, ICER concluded that to reach thresholds of $100,000 to $150,000 per life year gained, a value-based price benchmark for Zolgensma would range from $1.2 million to $2.1 million.5


Zolgensma appears to be efficacious as a 1-time gene therapy for SMA. Upon its approval, Zolgensma became the fourth gene therapy product to be approved by the FDA and the first for SMA.

Although most pharmacists will never encounter Zolgensma due to the limited number of sites that will be administering the treatment and the overall low incidence of SMA (estimated that only 700 patients would eligible for Zolgensma treatment in the United States), it is important for pharmacists to keep up-to-date on gene therapy because it represents a paradigm shift from chronic, life-long treatment to treatment in as little as a single dose. Additionally, the pipeline is full of gene therapies for a variety of diseases, including hemophilia, Fabry disease, Huntington disease, sickle cell disease, and various types of cancer.


  • About SMA. Cure SMA. Available at: Accessed May 30, 2019.
  • Zolgensma [prescribing Information]. AveXis. Bannockburn, IL. May 2019
  • AveXis Announces Innovative Zolgensma® Gene Therapy Access Programs for US Payers and Families. Novartis. May 24 2019. Available at:
  • Spinraza [prescribing Information]. Biogen. Cambridge, MA. October 2018.
  • Spinraza and Zolgensma for Spinal Muscular Atrophy: Effectiveness and Value. ICER. Updated May 24, 2019. Available at:

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