Clinical Insights: Zolgensma for 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.

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