Spinal muscular atrophy is a rare, neurological, genetic disease characterized by a mutation in the survival motor neuron 1 (SMN1) gene. Interestingly, the SMN2 gene is preserved in these patients. SMN1 and SMN2 code for the SMN protein. The SMN protein is critical for many functions within the motor neurons. The SMN protein helps in regulating cellular trafficking, cytoskeleton maintenance, and intracellular signaling. Mutations in the SMN1 gene lead to a lack of function SMN protein, which causes degradation of the alpha motor neurons in the CNS.1 These motor neurons help our body transmit signals from the central nervous system to all of the muscles we use for everyday functions. These muscles control our breathing, walking, talking, and even the simplest tasks like moving our toes. When patients with SMA have lack of the functional SMA protein, you see muscle weakness, respiratory insufficiency, and premature death.2 SMA occurs within every 1 in 11,000 births.4 Some clinical signs of SMA include soft or absent cry, lack of reflexes, belly breathing, hypotonia, and inability to eat. The most severe type of SMA, or infantile-onset spinal muscular atrophy, often presents within the first six months of life. About 50% of patients will die by the age of 10.5 months. Those who survive require more than 16 hours per day of ventilatory support. Without treatment, only 8% of patients survive free of respiratory support.1
Onasemnogene abeparvovec is an adeno-associated 9 (AAV9) vector based gene therapy. It is administered as a single intravenous infusion for the treatment of spinal muscular atrophy. This therapy uses an empty viral capsid to deliver a functional copy of SMN1 to the cell. The safety and efficacy of onasemnogene abeparvovec has been evaluated in the phase 1 START and the phase 3 STR1VE-US study. Both of these studies excluded patients who required nutritional and respiratory support. The STR1VE-EU study aimed to expand on the safety and efficacy parameters of onasemnogene abeparvovec in patients who require more support.4
In the STR1VE-EU study, all 32 patients received a dose of onasemnogene abeparvovec. The primary endpoint was the achievement of functional independent sitting for more than 10 seconds during any visit up to 18 months. 14 of 32 participants (44%) achieved the primary endpoint as compared to 0 patients in the PNCR matched natural history cohort. The secondary endpoint was ventilation free survival at 14 months. 31 of 32 patients achieved the secondary endpoint (97%) as compared to 6 of 23 (26%) of the natural history cohort patients. One patient in the study died from a hypoxic brain injury unrelated to the drug. The safety endpoints were similar to those that had been identified in the STR1VE-US and START studies. No new safety signals were identified. Overall, onasemnogene abeparvovec was proven to be safe and beneficial in patients with a more severe phenotype. This proves continued favor of the risk-benefit analysis in favor of onasemnogene abeparvovec. In patients with rare and devastating diseases, the chance of having a one-time treatment for patients is remarkable. This also leads to a lot of hope for the future of gene therapy.
Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017 Dec;82(6):883-891.
Singh RN, Howell MD, Ottesen EW, Singh NN. Diverse role of survival motor neuron protein. Biochim Biophys Acta Gene Regul Mech. 2017;1860(3):299-315.
Farrar MA, Park SB, Vucic S, Carey KA, Turner BJ, Gillingwater TH, Swoboda KJ, Kiernan MC. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017 Mar;81(3):355-368.
Novartis Gene Therapies. Zolgensma prescribing information. 2021. https://www.novartis.us/sites/www.novartis.us/files/zolgensma.pdf (accessed November 13, 2021).
Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-293.
Spinal Muscular Atrophy (SMA) is a progressive, rare genetic disease that is caused by missing or having a dysfunctional survival motor neuron 1 (SMN1) gene. When this gene is absent or not working properly, the body cannot make enough survival motor neuron protein which is required for motor neuron cell survival. At birth, everyone is born with a certain amount of motor neuron cells, which play a role in communicating with many body parts to make them work properly. Without enough survival motor neuron protein, some motor neuron cells throughout the body may lose their function and die. This results in patients experiencing muscle weakness and may have a difficult time breathing, swallowing, or speaking. About 1 in 50 people in the United States is a genetic carrier of spinal muscular atrophy and most don’t know it. This also affects about 1 in every 11,000 babies born in the United States.
There are currently three FDA approved medications used to treat spinal muscular atrophy. These medications are nusinersen (Spinraza), onasemnogene abeparvovec-xioi (Zolgensma), and risdiplam (Evrysdi). These treatments have shown clear efficacy in young children with SMA type 1 which resulted in a decreased need for respiratory support as well as improvement in motor skills. In clinical trials, patients who received gene therapy sooner had better results. These medications are extremely expensive and is difficult to obtain.
One of these drugs that I am familiar with is Zolgensma, which is marketed by Norvartis Gene Therapies. I currently work at Cohen Children’s Medical Center as a pharmacy intern, and we have treated three different patients with this drug since it has been approved. Each time, we compounded the medication and delivered it to the patient bedside for immediate intravenous infusion. This infusion is one of the most expensive drugs in the world costing approximately 2.1 million per dose. Zolgensma is a one-time intravenous infusion gene therapy used to treat children less than 2 years old with spinal muscular atrophy. This therapy has not been evaluated in patients with advanced spinal muscular atrophy. This is the only one-time treatment of spinal muscular atrophy.
Zolgensma is dosed based on weight as are many drugs for children. The recommended dose is 1.1 x 1014 vector genomes/kg as a single dose infused over 60 minutes and flushing with normal saline before and after administration. One limitation of using Zolgensma is that there has not been any safety or efficacy testing of repeated administration of this drug. Oral corticosteroids, such as prednisolone 1mg/kg/dose once daily or equivalent, should be prescribed one day prior to the infusion and be continued for at least 30 days.
Zolgensma is very expensive, but it seems like the best option considering the other treatments are all medications that must be taken for longer periods of time. Evrysdi treatment is about $60,000 dollars per month. Spinraza is also very expensive and is required for a patient to take it for their entire lives. Spinraza costs about $700,000 the first year then about $375,000 every year after. I believe a one-time infusion of Zolgensma could potentially be the cheapest option long term.
1. Stevens D, Claborn MK, Gildon BL, Kessler TL, Walker C. Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy. Ann Pharmacother. 2020 Oct;54(10):1001-1009. doi: 10.1177/1060028020914274. Epub 2020 Mar 23. PMID: 32204605.
2. “Zolgensma® (Onasemnogene Abeparvovec-Xioi).” ZOLGENSMA, https://www.zolgensma.com/.