Zolgensma (onasemnogene abeparvovec-xioi) for SMA
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What is Zolgensma for SMA?
A one-time gene therapy, Zolgensma (onasemnogene abeparvovec-xioi) is widely approved for the treatment of spinal muscular atrophy (SMA). It was the second SMA treatment ever to be approved in the U.S. and the first approved gene therapy for the rare disease.
Zolgensma was originally developed by AveXis, now known as Novartis Gene Therapies after being acquired by Novartis, which is further developing and marketing the treatment.
It’s now available in at least 40 countries worldwide, according to Novartis.
Therapy snapshot
| Brand name: | Zolgensma |
| Chemical name: | Onasemnogene abeparvovec-xioi |
| Usage: | Disease-modifying therapy for SMA; can improve or maintain motor function |
| Administration: | Intravenous (into-the-vein) infusion |
How does Zolgensma work?
SMA is mainly caused by mutations in the gene SMN1, which provides instructions for making the SMN protein. This protein is essential for the proper functioning of motor neurons, the specialized nerve cells that control voluntary movement. Mutations in SMN1 lead to little or no SMN production, which results in motor neurons dying and, ultimately, the development of SMA symptoms.
Zolgensma uses a genetically engineered and harmless adeno-associated virus serotype 9 (AAV9) to deliver a working copy of SMN1 to the body’s cells. The delivered gene consists of double-stranded DNA, meaning that it takes the same form as natural genes and can be activated quickly once inside the cell. With this working gene, motor neurons and other cells can produce functional SMN protein.
While most cellular DNA is stored in a central compartment called the nucleus, the DNA delivered by Zolgensma remains outside the nucleus. Because motor neurons do not divide to make new cells, they are unlikely to lose the delivered gene, so a single dose of Zolgensma is expected to promote sustained increases in SMN levels in these highly susceptible cells.
Who can use Zolgensma?
The U.S. Food and Drug Administration approved Zolgensma in May 2019 to treat newborns and toddlers up to age 2 with all types of SMA that are caused by mutations in the SMN1 gene. The therapy is considered one of the most expensive in the world, with a U.S. list price of $2.1 million for a single dose. Novartis allows for installment payments of $425,000 over five years.
The European Commission granted conditional approval to the therapy in May 2020 for children with SMA type 1 or those still without symptoms but carrying up to three copies of the SMN2 gene. SMN2 is a so-called backup gene to SMN1, and these patients are expected to develop type 1 or 2 SMA.
The European approval covers children weighing up to 21 kg (about 46 pounds), which generally includes youngsters through around 5 years of age. The therapy is available at low or no cost to eligible SMA patients in England and Scotland through the countries’ national health services.
Health Canada approved Zolgensma in December 2020 for a similar indication as in Europe. The therapy was recommended for reimbursement in the country only for eligible children younger than 6 months of age. Those older than that may receive the therapy at low or no cost in Quebec on a case-by-case basis.
According to Novartis, the therapy also is available in many other countries, including Australia, Brazil, Japan, South Korea, and Switzerland.
Who should not use Zolgensma?
Zolgensma has no contraindications. However, the medication carries a boxed warning for serious liver injury and liver failure, and the risks and benefits of treatment should be carefully evaluated in patients with preexisting liver impairment.
The therapy is not recommended for premature babies before reaching their full-term gestational age, due to the potential neurological effects of the corticosteroid regimen that’s used along with Zolgensma to prevent liver damage.
It also should not be given to anyone with an active infection. If a patient has an infection, administration of the gene therapy should be delayed until after the infection has fully resolved.
How is Zolgensma administered in SMA?
Zolgensma is given via a single infusion into the bloodstream, which takes approximately one hour to complete. The recommended dose is 110 trillion vector genomes — the number of individual viral vectors containing the SMN1 gene — per kilogram of body weight.
Starting the day before Zolgensma’s administration, and for at least one month thereafter, patients should be given corticosteroids equivalent to oral prednisolone at 1 mg/kg of body weight.
After 30 days on corticosteroids, liver function should be checked. If values are normal, the patients can be weaned off corticosteroids; if not, corticosteroids should be continued until values normalize. If liver markers remain very high after 30 days on corticosteroids, a specialist should be consulted.
Zolgensma in clinical trials
The approval of Zolgensma in the U.S. was supported by data from a Phase 1 clinical trial called START (NCT02122952) and a U.S.-based Phase 3 clinical trial called STR1VE (NCT03306277). Both tested the gene therapy in babies up to 6 months of age with type 1 SMA.
Phase 1 START study
The START study enrolled 15 babies who had already begun to experience disease symptoms. The children received ascending doses of the gene therapy and were monitored for two years, after which they could enter a long-term study called LT-001 (NCT03421977). That ongoing study is following patients for up to 15 years.
Two years after Zolgensma treatment, all of the babies given the now-approved dose were still alive without a need for permanent ventilation. Two of these children could stand and walk without assistance, and nine could sit unsupported for at least 30 seconds.
At a mean of 6.9 years after Zolgensma’s use, gains in motor function were maintained in all evaluable patients given the therapeutic dose, and three children reached the milestone of being able to stand with support. Generally, more substantial motor improvements were documented in children who had better motor function when they were treated with Zolgensma.
Phase 3 STR1VE trials
The STR1VE trial tested the therapy in 22 babies. At age 18 months, all but two (91%) were still alive and did not require permanent ventilation. Of the two outliers, one died of SMA complications early on in the study, and one withdrew from the trial before age 1.
Most of the children in STR1VE (82%) did not require any ventilation support by age 18 months, and more than half (59%) were able to sit unsupported for at least 30 seconds by that age. In standardized measures of motor function, nearly all of the children reached scores that are almost never seen in untreated SMA type 1.
Two similar Phase 3 clinical trials tested the therapy in other locations: STR1VE-EU (NCT03461289) in Europe and STR1VE-AP (NCT03837184) in the Asia-Pacific region. Collectively, these three trials enrolled a total of 57 babies with type 1 SMA, and results were generally consistent across the studies.
SPR1NT study in presymptomatic babies
The Phase 3 clinical trial SPR1NT (NCT03505099) enrolled 29 babies genetically diagnosed with SMA but not yet showing symptoms of the disease. Based on genetic tests, these babies would be expected to develop either type 1 or type 2 SMA. All of the infants were treated with Zolgensma before 6 weeks of age.
After two years, all of the children were still alive and did not require ventilation or feeding tube support. Among those predicted to develop type 1 SMA, 79% were able to stand and 64% could walk independently; for those predicted to develop type 2 disease, all could stand and all but one could walk independently. Many of these children reached these motor milestones within timeframes that are typical for children who do not have SMA.
SMART trial in heavier children
The ongoing Phase 3b SMART trial (NCT04851873) is evaluating Zolgensma’s one-year safety and effectiveness in children with SMA who weigh 8.5 to 21 kgs (about 18 to 46 pounds). The study aimed to recruit about 24 children with SMA, ages 17 or younger, who were never given any disease-modifying treatment. The trial is being conducted at more than a dozen sites around the world. SMART is due to conclude in July 2023.
Studies of OAV-101
OAV-101 is a version of Zolgensma that is administered intrathecally, or via injection into the spinal canal, rather than into the bloodstream. Novartis conducted a Phase 1/2 trial called STRONG (NCT03381729) to test OAV-101 in children with SMA types 2 or 3. The participants ranged in age from 6 months to 5 years.
STRONG was put on a partial clinical hold by the FDA in October 2019 after troubling safety findings were reported in nonhuman primates given OAV-101. Such safety concerns were not detected in children treated in the trial, and comprehensive toxicology studies addressed all issues identified by the agency. That prompted the lifting of the trial’s hold in August 2021.
Interim results before the clinical hold showed that treated children continued to show gains in motor function and that no new safety concerns were identified relative to those previously reported with into-the-vein (intravenous) Zolgensma.
Novartis now is running the Phase 3 STEER trial (NCT05089656), which is testing OAV-101 in approximately 125 children and adolescents, ages 2 to 17. The participants have SMA type 2 and are able to sit but not walk; none were given any prior disease-modifying treatment.
In STEER, patients are given either OAV-101 or a sham procedure and then monitored for about a year. After that period, those given the sham procedure will receive the therapy, and vice versa. STEER was requested by the FDA to aid in the potential approval of this new administration route for older patients. The trial is expected to conclude in October 2024.
An open-label Phase 3b study called STRENGTH (NCT05386680) is evaluating OAV-101’s safety and efficacy in up to 28 children with SMA, ages 2 to 12. These children previously were treated with Spinraza (nusinersen) or Evrysdi (risdiplam), but had stopped taking these two disease-modifying medications.
Common side effects of Zolgensma
The most common side effects of Zolgensma reported in clinical trials are:
- vomiting
- elevated levels of aminotransferases (markers of liver injury).
Liver toxicity
Zolgensma’s label contains a boxed warning highlighting the risk of higher than normal levels of liver enzymes, acute liver damage, and acute liver failure. Individuals with pre-existing liver issues may be at increased risk.
Liver function should be checked in all patients before administering Zolgensma, and it should be regularly monitored for at least three months after treatment. Liver injury due to Zolgensma is thought to occur due to an inflammatory immune reaction against the viral vector. Thus, a course of anti-inflammatory corticosteroids is administered starting the day before Zolgensma infusion, with the aim of reducing the risk of liver injury.
Blood clotting conditions
Levels of platelets — cell fragments involved in blood clotting — tend to show a transient decline following Zolgensma treatment, a condition known as thrombocytopenia. Platelet counts should be regularly monitored following Zolgensma’s use until they normalize.
Patients treated with Zolgensma who show signs of thrombotic microangiopathy — a group of conditions characterized by abnormal clotting in the body’s small blood vessels — should immediately be referred to a specialist in pediatric kidney and/or liver health for evaluation.
Increases in troponin-I
Levels of the troponin-I protein can sometimes increase after treatment with Zolgensma, indicating potential damage to cardiac and skeletal muscles. These levels should be monitored before and after Zolgensma treatment, and until they return to normal.
Use in pregnancy and breastfeeding
No data are available regarding Zolgensma use in pregnant women or its presence in human milk, the effects on breastfed infants, or the effects on milk production.
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Zolgensma
The U.S. Food and Drug Administration approved Zolgensma in 2019 for the treatment of babies and toddlers up to age 2 with spinal muscular atrophy (SMA) caused by mutations in the SMN1 gene. This marked the first approval of a gene therapy for SMA and the second approval of a disease-modifying therapy for the disease.
By delivering a healthy copy of the gene that’s mutated in spinal muscular atrophy (SMA), Zolgensma can slow and even stop the progressive muscle weakness that marks the disease, enabling most patients to reach milestones that generally were not attained without treatment. In clinical trials, gains in motor function were seen as early as after one month of treatment, but some patients will take longer to experience benefits.
Based on data from four clinical trials, the most common side effects of Zolgensma were vomiting and elevated levels of liver enzymes, indicating possible liver injury. Other side effects that have been reported by patients since the gene therapy’s approval include fever, acute liver injury or failure, and clotting disorders such as thrombocytopenia (low platelet levels) and thrombotic microangiopathy (abnormal clotting in small blood vessels). There also have been reported increases in troponin-I protein levels, indicating potential damage to the heart muscle.
Zolgensma has been shown in trials to possibly be associated with liver damage that can ultimately result in serious liver failure and death. To prevent this potentially life-threatening side effect, patients who receive the gene therapy are also given corticosteroids for a month; however, they still should be regularly monitored for signs of liver damage. It is recommended that families and caregivers of children with spinal muscular atrophy who are preparing for Zolgensma treatment speak with their healthcare providers to know more about other potential complications.
Zolgensma has been mostly tested in infants and toddlers with spinal muscular atrophy, in whom it was deemed safe and able to improve or maintain motor function. A couple of trials also have enrolled adolescents as old as age 17 but the gene therapy has never been tested in adults, who tend to have milder forms of the disease. In the U.S., the therapy is only approved for children in the first two years of life.
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