Brian Murphy, PhD, is a medical/science writer and educator who has written over 300 resource articles about rare diseases. He holds a BS from Georgia Institute of Technology and a PhD from Case Western Reserve University, both in Biomedical Engineering. After graduation, Brian worked as a clinical neural engineer to help restore movement in spinal cord injured patients by reconnecting their brain to their paralyzed muscles using experimental medical devices. In addition to resource pages, Brian has also authored/co-authored several research articles in journals including The Lancet, Journal of Neural Engineering, and PLOS ONE.
Zolgensma® (onasemnogene abeparvovec-xioi) is a US Food and Drug Administration (FDA)-approved disease-modifying treatment for spinal muscular atrophy (SMA). It is indicated for all types of SMA in patients aged less than 2 years who have biallelic mutations in the survival motor neuron 1 (SMN1) gene.1
The FDA gave initial approval for Zolgensma in 2019, making it the first approved gene therapy for SMA and the second disease-modifying treatment, after Spinraza® (nusinersen). Zolgensma was initially developed under the name AVXS-101 by AveXis, which was later acquired by Novartis Pharmaceuticals Corporation.
Zolgensma is also approved in 36 other countries,2 including Japan3 and Canada,4 and has conditional approval in the European Union.5 Approval in several additional countries is expected in 2021.1
Zolgensma’s Mechanism of Action
Spinal muscular atrophy is caused by mutations in the SMN1 gene, leading to a lack of survival motor neuron (SMN) protein, which is normally found throughout the body, primarily in the spinal cord. SMN is important for the maintenance and survival of motor neurons through homeostatic pathways in cells, such as the creation of ribonucleoproteins through the assembly of the spliceosome, transport of mRNA, endocytosis, modification of the cytoskeleton related to dendrite and axon formation, and autophagy.6 A second gene, SMN2, can also produce small amounts of SMN, although the yield is usually low (about 10%-20%).7 Without sufficient amounts of SMN, motor neurons die, which leads to progressive muscle weakness.
Zolgensma is a gene therapy utilizing an adeno-associated virus, serotype 9 (AAV9) vector to insert a fully functional copy of the human SMN gene into cells. Treatment is given as a single intravenous infusion. After infusion, the AAV9 vector passes through the blood-brain barrier and is able to target motor neurons.8 The vector inserts the SMN gene as a recombinant self-complementary DNA episome rather than integrating it with the patient’s genome.8 The DNA also contains a cytomegalovirus enhanced chicken beta-actin hybrid promoter to express the recombinant SMN gene.9 Transfected motor neurons will produce continuous and sustained levels of the SMN protein, halting the degeneration of these cells and the subsequent muscle atrophy associated with SMA.8
Get detailed prescribing information on the Zolgensma monograph page at Rare Disease Advisor.
Warnings, Precautions, and Adverse Reactions
Patients may experience serious acute liver injury and elevated levels of aminotransferases, making patients with liver complications at higher risk for adverse events. Screening liver function and the use of corticosteroids before, and for a period of time after, infusion with Zolgensma is recommended.
Zolgensma infusions have also resulted in thrombocytopenia, thrombotic microangiopathy, and elevated levels of troponin-I in the heart. Platelet counts, creatinine levels, complete blood counts, and troponin-I levels should be recorded at baseline and periodically after infusion.
The most common adverse reactions experienced by ≥5% of patients in the trials were elevated levels of aminotransferases and vomiting.
In October, 2021, the FDA approved several revisions to the Boxed Warning of Zolgensma’s prescribing information. These revisions included the risk of acute liver failure, acute serious liver injury, and and elevated aminotransferases in patients who receive the therapy. As a result of these reported cases, prescribing physicians are encouraged to weigh the risks and benefits of prescribing Zolgensma for SMA patients with preexisting liver impairment. If abnormalities in liver function are seen to persist in patients at levels that are at least 2 x ULN after a 30-day period of systemic corticosteroids, pediatric hepatologists or gastroenterologists should be consulted.17
Read about all of the FDA approved therapies for spinal muscular atrophy.
Zolgensma Efficacy in Trials and Trial Results
The START trial (NCT02122952) was a phase 1, open-label, ascending-dose clinical trial in patients with SMA type 1. The study concluded in 2019 and enrolled 15 patients who received a single infusion of a low dose (3 infants) or a high dose (12 infants) of Zolgensma. The average age of patients in the low-dose cohort and high-dose cohorts were 6.3 (range, 5.9-7.2) months and 3.4 (range, 0.9-7.9) months, respectively.
Results after all patients had reached age 20 months showed that all 15 patients were still alive and did not require permanent mechanical ventilation,11 compared with 8% of patients in historical controls. Motor milestones and changes in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)12 score, a 16-measure test specifically designed to assess motor abilities in patients with SMA, were also recorded. Of the 12 patients in the high-dose cohort, 11 were able to sit unassisted for ≥5 seconds and 9 could for ≥30 seconds.11
At the data cutoff, patients in the low-dose cohort had average increases in their CHOP-INTEND scores of 7.7 points above their baseline of 16.3 points, whereas the high-dose cohort improved by an average of 24.6 points from a baseline of 28.2 points.11 The CHOP-INTEND scale has a maximum of 64 points and a score >40 was regarded to be clinically meaningful to patients with SMA.
During the trial, researchers recorded 56 serious adverse events from 13 of the 15 participants, with only 2 events determined to be treatment-related.11 The first patient dosed in the trial had elevations in liver-function testing including alanine aminotransferase (ALT) levels 31 times the upper limit of normal (ULN) and aspartate aminotransferase (AST) levels 14 times above the ULN; however, no clinical manifestations were observed and no other liver-function levels were abnormal. To prevent this reaction, subsequent patients received prednisolone treatment. A second patient, in the high-dose cohort, also had high ALT and AST levels requiring additional prednisolone.
Further analysis of the high-dose cohort divided the infants into 3 categories according to their initial CHOP-INTEND scores and ages at baseline: early dosing (age <3 months) with CHOP-INTEND scores <20 (3 patients), early dosing with CHOP-INTEND scores ≥20 (3 patients), and late dosing (age ≥3 months; 6 patients).13
The analysis showed that the early-dosing group with low scores had the largest increase in scores, with an average increase of 35 points above a baseline of 15.7. The late dosing group improved by an average of 23.3 points from a baseline of 26.5, whereas the early dosing group with high scores improved by 16.3 points from a baseline of 44.13
A total of 13 of the 15 patients (3 from the low-dose cohort and 10 from the high-dose cohort) from the START trial are enrolled in a long-term follow-up study (NCT03421977). Patients in the study will be monitored for long-term safety effects for ≤15 years.
An open-label, phase 3 clinical trial called “STR1VE” (NCT03306277) enrolled 22 infants aged younger than 6 months with SMA type 1. All patients received a single intravenous infusion of 1.1 × 1014 vector genomes/kg over a 30- to 60-minute time period.14 At 18 months, 13 (59%) of the 22 children were able to achieve one of the primary study endpoints of unassisted sitting for ≥30 seconds, compared with 0 of 23 patients in a separate Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort of patients with SMA.14 A total of 20 participants survived without the need for permanent ventilation at age 14 months compared with 6 of 23 in the PNCR cohort.14
A total of 9 of 22 patients met the secondary endpoint criteria of the ability to thrive, which was determined as a function of independence from nutritional support, maintenance of the child’s body weight, and their ability to swallow.14 Independence from ventilatory support was achieved by 18 children by their appointment at age 18 months.14 Patients in the study also showed improvement in CHOP-INTEND scores, with scores increasing by an average 6.9 points after 1 month, 11.7 points after 3 months, and 14.6 points 6 months after infusion.14 Nearly all (21/22) patients achieved CHOP-INTEND scores ≥40, a score only rarely achieved by patients with SMA type 1.14
The STR1VE trial took place at 12 medical centers in the United States. Similar trials were performed in the European Union (NCT03461289), called “STR1VE-EU,” and the Asia-Pacific (NCT03837184) called “STR1VE-AP.”
Another phase 3, open-label clinical trial called “SPR1NT” (NCT03505099) enrolled 30 participants aged younger than 6 weeks with 2 mutant copies of the SMN1 genes and 2 or 3 copies of the SMN2 gene (SMA type 2). Preliminary results of the trial from December 2019 showed that all patients were still alive and free of permanent mechanical ventilation.15 Also, 8 of the 14 patients with 2 copies of the SMN2 gene were able to achieve the primary endpoint of independent sitting for ≥30 seconds.15 For the group of patients with 3 copies of SMN2, 4 of 15 patients were able to stand without support.15 The trial is expected to conclude in July 2021, with results expected shortly after.
Zolgensma was also investigated in an open-label, phase 1 trial called “STRONG” (NCT03381729). The STRONG trial investigated the use of intrathecal injections for patients with SMA with 3 copies of the SMN2 gene and an age of 6 to 60 months. The trial enrolled 51 participants but was placed on clinical hold by the FDA based on findings in a small animal study of intrathecal injections.16 Based on promising findings from the patients who were enrolled in the STRONG trial before the clinical hold, the FDA recommended another clinical study of intrathecal Zolgensma to take place outside of the United States.16
Reviewed by Michael Sapko, MD on 7/1/2021
1. Zolgensma® [package insert]. AveXis, Inc.; 2021. Accessed April 12, 2021.
2. Novartis Gene Therapies recommits to global Managed Access Program for 2021. News release. Novartis AG; January 15, 2021.
3. Novartis receives approval from Japanese Ministry of Health, Labour and Welfare for Zolgensma® the only gene therapy for patients with spinal muscular atrophy (SMA). News release]. Novartis AG; March 19, 2020.
4. Health Canada approves Zolgensma®, the one-time gene therapy for pediatric patients with spinal muscular atrophy (SMA). News release. Novartis Pharmaceuticals Canada Inc.; December 16, 2020.
5. Zolgensma® [authorisation details]. European Medicines Agency (EMA). Updated September 11, 2020. Accessed April 12, 2021.
6. Chaytow H, Huang Y-T, Gillingwater TH, Faller KME. The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci. 2018;75(21):3877-3894. 10.1007/s00018-018-2849-1
7. Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. 2017;12(1):124. doi:10.1186/s13023-017-0671-8
8. Mechanism of action. Zolgensma® HCP website. Accessed April 12, 2021.
9. Hoy SM. Onasemnogene abeparvovec: first global approval. Drugs. 2019;79(11):1255-1262. doi:10.1007/s40265-019-01162-5
10. Dosing. Zolgensma® HCP website. Accessed April 12, 2021.
11. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-1722. doi:10.1056/NEJMoa1706198
12. Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-161. doi:10.1016/j.nmd.2009.11.014
13. Lowes LP, Alfano LN, Arnold WD, et al. Impact of age and motor function in a Phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy. Pediatr Neurol. 2019;98:39-45. doi:10.1016/j.pediatrneurol.2019.05.005
14. 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;20(4):284-293. doi:10.1016/S1474-4422(21)00001-6
15. SPR1NT. Zolgensma® HCP website. Accessed April 12, 2021.
16. Novartis announces AVXS-101 intrathecal study update. News release. Novartis AG; October 30, 2019. 17. Novartis provides update on AVXS-101 intrathecal clinical development program. News release. Novartis AG; September 23, 2020.
17. Zolgensma. Package insert. Novartis Gene Therapies, Inc.; 2021. Accessed October 27, 2021. https://www.fda.gov/media/126109/download.