Zolgensma alone helps children with SMA type 1: Real-world study
Gains in motor skills, lung health seen over 2 years after treatment in infancy
The gene therapy Zolgensma (onasemnogene abeparvovec-xioi), given as a sole treatment, improves motor skills and preserves lung health and feeding abilities in infants with spinal muscular atrophy (SMA) type 1, according to a real-world study.
Despite such benefits to patients treated at a mean age of 7.5 months, the therapy did not prevent spinal deformities, with nearly all of 17 children followed for at least two years requiring a spinal brace.
The study, “Real-world multidisciplinary outcomes of onasemnogene abeparvovec monotherapy in patients with spinal muscular atrophy type 1: experience of the French cohort in the first three years of treatment,” was published in the Orphanet Journal of Rare Diseases.
The gene therapy is widely approved for patients up to age 2 or 21 kg
SMA is caused by mutations in the SMN1 gene that lead to a deficiency in SMN, a protein essential for the health of nerve cells that control movement. Hallmark disease symptoms include muscle weakness and wasting, but patients can also experience problems with speaking, swallowing, and breathing.
Cells carry a second, almost identical SMN2 gene that encodes for the SMN protein. Generally, more SMN2 copies are linked to less severe disease.
SMA type 1 is the most common type of SMA and one of the most severe, occurring in about 60% of all cases. Symptoms typically emerge between birth and 6 months of age. These include low muscle tone, failure to reach such motor milestones as sitting up and rolling, difficulties with breathing and feeding, and scoliosis, a sideways curvature of the spine.
Zolgensma, by Novartis, is a one-time gene therapy designed to provide cells with a healthy copy of the SMN1 gene. In the U.S., it’s approved for children younger than age 2. In Canada and the European Union, it’s approved for patients of any age with three or fewer SMN2 gene copies weighing up to 21 kg (about 46 pounds).
In clinical trials, the gene therapy demonstrated its ability to enhance motor function, improve breathing and feeding, achieve motor milestones, and prolong survival.
Because people with SMA tend to have more variable disease at presentation, clinical trials may not reflect the real-world impacts of Zolgensma. While real-world data have been published, most studies included a small number of patients, with many undergoing multiple treatments, and varied in terms of age and SMA type.
A team of scientists across France reported on the real-world effects of Zolgensma as a single therapy given to previously untreated SMA type 1 babies.
Significant motor gains seen in 27 treated children over two years
The analysis included 29 patients, treated with Zolgensma between 2.1 and 12.5 months old and followed for at least one year and up to two years. Seven children with three SMN2 copies at diagnosis were older, and had better motor function, than the 22 patients with two SMN2 copies. Before treatment, none of the infants needed feeding support. Two children died in the month after treatment; one due to a lung infection and the other from blood clots.
All 17 patients with two years of follow-up could hold up their heads. All children with three SMN2 copies could sit unaided for 30 seconds and stand for a few seconds with assistance. Among those with two SMN2 copies, 11 (85%) reached the sitting milestone, and eight (62%) achieved the standing milestone.
None of the patients with three SMN2 copies required breathing support, whereas three children (23%) with two copies needed noninvasive ventilation, and two others (15%) required nutritional support. No child needed feeding tube placement or a modified diet.
Nearly all of the 17 patients with two years of follow-up (88%) required a brace to treat spinal collapse or scoliosis, which was prescribed earlier to those with two SMN2 copies.
Motor function significantly improved in all 27 evaluable patients, as indicated by changes in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and Hammersmith Infant Neurological Examination-2 (HINE-2) scores over two years. Still, little motor progress was seen between one and two years of follow-up on the CHOP-INTEND scale, while HINE-2 continued to increase. This finding might be due to “saturation” on the CHOP-INTEND scale, the team noted.
Researchers also assessed the ratio between the thoracic (chest) circumference (TC) and head circumference (HC), which was used as a proxy for chest growth and an indirect measurement of lung function. Values below 0.85 have been associated with mortality in untreated SMA children.
Here, the TC/HC ratio increased in all patients, which was significant for patients with three SMN2 copies but not for those with two copies. This suggested slower lung growth among children with two SMN2 copies, the researchers noted.
“The TC/HC ratio revealed favorable thoraco-pulmonary growth,” the researchers wrote, a finding that’s “strikingly different from our previous experience in the natural history of SMA1 … and [whose] results suggest the fairly good health of the respiratory and bulbar muscles.”
Spinal deformities noted despite motor and respiratory benefits
A side effect reported in all patients was a rise in liver enzymes in blood tests, a sign of liver injury. These enzymes soon normalized in 24 of 27 patients. All children also had a post-treatment increase in troponin 1, a sign of heart problems, which also eventually fell into the normal range. None showed heart abnormalities on ECG and echocardiogram assessments.
About half (47%) of those with two years of follow-up experienced lung problems, and 1 in 4 (26%) were hospitalized at least once for lung infections.
“Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by [Zolgensma] as the first and only therapy,” the researchers concluded. “Nevertheless, almost all patients developed spinal deformities.”
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