However, “if the children are older and heavier, there is a potential for more liver injury [a known side effect of gene therapy] and those patients require closer monitoring and may require longer [immunosuppressive] treatment,” Megan Waldrop, MD, the study’s first author and a pediatric neurologist at Nationwide Children’s Hospital, said in a news story published by the hospital.
“But if they are monitored appropriately, they tolerate the treatment well,” she added.
The data, which included children treated with Zolgensma at older ages than those reported in clinical trials, also highlighted that when treated before symptom onset, infants showed no signs of the disease, which highlights the importance of earlier treatment for SMA.
These findings suggest that with careful post-treatment monitoring and management, Zolgensma is safe and effective in children with SMA, the researchers noted.
The study, “Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes,” was published in the journal Pediatrics.
Zolgensma is a gene therapy that was approved in the U.S. in May 2019 for the treatment of all SMA types in children up to age 2. This year, it also became available in Japan for the same patient population, and in Europe for almost all SMA types in children weighing up to 21 kilograms (about 46 pounds).
The therapy works by delivering a functional copy of SMN1, the mutated gene in SMA, to cells. Administered directly into the bloodstream, it can be given only once, due to the body’s natural immune reaction against the modified virus that is used to deliver the gene to cells.
Still, children can develop immune reactions after the single dose, which may raise the levels of liver enzymes — an indicator of liver damage — and drop the levels of platelets.
For that reason, children should start a prednisolone course for immunosuppression on the day before treatment and have their liver function and platelet counts monitored before treatment, and at regular periods thereafter.
Notably, while the therapy was approved for children up to age 2, clinical trials evaluated its safety and effectiveness only in children younger than 8 months with SMA type 1, a severe form of the disease.
Now, researchers from four children’s hospitals in Ohio have reported safety and early effectiveness data from 21 additional children (1 month to 23 months old) with SMA, who were treated with Zolgensma in that state. Children were predicted to have SMA type 1, 2, and 3.
Most of the children (17 patients or 81%) were treated with Zolgensma after its approval, while four were dosed through a free managed and expanded access program. About half of them (52%) had previously been given Biogen’s Spinraza, the first approved disease-modifying therapy for all SMA patients.
Patients had a mean age of 10 months, with nine being treated at 6 months or younger (younger group) and the remaining 18 at 8 months or older (older group). Five infants (24%), all in the younger group, received Zolgensma before symptom onset (presymptomatic) following a positive result from newborn screening.
Results showed that most infants (78%) in the younger group had no noteworthy rise in liver enzymes after treatment. In the two infants with higher enzyme levels, the increase was associated with difficulties in prednisolone administration, resulting in suboptimal dosing, the team noted.
“Overall, gene transfer was well tolerated in those 6 months of age or younger with the ability to ensure appropriate prednisolone administration as the key safety factor,” the researchers wrote.
In turn, Zolgensma’s impact on the liver was greater in older children, as 67% of them showed levels of liver enzymes that were at least two times higher than the upper normal limit, requiring higher doses of prednisolone. However, these patients remained clinically well and showed no symptoms of liver dysfunction.
Moreover, 90% of all children, regardless of age or weight, showed a drop in platelet counts in the first week after treatment, which returned to normal without intervention.
Of the 19 children with repeated motor skill assessments over four months of follow-up, 17 (89%) achieved functional improvements, and two (11%) experienced stabilization. Most children who were able to be fed orally or breathe on their own maintained these abilities.
Notably, presymptomatic infants showed no signs of SMA’s characteristic muscle weakness over follow-up periods of two to eight months.
“Our experience suggests that when a thorough screening process is completed, social isolation is implemented to minimize the risk of illness after gene transfer, and patients are monitored closely in the weeks to months after gene transfer, adverse events are few,” the researchers wrote.
Waldrop, who is also an assistant professor of pediatrics and neurology at The Ohio State University College of Medicine, added: “We think this is a good treatment for SMA that can make a dramatic clinical impact in the lives of children.”
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