Zolgensma helps boy with unstable SMA symptoms on Spinraza
1 year after gene therapy at age 13 months, boy is stable, per case report
Treatment with the gene therapy Zolgensma (onasemnogene abeparvovec) led to improved breathing and motor function for a young boy who was experiencing unstable spinal muscular atrophy (SMA) symptoms on Spinraza (nusinersen), according to a case report from Japan.
A year after receiving Zolgensma at the age of 13 months, the toddler’s condition had improved — and he was learning to stand with a brace.
However, the researchers noted that the clinical management of this case was unique: During preparation for Zolgensma, the boy tested positive at some point for antibodies against AAV9, the viral carrier used to deliver the gene therapy to a patient’s cells, and for elevations in certain liver enzymes. Both of these developments deem a patient ineligible for treatment until they’re resolved.
“We believe that our experience in the management of unstable SMA … symptoms, anti-AAV9 antibody test results, changes in [liver enzymes], and consideration of additional treatments will be helpful in the management of other patients with SMA requiring treatment,” the researchers wrote.
The report, “Onasemnogene Abeparvovec Treatment after Nusinersenin an Infant with Spinal Muscular Atrophy Type 1,” was published in The Kurume Medical Journal.
Given recent approvals, real-world evidence on SMA treatments still scant
Clinical trial evidence indicates that disease-modifying therapies, or DMTs, now widely approved for treating SMA can substantially alter the prognosis of the rare genetic condition. Specifically, Zolgensma, Spinraza, and Evrysdi (risdiplam) each has been linked in such trials to the achievement of motor milestones, prolonged survival, and other gains not typically seen in the natural course of disease.
However, because these treatments are still relatively new, information about real-world treatment strategies and outcomes are still being collected.
To contribute to that body of evidence, a team of researchers from two medical universities in Japan reported on the case of a young boy with SMA type 1 who received Spinraza followed by Zolgensma gene therapy at a treatment clinic.
The patient had been diagnosed with the condition at the age of 4 months after experiencing early SMA symptoms, and was started on Spinraza at 6 months old.
Use of the therapy — the only one approved in Japan at the time — led to improvements in motor function, but the infant’s altered breathing patterns persisted. His swallowing function remained unstable and he still required a feeding tube for nutritional support.
Zolgensma was approved in the country when the boy was 10 months old. At that point, “the parents requested gene therapy in the hope of further improving activities of daily living” for their son, the researchers wrote.
The boy’s doctors began preparing for the procedure, but four different AAV9 antibody tests returned positive. Such antibodies render a person ineligible for treatment, as they can compromise the therapy’s efficacy.
The patient thus was unable to receive Zolgensma, and developed respiratory failure from a common cold that temporarily required a ventilator.
Eventually, a new blood test came back negative for AAV9 antibodies, and the boy was transferred to another hospital to receive Zolgensma. At this point, the child had lost weight and his motor function had declined, with continued swallowing issues.
Additionally, he now had elevated levels of certain liver enzymes. Zolgensma also cannot be given when this occurs because the gene therapy itself is mainly targeted to cells of the liver — and it now would be associated with an elevated risk of liver injury.
The enzymes, with a suspected viral cause, declined again a couple of weeks later. The boy then was started on the steroid prednisone, which is commonly given to prevent liver injury around the time of gene therapy.
Boy given Zolgensma at 13 months after earlier Spinraza treatment
The boy finally received Zolgensma at 13 months, or when he was a little more than a year old.
He generally was stable after the procedure and did not develop any of the known serious reactions that can occur after gene therapy. Prednisone eventually was discontinued.
The toddler’s motor function improved — he was training to stand with a brace a year later, researchers noted — and he no longer required breathing support. Likewise, saliva aspiration, where saliva is mistakenly inhaled into the respiratory tract, had decreased.
Further, his parents reported that he now was able to sleep better at night.
Still, swallowing function remained an issue, requiring a feeding tube for nutrition. While the parents initially wanted their son to be treated with Evrysdi to address that issue, they decided against it after expert consultations.
“Since we could not find reports on the efficacy and safety of [Zolgensma] and [Evrysdi] combination therapy, we did not add [Evrysdi],” the researchers wrote.
“The effects of this decision remain to be seen,” they added.
This case presented many challenges and required many decisions. We believe that [this report] will be helpful in considering future treatment strategies for SMA and in highlighting the potential challenges of SMA therapy.
Given the relative newness of all of the approved SMA treatments — Spinraza was approved in Japan in 2017, about six months after its U.S. approval — the researchers noted that clinicians are in “a new era in the treatment of SMAs.”
“This case presented many challenges and required many decisions. We believe that [this report] will be helpful in considering future treatment strategies for SMA and in highlighting the potential challenges of SMA therapy,” the team wrote.
They did acknowledge a potential limited window for the utility of their findings, however.
“In the future, patients with SMA will tend to be diagnosed at an early stage, such as during a newborn screening, and the number of patients with a clinical course similar to our case will decrease,” they concluded.
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