Switch to Zolgensma From Evrysdi Found Safe, Effective for Baby Girl
The one-time gene therapy Zolgensma (onasemnogene abeparvovec-xioi) was safe and effective in a baby girl with spinal muscular atrophy (SMA) type 1 who was previously on Evrysdi (risdiplam) for about three months, a case study reports.
This likely represents the first report of safety and efficacy outcomes of a therapeutic switch from Evrysdi to Zolgensma in infants with SMA.
The case study, “Switching therapies: safety profile of Onasemnogene abeparvovec-xioi in a SMA1 patient previously treated with Risdiplam,” was published in Acta Myologica.
Zolgensma delivers working version of SMN1 gene
Zolgensma is a gene therapy that delivers a working version of SMN1, the gene that provides instructions for making a protein called SMN and that is mutated in people with SMA.
Without enough SMN protein, the nerve cells responsible for regulating voluntary movement stop working. This makes the muscles weaker and causes motor symptoms.
The Novartis’ therapy is approved for children up to age 2 in the U.S., Japan, and Canada, and for those with up to three copies of the “backup” SMN2 gene and weighing up to 21 kilograms (about 46 pounds) in Europe, which could cover children up to age 5.
The SMN2 gene makes up for the production of only a small amount of the SMN protein in cells. People typically carry two copies of the SMN2 gene, and in SMA patients, a higher number of copies is associated with less severe symptoms.
Zolgensma can be given to patients who have never received any disease-specific treatment or to those who are already being treated with Biogen’s Spinraza (nusinersen) or Roche’s Evrysdi — two other SMA disease-modifying therapies.
While there have been a number of reports on switching to Zolgensma from Spinraza, there is limited evidence on the outcomes of a switch from Evrysdi, the latest SMA approved therapy.
Baby girl with SMA type 1 treated with Zolgensma at 5 months old
Now, a team of researchers in Italy described the case of a baby girl with SMA type 1, the most common and second most severe disease type, who was switched from Evrysdi treatment to Zolgensma at 5 months of age.
“To the best of our knowledge, this is the first report describing the safety profile and the clinical outcome of a switching from [Evrysdi] to [Zolgensma],” the team wrote.
SMA type 1 is characterized by progressive muscle weakness and wasting that affects not only motor function, but also the ability to breathe and eat. It is associated with a life expectancy of less than two years if left untreated.
“The baby was the first child of unrelated parents coming from an eastern European country,” the researchers wrote.
The baby’s parents noticed she had reduced leg movement when she was about one month old. Doctors conducted a neurological examination and suspected SMA. A genetic test revealed the presence of disease-causing SMN1 mutations and two copies of SMN2, “thus confirming the diagnosis of a SMA type 1,” the team wrote.
At the age of 2 months, the girl began oral treatment with Evrysdi at a dose of 1.6 milliliters per day, which was gradually increased over time according to her weight. During a neurological examination about one month later, the girl was “alert, reactive, showing good visual tracking and interaction with the examiner,” the researchers wrote.
She was able to control her head while sitting with support, but not while lying down with her face facing up. The movement of her legs, arms, and hands was somewhat limited. She showed no breathing or swallowing difficulties.
Her CHOP-INTEND score was 32 out of a total of 64 points. The CHOP-INTEND score is a measure of motor skills, and the higher the score, the better the motor function. By 6 months of age, scores of 40 points or greater are rarely observed in untreated type 1 infants.
In the following months, her parents asked for access to Zolgensma, as they were planning to move back to their home country, where Evrysdi was not available.
Before Zolgensma can be given to a patient, doctors need to assess the levels of antibodies against the adeno-associated virus 9, whose modified and harmless version is used in Zolgensma to deliver the working SMN1 gene to cells.
If a person’s immune system has built up a certain level of antibodies against the virus, the person may not qualify for treatment as it may lead to stronger immune reactions against the therapy.
Since these reactions may increase the levels of liver enzymes, indicating liver damage, and reduce those of platelets, doctors also need to confirm that these levels are within the normal range before Zolgensma treatment.
All these tests came back clear for the girl to be treated with Zolgensma. At the age of 5 months, and three days after stopping Evrysdi, she was treated with the gene therapy.
To the best of our knowledge, this is the first report describing the safety profile and the clinical outcome of a switching from [Evrysdi] to [Zolgensma]
Motor function improvement observed nine months after Zolgensma treatment
One day before the infusion, she was started on oral prednisolone, a corticosteroid, at the dose of 1 milligram per kilogram per day. The use of a corticosteroid is recommended to prevent strong immune responses against the virus.
Two days after treatment, the girl experienced fever and loss of appetite. A few days later, she showed an increase in liver enzymes and a drop in platelets. Her oral prednisolone dose was therefore doubled, and liver enzymes and platelet count gradually returned to normal within three months.
At the last clinical evaluation, nine months after treatment with Zolgensma, “she presented significant improvement in motor function,” the researchers wrote.
She was able to sit and to stand with minimal support, scored 59 points on CHOP-INTEND, and had no breathing, swallowing, growth, or cognitive problems.
“The clinical decision regarding the opportunity in switching and the timing of administration of a second therapy is always challenging,” the researchers wrote.
In this case, “the switch was well tolerated,” the team wrote, with the baby girl experiencing “expected side effects … that resolved in 3 months under prednisolone treatment.”
The team also added that the observed clinical improvements were likely associated with the girl’s young age, low weight, and positive clinical status at the time of Zolgensma treatment.
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