Approved SMA gene therapies’ benefits outweigh cancer risks, FDA says
Agency evaluating whether regulatory action is needed on Zolgensma, Itvisma
Written by |
The U.S. Food and Drug Administration has shared new details concerning reports of cancer developing following treatment with gene therapy for spinal muscular atrophy. (Photo by iStock)
- Gene therapies for SMA, specifically Zolgensma and Itvisma, carry a potential cancer risk, the FDA said.
- The FDA maintains that the overall therapeutic benefits of these therapies continue to outweigh their potential risks.
- Patients treated with these therapies should receive regular tumor monitoring.
The U.S. Food and Drug Administration (FDA) has shared new details concerning reports of cancer developing following treatment with gene therapy for spinal muscular atrophy (SMA).
Last week, Novartis confirmed that there have been nine cases of tumors developing after treatment with its gene therapy Zolgensma (onasemnogene abeparvovec-xioi), which is approved in the U.S. for SMA patients younger than 2. Of the nine tumor cases, there were at least two cases where biological data indicated that the gene therapy directly triggered the tumor.
The FDA has now shared specific findings about exactly how Zolgensma caused the tumors to develop. Based on the data, the agency said that the risk of cancer probably applies not only to Zolgensma, but also to Itvisma (onasemnogene abeparvovec-brve), a similar gene therapy developed by Novartis that’s approved for patients ages 2 and older.
“FDA has determined that the risk of [cancer] is applicable to both [Zolgensma and Itvisma], as the two products contain the same vector and construct,” the agency said in a statement.
“The overall benefits of Zolgensma and Itvisma continue to outweigh their potential risks for their approved uses, though FDA is investigating the identified risk of [cancer] with serious outcomes, and is evaluating whether regulatory action is appropriate,” the agency added.
Of note, the prescribing information for both Itvisma and Zolgensma includes a theoretical risk of cancer, but these cases suggest that this risk is not purely theoretical. The FDA said it is “expeditiously evaluating the adequacy of the current prescribing information and long-term follow-up studies to investigate and mitigate the serious risk of [cancer] based on the new safety information.”
Patients who received therapies should be monitored for tumors
For families, the take-home message right now is much the same as it was last week: If you or your child has received Zolgensma or Itvisma, get in contact with your healthcare team to discuss appropriate next steps in regard to your specific situation. The FDA is recommending that anyone who has received either of these therapies should be monitored for tumors, and any tumors identified should be reported to the FDA and Novartis Gene Therapies.
SMA is caused mainly by mutations in the SMN1 gene. Zolgensma and Itvisma both work to deliver a healthy version of this gene to the body’s cells, thus addressing the root cause of SMA. To deliver their genetic payloads, these gene therapies use a viral vector — basically a virus that’s been modified to deliver a therapeutic gene instead of causing an infection.
Zolgensma and Itvisma are designed so that DNA delivered by the gene therapy is supposed to stay separate from the cell’s own DNA. However, it’s long been known that there’s a risk that viral vector DNA can, in some cases, accidentally stick itself into the cell’s own DNA. Theoretically, this could change a cell’s DNA in a way that leads to cancer — and that’s exactly what seems to have happened here.
Specifically, in the two cases reported as linked to Zolgensma, the vector DNA inserted itself near or within a gene called GLI1. This gene is a well-established oncogene — in other words, it’s well-established that increasing GLI1 activity can lead to cancer. In fact, these two cases showed abnormal activation of GLI1.
A third tumor case has been confirmed to show abnormal GLI1 activation, but how this occurred remains under investigation.
The FDA noted that there have also been reports of two experimental gene therapies that use viral vectors (one of which has been discontinued) causing cancers due to abnormal integration into the genome. One of these cases was caused by integration into GLI1. The agency said it is closely monitoring these and other similar gene therapy programs.
According to the FDA, specific types of cancer reported in patients given Zolgensma include tumors of the central nervous system (the brain and spinal cord) and peripheral nervous system (the nerves outside the brain and spinal cord), as well as the spinal region and kidney. The agency didn’t give further specifics or specify which tumor types had been definitively linked with Zolgensma.
Leave a comment
Fill in the required fields to post. Your email address will not be published.