Two Patient Deaths Reported With Zolgensma Administration in SMA


The deaths, occurring shortly after treatment infusion, were because of acute liver injury, which is a known risk associated with the Novartis gene therapy.

A version of this story originally appeared on our sister site, CGTLive™.

Reports indicate that 2 children with spinal muscular atrophy (SMA) in Russia and Kazakhstan who were administered the gene therapy onasemnogene abeparvovec (Zolgensma; Novartis) have died because of acute liver injury. The deaths occurred at some point in the past few months, occurring an estimated 5 to 6 weeks post infusion of treatment and 1 to 10 days post tapering of corticosteroids.1

Novartis has notified the physicians and payers of the deaths, according to the original report from STAT.1 The company also noted in a statement issued to NeurologyLive® that it plans to update the therapy’s label to include information on the deaths. Zolgensma’s labeling currently includes a boxed warning about the risk of liver injury and instructs clinicians to assess liver function before treatment and to manage liver enzyme counts with steroid treatment.

"We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” Novartis said in an emailed statement to NeurologyLive®. It added, "while this is important safety information, it is not a new safety signal and we firmly believe in the overall favorable risk/benefit profile of Zolgensma, which to date has been used to treat more than 2300 patients worldwide across clinical trials, managed access programs, and in the commercial setting.”

The company noted in its statement that it "is committed to patient safety and the ongoing monitoring of adverse events as it relates to the use of Zolgensma, a one-time gene therapy for spinal muscular atrophy. Acute liver failure is a known side effect and is highlighted in the Zolgensma product labeling, including in the Box Warning in the US Prescribing Information."

New information revealed by Novartis and reported by Bloomberg2 indicates that 1 patient was outside of the FDA-approved max age for treatment that is indicated in the US; however, the patient's age and weight were in alignment with the approved indication in the country of treatment. In the US, the FDA approved treatment with Zolgensma in patients under 2 years of age; the European Union approved it for patients weighing up to 21 kg, which in patients with SMA, can equate to a child up to 5 years old; and in Russia, there is no upward age limit in effect.

In June 2022, Novartis published the final results from the phase 3 SPR1NT trial (NCT03505099), of the gene therapy, with data demonstrating that those with presymptomatic SMA with either 2 or 3 copies of the SMN2 gene achieved age-appropriate motor milestones, including sitting independently, standing, and walking up to 18 months after infusion.3,4

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Across both cohorts assessed, reported adverse reactions were consistent with prior data, with no new safety signals identified. To mitigate the inflammatory response to AAV9, all 14 children in the 2-copy cohort commenced oral prednisolone therapy 1 day prior to Zolgensma infusion and completed a median of 60 days (range, 49-100) of therapy. All children in the 2-copy cohort experienced at least 1 treatment-emergent adverse event (TEAE), and 5 (36%) had at least 1 TEAE deemed to be serious. Of note, 10 of the 14 children had at least 1 TEAE considered to be related to study treatment by the investigator, but none of those were deemed serious.4

Safety concerns with gene and cell therapies have been a focal point of the FDA in recent months. Last fall, in September 2021, the FDA hosted a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee, focusing a discussion on adverse events (AEs) arising from AAV vector-delivered gene therapies, including onasemnogene abeparvovec and voretigene neparvovec (Luxturna; Spark Therapeutics), which was approved for the treatment of retinitis pigmentosa and Leber congenital amaurosis in 2017.5

At the time, the committee expressed a need for caution but promoted no actions that would slow or halt the development of this class of medications. Among the serious AEs observed with AAV gene therapies, the group discussed hepatoxicity, thrombotic microangiopathy, and neurotoxicity that have been observed in gene therapy studies, both preclinically and in humans. The committee also discussed the appropriate use of animal models in studying these AEs, including mice, dogs, and nonhuman primates, and the translatability of AEs reported in such studies.

"Our enthusiasm for this field must be balanced by caution," Wilson Bryan, director, Office of Tissues and Advanced Therapies, FDA, said during the meeting’s opening presentation.4 "The greatest risks in drug development fall on the patients who receive an investigational product."

1. Silverman E. Novartis reports two children died from acute liver failure after treatment with Zolgensma gene therapy. STAT. August 11, 2022. Accessed August 12, 2022.
2. Kresge N. Child Who Died on Novartis Gene Therapy Was Past US Age Limit. Bloomberg. August 12, 2022.
3. Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. Accessed August 12, 2022.
4. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with 2 copies of SMN2 at risk for spinal muscular atrophy type 1: the phase 3 SPR1NT trial. Nat Med. 2022;28(7):1381-1389. doi:10.1038/s41591-022-01866-4
5. Cellular, Tissue, and Gene Therapies Advisory Committee September 2-3, 2021 Meeting Announcement. FDA website. September 2-3, 2021. Accessed August 12, 2022.
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