New recommendations offered in Zolgensma guidance for SMA

Marisa Wexler MS avatar

by Marisa Wexler MS |

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A group of European experts has published updated recommendations for using the gene therapy Zolgensma (onasemnogene abeparvovec-xioi) in people with spinal muscular atrophy (SMA) that includes new cautions with older, heavier patients.

2024 Update: European Consensus Statement on Gene Therapy for Spinal Muscular Atrophy,” was published in the European Journal of Paediatric Neurology.

SMA is caused by mutations in the SMN1 gene, and results in the death and degeneration of nerve cells responsible for controlling movement. Zolgensma, by Novartis, is a one-time gene therapy that delivers a healthy copy of the gene to cells, helping preserve motor neuron health to slow the disease’s progression.

Zolgensma was approved in Europe in 2020. Shortly after its approval, a group of neuromuscular disease experts assembled to develop recommendations to guide its use.

In the original guidelines, the researchers emphasized that initial clinical trials of Zolgensma covered young, small infants who were just a few months old when they received the gene therapy, so there was minimal data to inform its use in older, heavier patients. Weight is a particular concern with Zolgensma because the therapy is dosed based on it. Heavier patients need a higher dose, which can increase the risk of problematic side effects.

In the four years since the guidelines were published, there’s been more research on using Zolgensma in SMA. Here, the same experts plus others from countries that weren’t represented in the 2020 guidelines assembled to offer updated guidance on the therapy.

“Since the 2020 publication … significant new data have emerged, with over 3,700 SMA patients worldwide treated with [Zolgensma],” the researchers wrote. “Given the growing evidence of its effectiveness and safety, the authors have found it necessary to revisit the original statements and present an update that reflects the current treatment landscape.”

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Updates to guidelines about Zolgensma use

Some guidance remains unchanged. For example, it continues to advise that centers that administer the therapy should be well equipped to address side effects.

Other recommendations have been updated, particularly to reflect emerging data about older, heavier patients. There still isn’t much information on how effective Zolgensma is in older patients, but data have suggested that heavier children may be more likely to have liver damage, a common and potentially life-threatening side effect of the therapy.

For this reason, the guidelines emphasize that clinicians must clearly communicate that the risk-to-benefit ratio of Zolgensma in older/heavier children isn’t known, though it’s likely to be different from what’s been seen in trials of very young babies. They also note that treatment isn’t recommended for children who weigh more than 21 kg, or about 46 pounds). In Europe, Zolgensma is authorized to treat kids who weigh 21 kg or less.

Given the potential for increased risks, the guidelines note that “heavier and older patients should be treated very cautiously,” and highlights the importance of considering other treatments as options. If Zolgensma is chosen, it “should only be performed under a rigorous protocol with continuous monitoring of safety and efficacy,” the guidelines state.

Since Zolgensma isn’t the only SMA therapy available, some have wondered if combining treatments might improve outcomes. The guidelines note, however, that there’s no published data from controlled clinical trials with direct comparisons between Zolgensma and other therapies to suggest that taking another SMA treatment with Zolgensma will affect outcomes. For this reason, the new guidelines don’t recommend combining therapies.

SMA treatments like Zolgensma can slow disease progression, but they can’t reverse damage that’s already accrued. Because of this, experts recommend treatment be given as early as possible after the disease is diagnosed, ideally before any symptoms develop, no matter what therapy is chosen. To aid early diagnosis, the new guidelines recommend that newborn screening be implemented anywhere SMA treatments are available.

“In newly diagnosed patients, including those identified by [newborn screening], any delay of treatment should be avoided. Ideally, the time frame between diagnosis and initiation of a disease-modifying treatment should be the shortest possible,” the experts wrote.

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