20th July 2024

In 2020, a European working group of expert neuromuscular clinicians  was set up to consider and support the safe use of Zolgensma. They published a consensus statement . This advised caution with Zolgensma for older, heavier people with SMA due to limited data in this population. Now, a similar but larger group of European experts has looked at new evidence from clinical trials and real-world data. This has led to twelve consensus statement updates Published in June 2024. These cover factors such as age, disease duration and motor function. They also stress the importance of SMN2 copy number in early-stage SMA. However, the risk-benefit balance for older, heavier patients still needs careful family discussions.

Main points from the consensus:

Treatment Response Predictors: traditional SMA classifications (types) poorly predict gene therapy benefits. Key factors include age at disease onset, disease duration and motor function at the start of treatment. More data are needed on bulbar and respiratory functions.

Presymptomatic Patients: the number of SMN2 copies is key. It is currently the best predictor for disease severity and when symptoms are likely to start. Doctors should base treatment decisions on this number, which must be done by expert laboratories. Some babies screened through the newborn screening programme might have symptoms at birth.

Older and Heavier Patients: The effectiveness of Zolgensma is not well-documented in older or heavier patients. Doctors should inform families that the risks and benefits are not clear – with age possibly posing more risk than weight. Caution is advised in treating these patients due to higher risks with larger doses. Alternative treatments or the approach of administering Zolgensma directly into the spine, which is still being tested in clinical trials, may be considered.

Personalised assessments of risks and benefits are crucial. If intravenous gene therapy is chosen, strict protocols must be followed, and ongoing safety and effectiveness monitored closely. Treatment is not recommended for patients over 21 kg. Recent guidelines have lifted the 13.5 kg limit, but stress the importance of continually gathering data on safety and effectiveness across patient populations. Older and heavier patients face increased risk of immune responses, underscoring the need for improving treatment protocols through continuous data collection.

Severely Affected: for patients with symptoms at birth, a long disease duration before treatment, or severe disease progression, it is important to inform parents of likely outcomes. They need to know about the potential for major disability despite gene therapy. In these circumstances, it may also be appropriate to consider palliative care as an alternative option.

Combining Treatments: there is currently no evidence to support that combining disease-modifying treatments gives a better outcome. Controlled clinical trials are needed to assess this.

Therapy administration: gene therapy should be offered at highly experienced centres that adhere to international standards and are capable of managing side effects. Centres should use standardised outcome measures and aim to become European Reference Centres.

Early Treatment: starting treatment early, before symptoms appear, greatly improves outcomes. Newly diagnosed patients should start treatment immediately. This includes newborns identified through screening. It is particularly important for those with SMA type 1 and/or who have two SMN2 copies.

Data Collection: systematic collection of effectiveness and safety data for Zolgensma is essential. Treatment centres need resources for long-term monitoring and data should be collected using disease-specific registries. Treatment for patients over 21 kg should follow a rigorous protocol with continuous monitoring.

Availability of new data: collaborative efforts are needed to ensure that new data on the effectiveness and safety of gene therapy is publicly available. This collaboration must involve the pharmaceutical industry, regulators, patient representatives and academic networks.

Newborn Screening: SMA should be included in newborn screening programmes where at least one disease-modifying treatment is available for administration. Identified patients should be promptly evaluated by experienced paediatric neurologists and treatment started without delay if symptoms or three SMN2 copies or less (≤3) are detected. Immediate evaluation and treatment initiation are crucial, especially for infants with two SMN2 copies, who may exhibit symptoms at birth.

Reference:

Kirschner J, Bernert G, Butoianu N, De Waele L, Fattal-Valevski A, Haberlova J, Moreno T, Klein A, Kostera-Pruszczyk A, Mercuri E, Quijano-Roy S, Sejersen T, Tizzano EF, van der Pol WL, Wallace S, Zafeiriou D, Ziegler A, Muntoni F and Servais L. 2024 2024 update European consensus statement on Gene Therapy for SMA