Guidance on Zolgensma in Europe Notes Lack of ‘Evidence’ for Broad Use

Identifying those spinal muscular atrophy (SMA) patients who will benefit most from treatment with Zolgensma requires more than assessing traditional SMA types, according to a consensus statement from a panel of European experts.

The statement covers 11 points, and highlights that clinical trials of Zolgensma to date involved a fairly specific patient group: babies up to age 6 months and weighing less than 8.4 kgs (about 18.5 lbs). As such, data on its use in the broader population needs to be collected, and in the meantime, patients and parents should be made aware of what is and is not known.

The statement, “European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy,” was published in the European Journal of Paediatric Neurology.

SMA is caused by mutations in the gene SMN1. Zolgensma, formerly known as AVXS-101 and developed by Novartis and its subsidiary AveXis, is a gene therapy that works by delivering a non-mutated copy of the SMN1 gene to motor nerve cells.

The European Commission approved Zolgensma in May to treat patients, up to 21 kg (about 46 lbs), with a clinical diagnosis of type 1 SMA or up to three copies of the SMN2 gene. SMN2 is able to partly compensate for defective SMN1; generally, more copies of SMN2 mean less severe disease.

Zolgensma’s use is also under consideration by England’s National Institute for Health and Care Excellence’s (NICE’s), with an agency recommendation expected on March 25, 2021.

Its fairly broad approval in Europe means that, in theory, many patients could be eligible for the gene therapy. However, trial data is lacking for those beyond early infancy, the panel of neuromuscular experts wrote.

“This discrepancy poses major challenges to patients, clinicians and payers associated with the question who should be treated under which circumstances,” their statement reads, “also in view of the fact that an effective and safe treatment, nusinersen [Spinraza, by Biogen] is already widely available in this patient population.”

While the consensus statement acknowledges that individual treatment decisions need to be made on a case-by-case basis, it offers general guidelines that may be helpful.

Some guidelines concern determining exactly who should be treated with Zolgensma. According to the statement, the traditional SMA types will be inadequate for this purpose, because there is considerable overlap between these types. Additionally, this classification system isn’t able to fully account for how treatments can change disease progression.

“Therefore, traditional SMA types alone are not sufficient to characterize individual patients and one should consider additional factors to define populations that might benefit most from gene replacement and other disease-modifying treatments,” the statement reads.

For symptomatic patients, the statement recommends considering age at onset, disease duration, and motor function when deciding on treatments. For presymptomatic ones, the number of SMN2 copies should be used to predict outcomes and guide treatment decisions.

The statement also stresses the importance of communication with patients and their families. For instance, it emphasizes that gene therapy may be less effective at preventing disability in people with more advanced disease and symptoms, and these risks should be explained clearly.

In severe cases, where a patient is already on respiratory support and tube feeding, “gene replacement therapy and other disease modifying treatments might stabilize the disease but not necessarily reduce disability or improve quality of life,” the statement reads.

Similarly, clinicians should ensure that patients and their families are aware if they fall into a group with little clinical data, such as those who are older and heavier. Conference presentations have supported Zolgensma in patients up to age 2 and 13.5 kgs (about 30 lbs), but these “data mainly come from non-systematic data collection in the US, where Zolgensma is approved up to the age of 2 years.”

Weight may be a particular concern in this regard, since heavier individuals will likely require higher doses, the statement noted, which increase the risk of side effects. As such, other therapies may be more amenable for these people.

It noted that a clinical trial on intrathecal [spinal canal] injection of Zolgensma, approved as an intravenous infusion, may allow for lower doses. But this trial, called STRONG (NCT03381729), is on clinical hold due to troublesome findings in non-human primates.

Spinraza was suggested by these experts for older and heavier patients, as this “approved drug” is “available as an alternative treatment and has been studied in a double-blind placebo-controlled trial in later-onset types of SMA.” Anyone in this group should be given Zolgensma only “under a more rigorous protocol with continuous monitoring of safety and efficacy.”

The statement also notes that, currently, no data support that Zolgensma used in combination with another disease-modifying therapy is superior to any single treatment alone. As such, “[b]efore more evidence is available, combination of both approved therapies [Zolgensma and Spinraza] should not be part of routine care.”

Since treatment of SMA tends to be more effective when started early — “ideally in the presymptomatic stage” — the statement supports SMA newborn screening and starting treatment for those newly diagnosed within 14 days.

It recommends that institutions using Zolgensma be adequately equipped to do so and staff trained. This includes having all appropriate resources to safely administer the therapy and provide care.

Finally, the statement stresses the importance of continued data collection on Zolgensma, and of sharing these data without regard to financial or other interests.

“As the use of Zolgensma will generate additional evidence during the coming years, pharmaceutical industry, regulators, patient representatives, and academic networks should collaborate to ensure that any new data on effectiveness and safety are publicly available in an unbiased and timely manner,” the statement reads.

“This growing body of evidence is indispensable for an improved risk-benefit assessment for future patients and should not be hampered by particular commercial or academic interests.”