#AANAM – Zolgensma May Lead to Faster, Greater Gains Than Spinraza

Zolgensma may result in faster and greater functional improvements than Spinraza (nusinersen) in infants with spinal muscular atrophy (SMA) treated up to 2 years of age, according to a survey of 22 health providers in the U.S.

Given the survey’s limitations, such as its small sample and subjective nature, larger and more objective studies are needed to confirm these findings, the researchers noted.

The survey results, “Outcomes of Single-Agent Onasemnogene Abeparvovec or Nusinersen, and of Nusinersen Switching to Onasemnogene Abeparvovec, in Patients With Spinal Muscular Atrophy: Results of a Provider Survey in the United States,” were presented in a poster at the 2021 Virtual American Academy of Neurology Annual Meeting, held April 17–22.

In December 2016, Biogen’s Spinraza became the first disease-modifying treatment to be approved in the U.S. for all types of SMA. Similar decisions soon followed in the European Union, Brazil, Japan, Australia, and other countries.

Administered directly into the spinal canal, Spinraza works by increasing the production of SMN — a protein essential for motor neuron and muscle health — that is largely absent or insufficient in SMA patients due to mutations in the SMN1 gene.

Novartis’ gene therapy Zolgensma, approved in several countries for treating infants and young children with all or almost all SMA types, uses a modified and harmless virus to deliver a working copy of SMN1 to cells, thereby increasing SMN production.

In the U.S., the one-time therapy, given directly into the bloodstream, was approved in 2019 to treat all types of SMA in newborns and toddlers up to age 2.

While the safety and effectiveness of both therapies were established in clinical trials, the studies do not include the full spectrum of a patient population.

As such, real-world data is key to better understand the effects of such therapies in a broad range of patients, including those combining the two therapies, and to help inform and improve treatment decisions.

Now, in collaboration with the Analysis Group, Novartis Gene Therapies (formerly known as AveXis, Zolgensma’s original developer) conducted a survey to assess U.S. health providers’ impressions of improvements in pediatric SMA patients treated either with Zolgensma or Spinraza, or both. The electronic survey was distributed by email in May 2020 to providers who treated children with SMA from 6 to 24 months of age with only one of the therapies, or with Zolgensma following Spinraza within the three years prior.

Patients’ improvements were defined as gains in one or more of the following functional domains: motor function, mobility, lung function, and bulbar function (that related to muscles involved in swallowing chewing, speaking, and breathing).

A total of 20 physicians and two nurse practitioners with a mean of about 10 years of practice treating SMA patients responded to the survey. Most (81.8%) worked in academic hospitals/medical centers and half were involved in the RESTORE registry (NCT04174157).

Launched by AveXis, the ongoing RESTORE is a multinational, observational study meant to follow more than 500 SMA patients, mainly those treated with Zolgensma, for up to 15 years.

A total of 13 providers had prescribed only Zolgensma to 30 children with SMA, 15 had treated 54 patients with Spinraza only, and 13 prescribed Zolgensma after Spinraza to 19 patients.

Results showed that all treatment regiments led to improvements, but Zolgensma was associated with the greatest overall improvement.

Gains were achieved by 83.3% of Zolgensma-treated children, 68.4% of those receiving the gene therapy after Spinraza, and 64.8% of patients given Spinraza alone. Also, a greater proportion of children treated with both therapies achieved functional stabilization, relative to the other two groups (10.5% vs. 3.3% with Zolgensma and 5.6% with Spinraza).

Zolgensma single therapy (or monotherapy) also appeared to be superior to the other two regimens in all evaluated functional domains, particularly in motor function (improvements in 80% of patients vs. 63 with Spinraza and 68.4% with both therapies) and mobility (70% vs. 53.7 with Spinraza and 57.9% with both).

Gains in bulbar function were observed in 63.3% of children treated with Zolgensma alone (versus 48.1% in those treated with Spinraza alone and 57.9% treated with both regimens), while gains in lung function were reported in 66.7% of children treated with Zolgensma alone (versus 50% in those treated with Spinraza alone and 63.2% treated with both regimens).

In addition, Zolgensma was associated with the fastest improvements in all domains, with most improvements being detected about two to almost four months earlier than in the other groups.

Notably, gains were first reported in children’s motor function (after 1.8 months with Zolgensma, 2.7 months with combination therapy, and 4.4 months with Spinraza only), followed by lung function (2.1 months, 3.9 months, and six months).

These findings indicate “a majority of patients with SMA achieved improvements with [disease-modifying therapy] administered between 6–24 months of age, with the greatest improvements seen in [Zolgensma single therapy] patients” the researchers wrote in the poster.

In addition, “mean time to reported improvement was shorter in patients receiving [Zolgensma] monotherapy compared with [Spinraza] monotherapy,” they added.

Among the survey’s limitations, the researchers noted the subjective and variable nature of reported improvements, and the fact that reporting or recall bias (differences in the accuracy or completeness of the recollections) may affect the results.

“Given inherent limitations of physician survey studies, additional research including patient-level data is needed to further assess these outcomes in this population,” the team concluded.