What the First Intrathecal Gene Therapy Means for SMA Clinicians and Researchers

In 2019, the FDA made a landmark decision approving Novartis’ onasemnogene abeparvovec, marketed as Zolgensma, as the first gene therapy for patients with spinal muscular atrophy (SMA), a historically life-limiting neuromuscular disease. Years after the decision, the agency approved a new intrathecal formulation of the drug, marketed as Itvisma, for a broad range of patients with SMA.^1,2

The FDA’s approval of the intrathecal formulation was supported by positive results from the phase 3 STEER study (NCT05089656), along with supportive data from the ongoing phase 3b STRENGTH study (NCT05386680). STEER was a 52-week, randomized trial that enrolled 126 treatment-naïve patients with SMA type 2, assigning them 1:1 to receive either intrathecal Itvisma or a sham procedure, followed by a crossover phase. The study met its primary end point, with patients treated with Itvisma achieving a statistically significant 2.39-point improvement in total Hammersmith Functional Motor Scale–Expanded (HFMSE) scores compared with a 0.51-point improvement in the sham group (P = .0074). Although secondary end points did not reach statistical significance due to the prespecified multiple testing procedure, all outcomes consistently favored Itvisma.³

Following the approval, NeurologyLive® sat down with Angela Lek, PhD, chief medical officer at the Muscular Dystrophy Association (MDA), who provided clinical perspective and thoughts on the new therapy. Lek, who currently serves as a program consultant for the NIH’s Somatic Cell Genome Editing program, outlined the significance of this new route of administration, as well as key considerations for clinicians around patient selection, safety monitoring, and counseling. Furthermore, Lek discusses the educational needs facing treatment centers, the role of multidisciplinary care, and how the SMA community can continue building momentum through research, registries, and equitable access to emerging therapies.

NeurologyLive: For clinicians and researchers who may be treating patients with SMA, can you talk about the significance of this FDA approval and what it means for the clinical community?

Angela Lek, PhD: I think this approval represents a major step for the SMA community, both for patients and clinicians. By enabling intrathecal delivery of an established gene therapy, which is Zolgensma, we now have a pathway for older children and adults who were previously ineligible for gene replacement therapy. These are patients over the age of two with a confirmed mutation in the SMN1 gene who now have a treatment option when it comes to gene therapy.

For families who have watched SMA progress over many years, this offers hope, and the community is very excited. Like Zolgensma, Itvisma is a gene replacement therapy that addresses the root cause of SMA with a one time fixed dose. The difference is the route of delivery. Zolgensma is administered systemically through intravenous infusion, while Itvisma is delivered intrathecally. Intrathecal dosing allows for more targeted delivery to motor neurons in the spinal cord using a significantly lower total viral dose compared with systemic administration. Itvisma uses a fixed dose regardless of patient age or weight, which is particularly important for older or heavier patients where systemic AAV dosing may pose higher risks. Overall, this offers a clinically practical and scientifically meaningful option for patients over the age of two.

Although you are not a clinician yourself, are there considerations you think treating physicians should be thinking about when discussing this therapy with patients and families?

As with all gene therapies, the most important thing is that each patient has an individualized discussion with their clinician about the risk benefit profile of the therapy. These assessments should take into account the patient’s current health status, disease progression, and the expected benefits.

The label recommends administering Itvisma to patients who are clinically stable at baseline. That includes having good respiratory function and no active infections. It also recommends assessment of vaccination status, liver function, blood work, and the presence of anti AAV antibodies. Clinicians should also discuss disease trajectory with families. Is the patient stable or declining, and what is a realistic expectation of benefit based on the clinical trial data that have been reported.

Can you walk us through how we got to this approval, including the key clinical studies that supported it?

The approval was built on data collected across three trials over about six years, involving more than 170 patients with SMA. The first study was the STRONG trial, which was an early dose finding, safety, and proof of concept study. That trial demonstrated that intrathecal delivery was safe, effective, and helped define the appropriate dose.

The second study was the STEER trial, which was the pivotal phase three randomized study conducted in treatment naive patients. In that study, treatment led to statistically significant improvements of about two points on the Hammersmith Functional Motor Scale, which is the gold standard assessment of motor function and disease progression in SMA.

The third study was the phase 3b STRENGTH trial, which evaluated real world treatment experience in patients who had discontinued nusinersen or risdiplam. Those data showed stabilization of motor function over a 52 week follow up period. A Nature Medicine publication on the STRENGTH trial results was released earlier this week, and that paper provides additional important context for the approval.

From MDA’s perspective, what education is needed to help clinicians safely and effectively bring this therapy into practice?

Earlier this year, MDA, together with PPMD, published consensus recommendations in the Journal of Neuromuscular Disorders on best practices for delivery and monitoring of gene therapy in Duchenne muscular dystrophy. While the disease and route of administration differ, many of the principles around institutional readiness, multidisciplinary coordination, and post treatment monitoring are highly relevant for Itvisma.

Education should focus on center readiness, access to lab monitoring protocols, and having a multidisciplinary team available to manage potential adverse events. That includes hepatologists, cardiologists, hematologists, pulmonologists, and others as needed. Clinicians also need to be comfortable monitoring for known risks such as elevated aminotransferases, thrombocytopenia, peripheral sensory neuropathy, thrombotic microangiopathy, elevated troponins, and potential tumorigenicity.

The most common adverse reactions reported include upper respiratory tract infection, gastrointestinal symptoms, fever, and headache. Education is also needed to distinguish how intrathecal gene therapy differs from intravenous Zolgensma and from ongoing nusinersen or risdiplam care. Finally, counseling patients and families with balanced expectations and a clear discussion of risks is essential.

We have seen tremendous progress in SMA over the last decade. How can the community continue building momentum from here?

Momentum is exactly the right word. This approval is a major milestone, but it is not the endpoint. Long term follow up through real world registries will be critical to understanding durability, safety, and outcomes in a broader SMA population. Registries will also help us understand outcomes when Itvisma is used alongside nusinersen or risdiplam, and whether there may be synergy between therapies.

Access and equity are also critical. Patients who are eligible and want this therapy should be able to receive it regardless of geography or demographics, and that is something MDA is committed to supporting.

Finally, while this approval is incredibly important, it does not signal the end of research. We still need to deepen our understanding of SMA biology, particularly developmental mechanisms, to unlock future therapeutic possibilities. MDA has invested more than 50 million dollars in SMA research since our inception and is currently supporting 1.5 million dollars in active grants to continue pushing the field forward.

Transcript edited for clarity.

REFERENCES
1. Novartis receives FDA approval for Itvisma®, the only gene replacement therapy for children two years and older, teens, and adults with spinal muscular atrophy (SMA). News release. Novartis. November 24, 2025. Accessed December 15, 2025. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-itvisma-only-gene-replacement-therapy-children-two-years-and-older-teens-and-adults-spinal-muscular-atrophy-sma
2. AveXis receives FDA approval for Zolgensma®, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA). News release. Novartis. May 24, 2019. Accessed December 15, 2025. https://www.novartis.com/news/media-releases/avexis-receives-fda-approval-zolgensma-first-and-only-gene-therapy-pediatric-patients-spinal-muscular-atrophy-sma
3. New Novartis Phase III data demonstrate meaningful efficacy and safety results of intrathecal onasemnogene abeparvovec in broad patient population with SMA. News release. Novartis. March 19, 2025. Accessed December 15, 2025. https://www.novartis.com/news/media-releases/new-novartis-phase-iii-data-demonstrate-meaningful-efficacy-and-safety-results-intrathecal-onasemnogene-abeparvovec-broad-patient-population-sma