Novartis is seeking accelerated regulatory pathways for a new intrathecal formulation of its gene therapy Zolgensma, as the European Medicines Agency (EMA) deliberates whether the treatment qualifies for expedited review. The pharmaceutical giant has confirmed plans to file marketing applications in both European and U.S. markets during the first half of 2025.
The intrathecal formulation represents a significant advancement in the administration of Zolgensma (onasemnogene abeparvovec), which is currently approved as an intravenous infusion for treating spinal muscular atrophy (SMA). This rare neuromuscular disorder affects approximately 1 in 10,000 births worldwide and is characterized by progressive muscle weakness and atrophy due to motor neuron degeneration.
Potential Expansion of Treatment Population
The development of an intrathecal formulation—delivered directly into the cerebrospinal fluid surrounding the spinal cord—could potentially address limitations of the current intravenous administration. The existing IV formulation of Zolgensma received EMA approval in 2020 for patients with SMA who have a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1, or those with up to three copies of the SMN2 gene.
Dr. Maria Chiara Manzini, Director of the SMA Research Program at a leading neurology institute, explains: "Intrathecal delivery may allow the therapy to more efficiently target motor neurons in the spinal cord, potentially improving efficacy while requiring lower doses. This could expand treatment options to older and larger patients who currently face dosing challenges with the intravenous formulation."
Regulatory Strategy and Timeline
Novartis' regulatory strategy includes parallel submissions to both the EMA and the U.S. Food and Drug Administration (FDA). The company's decision to pursue potential accelerated review pathways underscores the significant unmet medical need that remains in SMA treatment.
"The EMA's consideration of fast-track status for intrathecal Zolgensma reflects the continuing urgent need for effective therapies across the full spectrum of SMA patients," said a Novartis spokesperson. "While current treatments have transformed outcomes for many patients, there remain significant gaps in therapeutic options, particularly for patients with more advanced disease."
Clinical Evidence Supporting the Application
The marketing applications will likely be supported by data from Novartis' STEER trial, which evaluated the safety and efficacy of intrathecal Zolgensma in patients with SMA Type 2. The trial design included patients aged 2-18 years who retained the ability to sit independently but could not stand or walk.
Preliminary data presented at scientific conferences have shown promising results regarding the safety profile and functional improvements in treated patients. The intrathecal approach may also address some of the immunological challenges associated with systemic administration of adeno-associated virus (AAV) vector-based gene therapies.
Market Context and Competition
Zolgensma currently faces competition in the SMA treatment landscape from Biogen's Spinraza (nusinersen) and Roche's Evrysdi (risdiplam). Both competitors utilize different mechanisms of action—Spinraza is an antisense oligonucleotide administered intrathecally, while Evrysdi is an oral SMN2 splicing modifier.
The one-time gene therapy Zolgensma, with its list price exceeding $2 million per treatment in the U.S., represents a different value proposition compared to these chronic therapies. The intrathecal formulation could potentially strengthen Novartis' position in this competitive market by expanding the eligible patient population.
Implications for SMA Treatment Paradigm
If approved, intrathecal Zolgensma could significantly impact treatment algorithms for SMA. Clinicians currently face complex decisions regarding which therapy to use based on patient age, SMA type, disease progression, and administration preferences.
"The potential availability of intrathecal Zolgensma would add another important option to our therapeutic arsenal," noted Dr. Jonathan Katz, a pediatric neurologist specializing in neuromuscular disorders. "This could allow more personalized treatment approaches based on individual patient characteristics and needs."
The EMA's decision on accelerated review status will be an important indicator of the regulatory outlook for this new formulation. Fast-track designation would potentially shorten the review timeline, bringing this treatment option to patients more quickly if ultimately approved.
Healthcare systems across Europe are already developing frameworks for evaluating and implementing gene therapies like Zolgensma. The potential addition of an intrathecal formulation will likely prompt further refinement of these approaches to ensure appropriate patient access while managing budget impact.
