Spinal muscular atrophy (SMA), a devastating neuromuscular disease characterized by progressive muscle weakness and atrophy, has seen remarkable advancements in treatment over the past decade. Among these breakthroughs, Zolgensma (onasemnogene abeparvovec) stands out as a pioneering gene therapy that has transformed the lives of infants diagnosed with this debilitating condition. Developed by Novartis, Zolgensma, approved by the FDA in 2019, was the first gene therapy for SMA, delivering a functional copy of the survival motor neuron 1 (SMN1) gene directly to patients via an intravenous infusion. This single-dose treatment, utilizing an adeno-associated virus serotype 9 (AAV9) vector, has shown unprecedented efficacy in halting disease progression and improving motor function in young children, marking a significant milestone in the field of genetic medicine. Now, Novartis is poised to expand the landscape of SMA treatment with the development of an intrathecal (IT) formulation of Zolgensma, targeting older patients.
This initiative builds upon the company’s groundbreaking 2019 FDA approval of intravenous Zolgensma, the first gene therapy for SMA, which revolutionized treatment for children under two years old. Now, Novartis aims to address the needs of a broader patient population, including those who were previously ineligible for gene therapy due to age or weight limitations.
The recent presentation of late-stage data from the Phase III STEER and Phase IIIb STRENGTH trials at the Muscular Dystrophy Association’s Clinical & Scientific Conference in Dallas has generated significant interest. The STEER trial, a placebo-controlled study, demonstrated a statistically significant improvement in motor function, as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE), in patients receiving IT Zolgensma compared to those undergoing a sham procedure. While the trial did not meet its secondary endpoints, the primary endpoint results indicate a clinically meaningful benefit. The STRENGTH study further corroborated these findings by showing stabilization of motor function in patients who had discontinued other SMA treatments, such as Biogen’s Spinraza or Roche’s Evrysdi.
The development of the IT formulation of Zolgensma addresses a critical need in the SMA community. Unlike the intravenous version, which is limited to younger, smaller patients, the IT delivery method allows for safe and effective administration in older, heavier individuals. By delivering the gene therapy directly into the cerebrospinal fluid, Novartis can use a lower, flat dose, mitigating the risk of dose-related toxicities that would be associated with systemic administration in larger patients. This approach not only expands the potential patient population but also reduces the burden of chronic treatment, offering a one-time gene replacement therapy that addresses the genetic root cause of SMA.
The mechanism of action of both the intravenous and IT formulations of Zolgensma remains consistent: delivering a functional copy of the human SMN1 gene, which is deficient in SMA patients. Both formulations utilize an AAV vector to deliver the SMN1 gene. However, the IT formulation represents a significant advancement in delivery, making gene therapy accessible to a wider range of individuals. The data presented at the MDA conference suggest that IT Zolgensma can stabilize and, in some cases, improve motor function in older patients, preventing further disease progression and enhancing their quality of life.
Despite the promising results, experts acknowledge the challenges of treating older SMA patients who have already experienced significant motor neuron loss. The gains observed with IT Zolgensma are more nuanced compared to the dramatic improvements seen in infants treated with the intravenous version. Nevertheless, the ability to stabilize motor function and prevent further decline represents a substantial clinical benefit.
Novartis plans to file for regulatory approval of the IT formulation in the first half of 2025, potentially marking a significant milestone in SMA treatment. If approved, IT Zolgensma would be the first gene replacement therapy for SMA patients over two years old, offering a new treatment option for a population that has long awaited a more effective and accessible therapy.
The advancements in SMA treatment over the past decade, from the approval of Spinraza to the development of Evrysdi and now IT Zolgensma, have transformed the lives of countless patients. However, challenges remain, including the need for improved biomarkers to monitor disease progression and treatment response. As Novartis continues to expand its reach in SMA treatment, the company aims to address the full spectrum of patient needs, offering hope for a future where SMA no longer limits the potential of those affected.
Source:
https://www.biospace.com/drug-development/novartis-intrathecal-zolgensma-effective-in-older-children
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