Assessing New Long-Term Efficacy and Durability Data of Zolgensma for Spinal Muscular Atrophy

Currently, the only approved gene therapy for the treatment of spinal muscular atrophy (SMA) is onasemnogene abeparvovec (Zolgensma; Novartis), indicated in the United States for patients aged less than 2 years old and in Europe for patients with SMA Type 1 or up to 3 SMN2 copies. The gene replacement therapy is the only SMA treatment that targets the genetic root cause of the disease by replacing the function of the SMN1 gene to stop the disease progression and sustain SMN protein expression with a single, one-time IV infusion.¹

SMA, a rare genetic neuromuscular disease, is known as a leading genetic cause of infant mortality.^2,3 The most severe forms of SMA, caused by the lack of a functional SMN1 gene, results in the rapid loss of motor neurons. This impacts the patient’s muscle functions, including breathing, swallowing, and basic movement.⁴ It is critical to diagnose SMA and start treatment as early as possible since the loss of motor neurons is unable to be reversed.^5,6

In an interview with NeurologyLive®, Sitra Tauscher-Wisniewski, MD, vice president clinical development and analytics, Novartis Gene Therapies, talked about new data on the gene therapy presented at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas. She spoke about the data in regard to the transformational and sustained benefit of Zolgensma as an essential one-time gene therapy for SMA.¹ In addition, she shared the implications of the findings, as well as what research questions remain unanswered that need to be further investigated.

NeurologyLive®: What were the key findings of the long-term study about Zolgensma's efficacy and durability?

Sitra Tauscher-Wisniewski, MD: At the 2023 Muscular Dystrophy Association Conference, we presented new data from two of our long-term follow-up (LTFU) studies, LT-001 (NCT03421977) and LT002 (NCT04042025), which showed the continued efficacy and durability of Zolgensma across a range of patient populations, with an overall benefit-risk profile that remains favorable. LT-001 is a 15-year, ongoing observational LTFU study that follows the phase 1 START study, where the very first patients recieved our gene replacement therapy. LT-002 is a phase 4, 15-year ongoing follow-up safety and efficacy study of Zolgensma IV and investigational intrathecal (IT) OAV101 in patients previously treated in the phase 3 IV studies (STR1VE-US, STR1VE-EU, STR1VE-AP, SPR1NT) and the phase 1 IT study (STRONG).

Latest data show that patients maintained, and in some cases gained, motor-milestones in the follow-up period, and showed continued efficacy and durability across a range of patient populations. Notably, highlighting the remarkable durability of Zolgensma, data from LT-001, showed that up to 7.5 years post-dosing, children who were treated after presenting symptoms of SMA maintained all previously achieved milestones.

Interim results from the 15-year LT-002 study show 100% of children treated in the presymptomatic IV cohort either maintained the highest milestone achieved during the parent study (walking alone) or achieved the milestone by the data cut off.

What implications do these findings have for the treatment of SMA, and how might they impact future research and development in this field?

The LTFU data underscore the transformational and sustained benefit of Zolgensma as an essential one-time gene therapy for the treatment of SMA, providing further reassurance to patients, caregivers, and the scientific community. Latest data show patients not only maintained, but in some cases, gained additional motor milestones at follow up and that the long-term benefit-risk profile is favorable.

Additionally, findings from the RESTORE registry continue to highlight the importance of early identification and intervention to optimize outcomes for all patients with SMA, with results showing that patients with 4 or more copies of the SMN2 gene treated with Zolgensma alone attained improvements in motor function and achieved new milestones.

We were encouraged by these latest data and are continuing to evaluate gene therapy for SMA in different patient populations to bring the transformative impact of this treatment to more members of the SMA community.

How might the long-term effects of Zolgensma be studied further, and what research questions remain unanswered about this treatment?

Our priority remains focused on adding to the growing body of evidence for Zolgensma as a monotherapy that has demonstrated transformative efficacy, consistent benefit-risk profile and emerging long-term durability across a variety of patients with SMA.

To that end, our STEER trial (NCT05089656) is currently open and enrolling patients in site around the world. STEER is a global, phase 3 registration-enabling study to evaluate the clinical efficacy, safety, and tolerability of investigational OAV101 via intrathecal delivery in treatment naïve patients who are between two and 18 years of age, able to sit, but have never walked. We plan to submit for regulatory review in 2025 for this new SMA patient population.

Click here for more coverage of MDA 2023.

Transcript edited for clarity.

REFERENCES
1. Novartis shares Zolgensma long-term data demonstrating sustained durability up to 7.5 years post-dosing; 100% achievement of all assessed milestones in children treated prior to SMA symptom onset. News Release. Novartis. Published March 20, 2023. Accessed April 11, 2023. https://www.novartis.com/news/media-releases/novartis-shares-zolgensma-long-term-data-demonstrating-sustained-durability-75-years-post-dosing-100-achievement-all-assessed-milestones-children-treated-prior-sma-symptom-onset
2. Anderton RS, Mastaglia FL. Advances and challenges in developing a therapy for spinal muscular atrophy. Expert Rev Neurother. 2015;15(8):895-908. doi:10.1586/14737175.2015.1059757
3. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810-817. doi:10.1212/WNL.0000000000000741
4. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20(1):27-32. doi:10.1038/ejhg.2011.134
5. Soler-Botija C, Ferrer I, Gich I, Baiget M, Tizzano EF. Neuronal death is enhanced and begins during foetal development in type I spinal muscular atrophy spinal cord. Brain. 2002;125(Pt 7):1624-1634. doi:10.1093/brain/awf155
6. Glascock J, Sampson J, Haidet-Phillips A, et al. Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. J Neuromuscul Dis. 2018;5(2):145-158. doi:10.3233/JND-180304