By | Medicine & Pharma Insights

On October 21, the latest public notice from the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) indicated that Novartis has submitted a clinical trial application for OAV101 injection (Zolgensma) in China, which has been accepted. Developed by AveXis, this gene therapy was the subject of an $8.7 billion acquisition announced by Novartis in April 2018 to advance the development of Zolgensma. Public information indicates that Zolgensma is also the first gene therapy approved by the U.S. FDA for the treatment of spinal muscular atrophy (SMA).

Screenshot source: CDE official website

SMA is a severe neuromuscular disease. It is caused by mutations in the SMN1 gene, which encodes the survival motor neuron (SMN) protein, leading to a deficiency in SMN protein levels. Based on the degree of SMN protein deficiency, SMA can be classified into several types. Among these, patients with the most severe form, Type 1 SMA, typically experience rapid neuronal death and muscle damage, with the majority either succumbing to the disease or requiring permanent respiratory support by 24 months of age.

Zolgensma (OAV101 or AVXS-101) was originally the lead gene therapy candidate developed by AveXis. It utilizes an AAV9 viral vector to deliver a transgene encoding the normal SMN protein, which has been optimized to enhance SMN protein production. Designed for a single administration, it aims to enable long-term expression of the SMN protein within cells, thereby achieving a "curative" effect. Zolgensma has previously been granted Breakthrough Therapy designation by the U.S. FDA, PRIME designation by the European Union, and SAKIGAKE (Pioneer Drug) designation in Japan.

In April 2018, Novartis announced it would acquire AveXis for $8.7 billion to advance the development of Zolgensma. In December 2018, Novartis submitted a marketing application for this gene therapy to the FDA. In May 2019, the therapy received FDA approval in the United States for the treatment of patients under 2 years of age with spinal muscular atrophy (SMA) who carry biallelic mutations in the SMN1 gene encoding the survival motor neuron protein. Zolgensma thus became the first gene therapy approved by the FDA for the treatment of SMA.

In terms of clinical efficacy, according to data previously released by AveXis, in the pivotal STR1VE-US clinical trial, not only did 91% of patients with severe type 1 SMA treated with Zolgensma achieve the primary endpoint of event-free survival, but 9 out of 22 patients also met the more stringent "thriving" criteria. In the START clinical trial evaluating the long-term efficacy of Zolgensma, all patients remained alive and free from permanent ventilatory support as of March 2020, continued to achieve developmental milestones, and among them, some patients had been followed up for up to 5 years after receiving the gene therapy.

Clinical results of Zolgensma in treating patients with relatively mild type 2 SMA demonstrate that, when administered via intrathecal injection to patients aged 2–5 years, Zolgensma improved the patients' HFMSE motor function composite scores by an average of 6 points from baseline. This improvement is twice the threshold for clinically meaningful change (3 points). Additionally, 92% of patients achieved an increase in HFMSE scores that met the threshold for clinical significance.

Results from another clinical trial named SPR1NT demonstrated that administering Zolgensma to children with spinal muscular atrophy (SMA) prior to symptom onset significantly improves motor function. Among the 14 treated patients, 100% of the children achieved the primary endpoint of sitting independently for more than 30 seconds. This further underscores its potential as a cornerstone therapy for both symptomatic and presymptomatic SMA patients.

It should not be overlooked that gene therapy, as a revolutionary therapeutic modality, also carries potential side effects and safety concerns. For instance, a study published in *The New England Journal of Medicine* indicated that adverse events, such as significantly elevated liver enzyme levels, were observed in a small subset of patients treated with Zolgensma.

In a press release, AveXis stated that clinical trial evidence for Zolgensma demonstrates that it not only saves patients' lives but also enables some patients to thrive like healthy children. Following a single administration, the therapeutic efficacy of Zolgensma can be sustained for more than five years. Furthermore, this therapy is not only effective in treating infants with Type 1 SMA but also holds promise for benefiting patients with Type 2 SMA. It is hoped that the clinical trials of this Novartis gene therapy in China will also progress smoothly, bringing breakthrough treatment options to more SMA patients in the near future.

References:

[1] Official website of the Center for Drug Evaluation, National Medical Products Administration. Retrieved Oct 21, 2021, from https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d

[2]AveXis receives FDA approval for Zolgensma®, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA)https://www.globenewswire.com/news-release/2019/05/24/1849953/0/en/AveXis-receives-FDA-approval-for-Zolgensma-the-first-and-only-gene-therapy-for-pediatric-patients-with-spinal-muscular-atrophy-SMA.html

[3]Novartis delivered strong Q2 performance, driven by momentum of key growth brands. FY 2021 guidance unchanged.Retrieved Jul 21, 2021，from https://www.novartis.com/news/media-releases/novartis-delivered-strong-q2-performance-driven-momentum-key-growth-brands-fy-2021-guidance-unchanged

[4] Zolgensma® data shows rapid, significant, clinically meaningful benefit in SMA including prolonged event-free survival, motor milestone achievement and durability now up to 5 years post-dosing, Retrieved March 24, 2020, from https://www.novartis.com/news/media-releases/zolgensma-data-shows-rapid-significant-clinically-meaningful-benefit-sma-including-prolonged-event-free-survival-motor-milestone-achievement-and-durability-now

[5] AveXis presents AVXS-101 IT data demonstrating remarkable increases in HFMSE scores and a consistent clinically meaningful response in older patients with SMA Type 2, Retrieved March 24, 2020, from https://www.novartis.com/news/media-releases/avexis-presents-avxs-101-it-data-demonstrating-remarkable-increases-hfmse-scores-and-consistent-clinically-meaningful-response-older-patients-sma-type-2

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