Novartis Reports New Long-Term Data Showing Durable Efficacy and Favorable Safety of Zolgensma in Spinal Muscular Atrophy

Today, AveXis, a Novartis company, announced new positive interim results for Zolgensma (onasemnogene abeparvovac-xioi), its gene therapy for the treatment of type 1 spinal muscular atrophy (SMA), from the Phase 3 SPR1NT and STR1VE trials and the Phase 1 START trial. Treatment with Zolgensma extended event-free survival to age 5, and initiating treatment before the onset of disease symptoms enabled patients to achieve developmental milestones that would be unattainable without treatment. Notably, the company had previously reported one patient death during the trial; subsequent analysis indicated that the cause of death was hypoxic-ischemic brain injury resulting from a respiratory tract infection. There was no evidence of central nervous system inflammation or toxicity, nor of therapy-related brain injury.

Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder characterized by progressive muscle weakness and paralysis resulting from the death of motor neurons. SMA is caused by mutations in the SMN1 gene, which encodes the survival motor neuron (SMN) protein, leading to deficient levels of SMN protein. SMA is the leading genetic cause of infant mortality. Based on the degree of SMN protein deficiency, SMA can be classified into several types. Patients with the most severe form, Type 1 SMA, typically experience rapid neuronal death and muscle damage; consequently, the majority (>90%) either die or require permanent respiratory support by 24 months of age.

▲AAV9 viral vector (Image source: AveXis official website)

Zolgensma is a gene therapy developed by AveXis that delivers a transgene encoding the SMN protein via an adeno-associated virus serotype 9 (AAV9) vector. The transgene has been optimized to enhance its capacity for SMN protein production. It is designed to enable long-term expression of the SMN protein in cells following a single administration, thereby achieving a “curative” effect.

STR1VE is an ongoing Phase 3 clinical trial designed to evaluate the safety and efficacy of Zolgensma in patients with Type 1 spinal muscular atrophy (SMA) under 6 months of age. These patients carry 1–2 copies of the SMN2 gene and have a deletion or mutation in the SMN1 gene. Trial results as of May 31, 2019, demonstrated that treatment with Zolgensma significantly prolonged event-free survival compared to natural history data and markedly improved motor function in patients with Type 1 SMA. Among these patients, 13 were able to sit independently for at least 30 seconds.

Additionally, one patient was able to stand and walk with assistance. Among patients in the U.S. trial, the mean CHOP-INTEND score increased by 6.7 points at one month and by 11.7 points at three months after gene therapy administration. In the European trial, the corresponding increases were 6.4 and 10.6 points, respectively. These findings indicate an improvement in motor function compared to baseline, a metric that is closely associated with the ability of patients to achieve expected developmental milestones.

Data from the START Phase 1 long-term follow-up study indicated that, as of May 31, 2019, all 10 patients enrolled in the long-term follow-up were alive and continued to maintain developmental milestones. The mean follow-up duration for these patients after receiving a one-time gene therapy was 3.9 years. Two patients who received Zolgensma but did not receive nusinersen were still able to stand with assistance.

Overall, no new safety issues were identified. Detailed data from the above three trials will be presented at the 2019 European Paediatric Neurology Society (EPNS) Congress. Furthermore, it is worth noting that there had been previous reports of an infant’s death in a Phase 3 trial, which could have led to a safety warning regarding the use of Zolgensma. However, further analysis by researchers into the cause of this patient’s death has alleviated these concerns.

“Zolgensma has brought hope to families who never dared to expect that their children would achieve motor milestones. The trial results demonstrate that Zolgensma can have a life-changing impact on children with Type 1 SMA,” said Dr. Olga Santiago, Chief Medical Officer of AveXis. “For patients with SMA, it is crucial to initiate treatment as early as possible to prevent irreversible loss of motor neurons and enable the achievement of key motor milestones such as crawling, sitting, and walking.”

References:

[1] Zolgensma didn't cause an infant death, AveXis execs say as they spotlight long-term data，Retrieved September 19, 2019, from https://endpts.com/zolgensma-didnt-cause-an-infant-death-avexis-execs-say-as-they-spotlight-long-term-data/

[2] AveXis presents new data at EPNS continuing to show significant therapeutic benefit of Zolgensma® in prolonging event-free survival now up to 5 years of age in patients with spinal muscular atrophy (SMA) Type 1，Retrieved September 19, 2019, from http://investors.avexis.com/news-releases/news-release-details/avexis-presents-new-data-epns-continuing-show-significant

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