Treatment for Presymptomatic SMA Proves Effective in Phase 3 Trial

Shephard Mpofu, MD, senior vice president and chief medical officer, Novartis Gene Therapies, discusses findings from SPR1NT, a phase 3 clinical trial in which Zolgensma (onasemnogene abeparvovec-xioi) was effective in treating patients with presymptomatic spinal muscular atrophy.

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My name is Shephard Mpofu. I'm the senior vice president and chief medical officer for Novartis Gene Therapies. I'm a board-certified rheumatologist, worked with patients for 15 years prior to joining Novartis, in clinical development for the last 15 years.

Regarding the phase 3 SPR1NT trial, what existing data led you and your coinvestigators to conduct this research?

It's undisputed that spinal muscular atrophy (SMA) is the leading cause of genetic death in infants. It's also very clear it's a devastating progressive disease. The importance of early diagnosis and treatment of patients with SMA is thus critical and clear.

With this in mind, we wanted to expand on the research to determine the potential outcome of presymptomatic patients when treated with our transformational gene therapy, Zolgensma.

The purpose of the two-year SPR1NT study was to evaluate the efficacy and safety of Zolgensma in patients younger than six weeks of age, showing no symptoms, thus presymptomatic, with SMA.

Can you briefly describe the study and its findings? Were you surprised by any of them?

We presented our phase 3 results at the European Academy for Neurology (EAN) recently from the final data cut of the SPR1NT copy cohort with two copies of SMN2. The results were outstanding and groundbreaking.

We achieved 100% improvement in the primary efficacy endpoint, which was children sitting independently for more than 30 seconds. These patients achieved this improvement within the World Health Organization window for normal development.

In addition, 100% of patients in this study achieved the secondary endpoint, which is survival free from permanent breathing support. This is something that's phenomenal as this is only seen in 26% of patients in the natural history.

In addition, there were multiple other improvements, in 100% of patients not requiring any feeding support and kids maintaining their ability to gain weight in an age-appropriate manner.

A majority of patients were able to stand independently and two-thirds of patients in this study were able to walk, something that's amazing when you think that this is only achieved in other children with non-SMA.

What are the possible real-world applications of these findings in clinical practice?

The SPR1NT study reinforced the importance of early possible diagnosis and treatment within SMA. Importantly, for physicians to be able to pick up the symptoms and signs early, and crucially, for global implementation of newborn screening in order to enable rapid diagnosis.

What's also important is that with early diagnosis, these data showed that patients can go on to achieve remarkable outcomes. This contrasts with the natural progression of the disease.

When treated with Zolgensma, we see rapid improvement in patients achieving normal milestones, and, as I mentioned, these children do thrive very well. When you consider newborns with SMA type 1, they are devastated and are robbed of the ability to even swallow, breathe, talk, or sit.

When we see our therapy achieving significant improvement, almost compared to normal children without SMA, these results are groundbreaking, life-altering, and nothing short of extraordinary.

What are the next steps after the SPR1NT trial?

What we presented was the cohort from two-copy. We have an ongoing three-copy cohort. We presented interim data at the MDA congress in 2020. In our interim data, we showed the same remarkable improvement in milestones such as standing support for at least three seconds and walking independently within the range of normal development.

We are now going to wait for the study to complete, and then we will share the results of the completed study in up-and-coming conferences.

Is there anything else you would like to add?

The SPR1NT trial demonstrated the critical importance of early diagnosis, newborn screening, and elevated the importance of how Zolgensma addresses the root genetic cause of the disease and results in children having remarkable improvement in development milestones, nothing that has been seen in the natural progression of the disease for similar-type children.

Therefore, this provides an important therapeutic utility for these children in the future.