Recently, we interviewed Shephard Mpofu, MD, Chief Medical Officer at Novartis Gene Therapies about the company’s clinical study, the SPR1NT trial, testing Zolgensma (onasemnogene abeparvovec) in presymptomatic patients with spinal muscular atrophy (SMA).


Can you describe the methodology of the SPR1NT trial

SPR1NT is a Phase 3, open-label, single-arm, multi-center trial designed to evaluate the safety and efficacy of a one-time intravenous (IV) infusion of onasemnogene abeparvovec in presymptomatic patients with a genetic diagnosis of SMA and two or three copies of SMN2 who were ≤6 weeks of age.

The SPR1NT trial was made up of 29 patients split into two cohorts. The two-copy SMN2 gene cohort had 14 patients and the three-copy SMN2 gene cohort had 15 patients. The mean age at dosing in the two-copy cohort was 20.6 days (8 – 34 days) while the mean age at dosing in the three-copy cohort was 28.7 days (9–43 days).


What were the key takeaway results from the trial?

When treated with onasemnogene abeparvovec before signs of SMA, not only did all 29 patients survive, they were thriving — breathing and eating on their own, with most even sitting, standing and walking without assistance.

The robust data from both the two- and three-copy SPR1NT cohorts support the significant and clinically meaningful benefit of onasemnogene abeparvovec in presymptomatic babies with SMA, and represent a significant contrast to the natural history of the disease.

The results from the SPR1NT study showed that, remarkably:

  • All children (100%) treated presymptomatically in the SPR1NT two-copy cohort met the primary endpoint of sitting independently for ≥30 seconds (Bayley), including 11/14 (79 percent) who achieved this milestone within the World Health Organization (WHO) window of normal development. A majority of patients went on to stand independently (11/14) and walk independently (9/14) (Bayley), most within the typical range of normal development.
  • In the three-copy cohort of SPR1NT, 14/15 children (93%) went on to walk independently (Bayley), most (11/15, 73%) within the WHO window of normal development. All 15 children (100 percent) met the primary endpoint of standing alone ≥3 seconds (Bayley), including 14/15 (93%) within the WHO window of normal development.
  • Reported adverse reactions were consistent with previous data, with no new safety signals identified.

Can you compare the outcomes in the study to outcomes in babies not receiving early treatment for both babies with two copies of SMN2 and three copies of SMN2, respectively?

The majority of patients with two copies of the SMN2 gene develop SMA Type 1, the most common – and one of the most severe – form of the disease, accounting for about 60% of cases. If left untreated, SMA Type 1 robs infants of their ability to walk, swallow and breathe and can lead to permanent ventilation and death in 90% of cases by the age of two.

Most patients with three copies of SMN2 develop SMA Type 2, which accounts for about 30% of SMA cases. According to natural history, patients with SMA Type 2 do not walk independently without intervention.

The SPR1NT data demonstrate that, whether they have two or three copies of the SMN2 gene, nearly all children with SMA treated presymptomatically with onasemnogene abeparvovec were able to achieve age-appropriate motor milestones.


How does this data compare to outcomes seen with other treatments for SMA in similar populations? 

It is not appropriate to compare data directly, considering the differences in study designs, including scales, endpoints, and study populations. There have been no head-to-head studies to date.

Onasemnogene abeparvovec is the only available therapy for SMA that directly addresses the genetic root cause of the disease by replacing the function of the missing or nonworking SMN1 gene. All other approved SMA therapies require repeated dosing over a patient’s lifetime and work on the backup SMN2 gene.


The gene therapy is currently approved for children with SMA under two years of age. Are studies underway to expand the indication?

We are always working with health authorities worldwide, including the FDA, to share the latest clinical data and real-world experience to date to best define the population for whom onasemnogene abeparvovecshould be made available.

In addition, we are currently enrolling patients in STEER – an ongoing, global, pivotal Phase 3, sham-controlled study to evaluate the clinical efficacy, safety and tolerability of intrathecally (IT) administered OAV101, an investigational one-time gene therapy for older patients with SMA. We believe that all people diagnosed with SMA should be able to benefit from gene therapy and that investigational OAV101 IT is a potential treatment path for older patients who often have ongoing unmet needs, and for whom a one-time treatment could be especially compelling.

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