Children Treated With Zolgensma for Presymptomatic SMA Achieve Age-Appropriate Motor Milestones


All children in the phase 3 SPR1NT study achieved the primary end point of independent sitting.

Onasemnogene abeparvovec (Zolgensma, Novartis) was shown to be both effective and well-tolerated for children expected to develop spinal muscular atrophy (SMA) type 1 or type 2, according to findings from SPR1NT (NCT03505099), a phase 3 multicenter, single-arm trial that were reported in 2 separate papers published in Nature Medicine.1,2 The data were previously presented at the European Academy for Neurology Virtual Congress in 2021 and the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference.

All children in both the type 1 (2 copies of the SMN2 gene) and type 2 (3 copies of SMN2) cohorts achieved the primary endpoint of independent sitting1,2 and nearly all children in both cohorts achieved other age-appropriate milestones including standing and walking.3 None of the children in the study required respiratory support nor nutritional support, and there were no serious treatment-related adverse events observed.3

"The robust data from both the 2- and 3-copy SPR1NT cohorts are being published together for the first time, further supporting the significant and clinically meaningful benefit of Zolgensma in presymptomatic babies with SMA," said Shephard Mpofu, MD, SVP, chief medical officer, Novartis Gene Therapies, in a statement.3 "When treated with Zolgensma prior to the onset of symptoms, not only did all 29 patients enrolled in SPR1NT survive, but were thriving—breathing and eating on their own, with most even sitting, standing, and walking without assistance."

Of the 44 newborns screened for the SPR1NT study, 14 were excluded for reasons including clinical signs of SMA at screening or immediately before dosing (n=4), peroneal nerve to tibialis anterior CMAP <2 mV (n=4), and elevated anti-AAV9 titers (n=2).1,2 The type 1 cohort ultimately enrolled 14 presymptomatic infants with genetically confirmed SMA and 2 SMN2 copies (71% female), while the type 2 cohort enrolled 15 infants (60% female) with 3 SMN2 copies. All infants were treated with a single infusion of onasemnogene abeparvovec (median age for type 1 cohort, 21 days; median age for type 2 cohort, 32 days). Results were compared to a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23).

All children in both cohorts began oral prednisolone therapy 1 day prior to onasemnogene abeparvovec infusion (completing a median of 60 days for the type 1 cohort; median 63 days for the type 2 cohort).1,2 In all, 159 treatment-emergent adverse events (TEAEs) were observed in the type 1 cohort. However, of the 71% in this cohort who experienced a TEAE deemed related to the treatment, none were considered to be serious.1 In the type 2 cohort, 166 TEAEs were reported, with 53% of children in this cohort experiencing a TEAE deemed related to treatment, none of which were considered serious.2 A single Grade 3 hepatotoxicity event occurred in the type 2 cohort that was deemed related to treatment, but resolved with augmented prednisolone.2 Overall, the data related to adverse events from both cohorts were in line with previous data and no new safety signals were identified.3

“Limitations of SPR1NT include the relatively small number of participants, the use of the PNCR external comparator group, and the exclusion of children with baseline CMAP <2 mV,” first author Kevin A. Strauss, MD, medical director, Clinic for Special Children, and colleagues noted.2

Strauss and colleagues concluded that the results of this study highlight the urgency for universal newborn screening for SMA in order to allow for early identification and intervention.

“[T]reating individuals who demonstrate no symptoms of disease remains controversial,” they wrote in the paper reporting on the type 2 cohort, who typically would show symptoms by the age of 18 months. “SMA offers an example of what can be achieved when newborn screening identifies at-risk infants who can potentially be spared the consequences of severe, debilitating weakness. Children with 3 copies of SMN2 have a greater likelihood of developing SMA type 2 or type 3, but SPR1NT demonstrates that treating 3-copy children before the appearance of SMA symptoms essentially allows them to grow and develop as normal children. This represents a remarkable evolution in the standard of care for SMA: from a reactive to a proactive paradigm, from a focus on patients who survive to children who thrive.”

The patients enrolled in SPR1NT have since been invited to participate in a long-term follow-up study to continue to collect safety and efficacy data. Updates evaluating motor function gains are planned for publication later this year.3

1. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nature Medicine. Published online June 17, 2022. doi10.1038/s41591-022-01866-4
2. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nature Medicine. Published online June 17, 2022.doi: 10.1038/s41591-022-01867-3
3. Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. 
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