Zolgensma Further Demonstrates Impact in Treating Presymptomatic SMA, Regardless of 2 or 3 SMN2 Copies


In total, 100% and 93% of those in the SMN two- and three-copy cohorts achieved the primary end point of sitting independently for at least 30 seconds after 18 months of treatment.

Shephard Mpofu, MD, senior vice president, chief medical officer, Novartis

Shephard Mpofu, MD

Novartis recently published final results from the phase 3 SPR1NT trial (NCT03505099), demonstrating that those with presymptomatic spinal muscular atrophy (SMA) with either 2 or 3 copies of the SMN2 gene treated with onasemnogene abeparvovec (Zolgensma) achieved age-appropriate motor milestones, including sitting independently, standing, and walking up to 18 months after infusion.1,2

In total, all 14 of the patients in the two-copy cohort met the primary end point of sitting independently for at least 30 seconds, including 11 (79%) patients who achieved this milestone within the World Health Organization (WHO) window of normal development. Similarly, 14 of the 15 (93%) children in the three-copy cohort achieved this milestone, with most (11 of 15; 73%) of the cohort completing this within the WHO window of normal development.

"The robust data from both the two- and three-copy SPR1NT cohorts are being published for the first time, further supporting the significant and clinically meaningful benefit of Zolgensma in presymptomatic babies with SMA," Shephard Mpofu, MD, senior vice president, chief medical officer, Novartis, said in a statement.1 "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 12 children with two copies assessed for independently sitting at the end of the study, all 12 (100%) retained this motor milestone at 18 months of age. Notably, half (n = 7) of these children were able to sit alone within the normal developmental window of less than 514 days. Ten of the 14 children (71%) walked alone, as defined by WHO-MGRS criteria, at a median age of 493 days, and 6 (43%) did so within the normal developmental window of less than 534 days.2

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On secondary end points, all of those with two SMN2 copies were ventilator-free by the end of the study, with no child requiring any mechanical respiratory support of any kind throughout the duration of the trial. Additionally, 13 (93%) children maintained weight at or above the third percentile without the need for nonoral/mechanical feeding support at all visits up to 18 months of age (P <.0001).

Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores, used to capture motor function, were increased rapidly during the initial 3 months after Zolgensma infusion. The mean CHOP-INTEND score for children in the two-copy cohort was 46.1 (SD, 8.8) at baseline, which increased by 3.9 (SD, 8.3) after 1 month of treatment, 11.2 (SD, 8.8) at the 3 months of age visit, and 14.8 (SD, 8.1) at the 6 months of age. All 14 children achieved a CHOP-INTEND score greater than 40, a threshold never achieved in patients with untreated SMA type 1 older than 6 months of age (P <.0001), whose CHOP-INTEND scores instead decreased by an average 10.7 points between 6 and 12 months of age.

For those in the three-copy cohort, 14 of 15 children (93%) walked without assistance, as measured by Bayley Scales of Infant and Toddler Development-III scores. The median age at earliest achievement was 14 months (range, 12-19). Furthermore, the same number of children stood with assistance (10 seconds or more) as measured by WHO Multicentre Growth Reference Study developmental window, with 11 of 14 children achieving this milestone within an age-appropriate time. At the end of the study, 9 of 10 children in the three-copy cohort had gross and fine motor skills similar to unaffected children of the same age.1

Across both cohorts, reported adverse reactions were consistent with previous data, with no new safety signals identified. To mitigate the inflammatory response to AAV9, all 14 children in the two-copy cohort commenced oral prednisolone therapy 1 day prior to Zolgensma infusion and completed a median of 60 days (range, 49-100) of therapy. Each child in that cohort experienced at least 1 treatment-emergent adverse event (TEAE), and 5 (36%) had at least 1 TEAE deemed to be serious. Of note, 10 of the 14 children had at least 1 TEAE considered to be related to study treatment by investigator, but none were serious.

1.Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. Accessed June 27, 2022. https://www.novartis.com/news/media-releases/novartis-announces-nature-medicine-publication-zolgensma-data-demonstrating-age-appropriate-milestones-when-treating-children-sma-presymptomatically
2. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with 2 copies of SMN2 at risk for spinal muscular atrophy type 1: the phase 3 SPR1NT trial. Nat Med. Published online June 17, 2022. doi:10.1038/s41591-022-01866-4.
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