New Data Showcase Onasemnogene Abeparvovec Efficacy in SMA


Updated findings from across a number of studies highlighted the significant benefits of onasemnogene abeparvovec for children with spinal muscular atrophy.

Kevin Strauss, MD, medical director, Clinic for Special Children in Pennsylvania

Kevin Strauss, MD

Updated findings from across a number of studies presented at the 2021 Muscular Dystrophy Association (MDA) Virtual Clinical and Scientific Conference highlighted the significant benefits of onasemnogene abeparvovec (Zolgensma) for children with spinal muscular atrophy (SMA).

In findings from the phase 3 SPR1NT trial, presymptomatic children with a genetic diagnosis of SMA achieved age-appropriate developmental milestones with onasemnogene abeparvovec treatment. In long-term findings with a mean follow-up of 5 years, 100% of children treated with a therapeutic dose of the gene therapy remained alive and free of permanent ventilation and previously achieved milestones were sustained with the longer follow up. Adding to these findings, data from the RESTORE registry showed CHOP INTEND improvement or maintenance in 96% of children treated with onasemnogene abeparvovec.

“When treated with Zolgensma prior to the onset of symptoms, children in the SPR1NT trial achieved milestones like sitting, standing, and walking at an appropriate age, grew as expected without nutritional assistance, and remained free of all forms of mechanical ventilatory support,” Kevin Strauss, MD, medical director, Clinic for Special Children in Pennsylvania, said in a statement. “This stands in sharp contrast to the natural progression of SMA Type 1, which would otherwise render them helpless within the first year of life and unable to swallow, breathe, or survive without mechanical support. The transformative benefit of early intervention, as seen in SPR1NT, further underscores the urgent need for newborn screening.”

SPR1NT Trial Update

The ongoing phase 3 SPR1NT trial included presymptomatic patients ≤6 weeks in age with biallelic deletions of SMN1 and 2 or 3 copies of the SMN2 gene. "Without the benefit of disease-modifying therapy, newborns with biallelic SMN1 deletions and 2 or 3 copies of SMN2 would normally develop SMA type 1 and SMA type 2, respectively," Strauss noted.

In those with 2 copies of SMN2 (n = 14), the median age of patients was 15.6 months (range, 8.8-18.8). The primary end point of sitting without support for at least 30 seconds was achieved by 79% of patients (11 of 14), with 10 of the 11 achieving this milestone within the World Health Organization (WHO) criteria for normal development. The remaining 3 patients continued to be assessed.

Additionally, 36% of patients (5 of 14) could stand independently, with 3 achieving this milestone within WHO criteria for normal development. Of the remaining 9 patients, 7 were still in the window for normal development at the follow-up. Additionally, 4 of 14 patients (29%) could walk independently, of which 3 were within WHO criteria for normal development. Of the remaining 10 patients, 7 were still within the window for normal development.

In those with 3 copies of SMN2 (n = 15), the median age was 15.2 months (range, 3.3-21.1). Overall, 53% of patients met the primary end point of standing alone for at least 3 seconds (8 of 15) and 40% walked independently (6 of 15). These achievements were all within WHO definition for normal development. Patients who had not yet achieved this end point were still within the window at the time of follow-up.

Across both groups, 100% of those treated with onasemnogene abeparvovec remained alive and free of ventilatory support and 100% did not require a feeding tube. As a single-arm study, there were not a comparator arm; however, in historical controls, 60% of patients with 2 copies of SMN2 would typically require feeding support by 15 months of age.

Additionally, 100% of patients had steady gains in mean raw score of Bayley-III fine and gross motor scales. Moreover, in the 2-copy group, 100% of patients achieved CHOP INTEND scores of ≥50 and 93% achieved scores ≥58. All patients experienced at least 1 adverse event and there were 7 reported serious adverse events in the study; however, all resolved and were deemed unrelated to onasemnogene abeparvovec.

Long-Term Follow-Up

Long-term findings were from LT-001, a long-term follow-up study of patients that completed the START study, and LT-002, which includes patients from other phase 1 and phase 3 studies of onasemnogene abeparvovec (STRONG, STR1VE, and STR1VE-EU). Data were presented for 13 patients from LT-001 with a mean age of 36.42 months (standard deviation [SD], 8.523) and 31 patients in LT-002 with a mean age of 33.6 months (SD, 12.92).

In LT-001, 8 patients reported SAEs, none of which led to study discontinuation or death and all of which were considered unrelated to treatment. The most common were acute respiratory failure, pneumonia, and dehydration. In LT-002, 2 patients reported SAEs and 1 AE of special interest was reported.

As of data cutoff dates, 2 of 3 patients (66.7%) remained free of permanent ventilation in the low-dose cohort of LT-001, and all patients in the therapeutic dose cohort (n = 10) were alive and free of permanent ventilation. Half the patients (n = 5) in the therapeutic dose cohort did not use respiratory support and 1 required it only when ill. The mean age at data cutoff was 5.2 years (range, 4.7-6.1) and mean time since dosing was 5.0 years (range, 4.6-5.6) as of data cutoff, June 11, 2020.

Among patients in LT-002 from the STR1VE studies, none of the 16 patients required permanent ventilation while 9 reported baseline respiratory support. The intravenous (IV) cohort had a mean age of 2.3 years (range, 1.6-3.2) at data cutoff and the mean time since dosing was 2.0 years (range, 1.5-2.7). The intrathecal cohort had a mean age of 4.3 years (range, 2.8-6.1) at data cutoff and the mean time since dosing was 2.4 years (range, 1.8-2.8).

No previously achieved motor milestones were lost during long-term follow-up in LT-001, with 2 patients gaining the milestone of standing with assistance without ever receiving nusinersen (Spinraza). In LT-002, 11 new milestones were achieved during long-term follow-up in 4 patients in the IV cohort, the highest of which was sitting without support, achieved without nusinersen or risdiplam (Evrysdi; Genentech) support in 3 patients and with risdiplam in 1.

Real-World Data

The RESTORE observational registry trial included 70 patients ≥6 months in age with a diagnosis of SMA. Overall, 64% of participants (n = 45) had SMA type 1. At the time of treatment with onasemnogene abeparvovec, 48.5% of patients were aged ≥6 to 12 months, 43% were ≥12 to 24 months, and 8.5% were ≥24 months of age. This study also revealed the efficacy of newborn screening for SMA. Overall, 28 of patients in the registry were identified during newborn/prenatal screening. These patients received treatment at a mean of 1.7 months of age versus 4.4 months for those clinically diagnosed.

At the assessment, 23 patients had at least 2 CHOP INTEND assessments. Of these, 22 had improved or maintained scores (96%), including 15 (65%) with a clinically meaningful ≥4-point increase. Overall, CHOP INTEND increases of ≥4 points were experienced by 68% of those clinically identified (15 of 22) and for 89% of those identified through newborn or prenatal screening (8 of 9).

“With more than 1,000 patients now treated, these data presented at MDA further reinforce what we’ve come to expect from Zolgensma," Shephard Mpofu, MD, SVP, chief medical officer, Novartis Gene Therapies, the company developing onasemnogene abeparvovec, concluded in a statement. "[There was] consistent, significant, and clinically meaningful therapeutic benefit in SMA, including prolonged event-free survival, achievement of motor milestones unseen in natural history of the disease, and durability now more than 5 years post-dosing."

Onasemnogene abeparvovec was approved in the United States in May 2019 for the treatment of SMA in children less than 2 years of age. Prior to this approval, the gene therapy was granted fast track, orphan drug, priority review, and breakthrough therapy designations. Studies will continue to assess the treatment.

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