Novartis recently announced data that reinforce the transformational benefit of Zolgensma® (onasemnogene abeparvovec), an essential, one-time treatment and the only gene therapy for spinal muscular atrophy (SMA). New late-breaker data from the completed two-copy cohort of the Phase 3 SPR1NT clinical trial demonstrate age-appropriate milestone development in presymptomatic children with SMA without respiratory or nutritional support of any kind, and with no serious, treatment-related adverse events. The completed Phase 3 STR1VE-EU trial demonstrated rapid improvements in motor function following treatment with Zolgensma, and most patients achieved motor milestones not observed in the natural history of SMA Type 1. Safety remained consistent with previously reported data.
The Zolgensma data represent a significant contrast to the natural history of SMA Type 1, which leads to progressive and irreversible loss of motor function and if left untreated, often death or permanent ventilation by the age of two years. Remarkably, all children (100 percent) treated presymptomatically in the SPR1NT two-copy cohort achieved event-free survival, were independent of respiratory and nutritional support and met the primary endpoint of sitting independently for ≥30 seconds, including 11/14 (79 percent) who achieved this milestone within the World Health Organization (WHO) window of normal development. Most patients went on to stand independently (11/14) and walk independently (9/14), most within the typical range of normal development.
Among symptomatic children with SMA Type 1 treated in the STR1VE-EU trial, including patients with more severe disease at baseline, most children (82 percent) achieved developmental motor milestones not observed in the natural history of SMA Type 1, including 16 children (49 percent) who sat without support for ≥30 seconds.
Final Phase 3 SPR1NT Two-Copy Cohort Results
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 Zolgensma in presymptomatic patients with a genetic diagnosis of SMA and two or three copies of SMN2 who were ≤6 weeks of age. Fourteen patients with two copies of SMN2 and 15 patients with three copies of SMN2 were treated. Many patients with two copies of SMN2 develop SMA Type 1, the most common form accounting for 60 percent of cases.
Data reported reflect the final data cut for SPR1NT two-copy patients. Mean age at dosing in the two-copy cohort was 20.6 days (8 – 34 days). The study of the three-copy cohort is ongoing. Two-copy cohort (n=14) results:
- One hundred percent of patients (14/14) met the secondary endpoint of survival without ventilatory support of any kind at 14 months of age, versus only 26 percent of patients in the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort.
- All patients (100 percent) achieved the primary endpoint of sitting independently for at least 30 seconds, including 11 (79 percent) who achieved this milestone within the WHO window of normal development.
- Eleven patients (79 percent) could stand independently, seven of whom achieved this milestone within the WHO window of normal development.
- Nine patients (64 percent) could walk independently, five of whom achieved this milestone within the WHO window of normal development.
- All patients (100 percent) were independent of nutritional and respiratory support for the duration of the study.
- Nearly all patients (13/14) achieved the additional secondary efficacy endpoint of age-appropriate weight maintenance without non-oral feeding support at any visit up to 18 months of age.
- All patients (100 percent) achieved or maintained a Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score of ≥58. According to natural history, untreated patients with SMA Type 1 almost never achieve a CHOP INTEND score of ≥40.
- All patients (100 percent) had Bayley-III fine motor performance scores like same-age peers without SMA and the majority (64 percent) had gross motor performance scores like same-age peers without SMA.
All patients experienced at least one adverse event (AE) after dosing, 10 (71 percent) of which were treatment related. There were no serious, treatment-related AEs. Five patients were reported to have had serious adverse events (SAEs), all of which resolved and were not related to treatment.
Final Phase 3 STR1VE-EU Results
STR1VE-EU was designed to evaluate the efficacy and safety of a single, one-time IV infusion of Zolgensma in patients with SMA Type 1 who had bi-allelic SMN1 gene deletion or point mutations and one or two copies of the SMN2 backup gene and were less than six months of age. Mean age at dosing was 4.1 months, and mean age at symptom onset was 1.6 months. The mean CHOP INTEND score at baseline was 28. All patients had two SMN2 copies and were symptomatic with a variable degree of severity. Patients with SMA Type 1 not treated with disease-modifying therapy will never sit unassisted. If left untreated, SMA Type 1 leads to death or permanent ventilation by the age of two in most cases.
STR1VE-EU was distinct in its broadened inclusion and exclusion criteria of enrolled patients compared with START or STR1VE-US. Some patients in STR1VE-EU had a more severe disease at baseline, including lower CHOP INTEND scores and the need for nutritional and ventilatory support. Of the 33 patients enrolled, nine (27%) required feeding support, an additional nine (27%) required ventilatory support and five (15%) required both at baseline. STR1VE-EU (n=33) results:
- Thirty-three patients were enrolled; and 32 patients completed the study.
- Twenty-seven of 33 patients (82 percent) achieved developmental motor milestones not observed in the natural history of SMA Type 1.
- Fourteen of 32 patients (44 percent) in the intention-to-treat (ITT) population achieved the primary endpoint of sitting independently for ≥10 seconds, observed at a median age of 15.9 months (7.7–18.6). The patient who was not in the ITT population also achieved this primary outcome measure.
- Twenty-three of 30 patients (77 percent) achieved head control (three already had control at baseline), 19 of 33 (58 percent) rolled from back to sides and 16 patients (49 percent) sat without support for ≥30 seconds, including all patients who met the primary endpoint of sitting without support for ≥10 seconds.
- In addition, two patients stood with assistance, and one crawled, stood, pulled to stand, and walked without assistance, all by 18 months of age.
- Thirty-one of 32 patients (97 percent) achieved the secondary efficacy endpoint of survival, free from permanent ventilatory support at 14 months, compared with a quarter of patients (26 percent) in the PNCR natural history cohort.
- Many patients (73 percent) achieved a CHOP INTEND score of ≥40 points, 14 (42 percent) achieved a score of ≥50 points and three (9 percent) achieved a score of ≥58 points. According to natural history, untreated patients with SMA Type 1 almost never achieve a CHOP INTEND score ≥40.
- Thirteen of 33 patients (39 percent) remained independent of any type of daily ventilatory support at 18 months of age, compared with none in the PNCR data set.
- Of the nine patients who required ventilatory support at baseline, two achieved independence and of the 24 patients who did not require ventilatory support at baseline, many patients (67 percent) remained free from this support at the end of the study.
The exploratory endpoint of the “ability to thrive” in symptomatic patients, inclusive of swallowing, feeding and age-appropriate weight maintenance, was also evaluated. Twenty-three patients were in the ability to thrive population, of which seven (30 percent) met the criteria of ability to thrive at 18 months of age, compared with none reported in the PNCR study. Improvements in each component of the ability to thrive composite endpoint were observed. Age-appropriate weight maintenance was seen by almost two-thirds of patients (65 percent) (greater than the third percentile for age and sex as defined by WHO guidelines) at 18 months. Of the nine patients who required feeding support at baseline, four were free of feeding support at 18 months of age, and of the 23 patients in the ability to thrive population, 20 (87 percent) were fed exclusively by mouth and remained free of support at the end of the study. Nine patients (39 percent) tolerated thin liquids.
As previously reported, one patient experienced a serious AE of hypoxic-ischemic brain damage and respiratory distress that resulted in death. Novartis and the investigator concluded the events and death to be unrelated to treatment with Zolgensma based on autopsy findings. Thirty-two of 33 patients were reported to have had at least one AE, of whom six experienced 13 serious adverse events concluded by the investigator to be related to Zolgensma. Reported adverse reactions in patients receiving Zolgensma were consistent with the previously described safety profile, and no new safety signals were identified.