The long-term follow up of the phase 1 START trial found that previously achieved motor milestones were preserved over a 5-year period.
Data from the 5-year extension of the phase 1 START trial suggest that onasemnogene abeparvovec (Zolgensma; Novartis) has a favorable long-term safety profile in patients with spinal muscular atrophy (SMA) up to 6 years of age and has sustained clinical durability.
Investigators found that serious adverse events (SAEs) occurred in 8 patients (62%). These included acute respiratory failure (n = 4; 31%), pneumonia (n = 4; 31%), dehydration (n = 3; 23%), respiratory distress (n = 2; 15%) and bronchitis (n = 2; 15%). No SAEs resulted in treatment discontinuation or death, and all 10 patients in the therapeutic-dose cohort remained without the need for permanent ventilation.
“These long-term study data will help in the assessment of any potential long-term consequences (with reference to hematologic or autoimmune events). In addition, any new incidences of malignancy and new incidences or exacerbations of existing neurologic or autoimmune disorders are monitored,” first author Jerry R. Mendell, MD, attending neurologist, and the Dwight E. Peters and Juanita R. Curran Endowed Chair in Pediatric Research, Abigail Wexner Research Institute, and professor of pediatrics and neurology, Nationwide Children’s Hospital and Ohio State University, and colleagues wrote. “Although the aforementioned potential safety risks occur within a narrow window after administration, the long-term risks associated with onasemnogene abeparvovec are unknown to date.”
Mendell and colleagues analyzed data from 13 patients from START enrolled in this long-term follow-up (LTFU) study as of the data cutoff on June 11, 2020. These patients had a median age of 38.9 months (range, 25.4-48.0) and 7 (53.8%) were female. Three patients were from the low-dose cohort and 10 were from the therapeutic-dose cohort. As of the data cutoff, the median time since dosing was 5.2 years (range, 4.6-6.2) overall, 5.9 years (range, 5.8-6.2) in the low-dose cohort, and 5.0 years (range, 4.6-5.6) in the therapeutic-dose cohort.
“The question to be answered in the LTFU of START is whether [any] elevations result in long-term sequelae. More recently, thrombotic microangiopathy has been identified as a new safety signal, with an apparent temporal relationship to time of administration. Thrombotic microangiopathy events have been observed 2 to 3 weeks after initiation of therapy. Given this new safety signal, ongoing monitoring is needed from all sources of safety data, including this and other long-term follow-up studies,” Mendell and colleagues wrote.
No AEs of special interest have been reported so far in the LTFU period. No patients in the LTFU period met any of the criteria for potential hepatotoxicity or thrombotic microangiopathy at any time point. One patient shifted from a low or normal baseline aspartate aminotransferase concentration to a high maximum value, which remained high at cutoff.
Prior to the START study, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support and 6 patients (60%) did not. This did not change during the LTFU. Two of 3 in the low-dose cohort remained free of permanent ventilation.
Two patients in the therapeutic-dose cohort attained a new video-confirmed motor milestone of standing with assistance without the use of nusinersen since completing the START study. The remaining patients in that cohort retained all motor milestones attained during the START study. All patients in the low-dose cohort and 4 in the therapeutic-dose cohort were receiving concomitant nusinersen, not because of a loss in motor function or perceived regression, but in an attempt to maximize benefit. The remaining therapeutic-dose patients received no further treatment for SMA apart from onasemnogene abeparvovec more than 4 years after dosing.
“Anticipated results from completed and ongoing phase 3 and 4 studies will further confirm the efficacy and safety of onasemnogene abeparvovec. Current evidence demonstrates that onasemnogene abeparvovec continues to have a favorable benefit-risk profile for the treatment of pediatric patients with SMA,” Mendell and colleagues concluded.