Gene replacement therapy enabled infants with symptomatic spinal muscular atrophy type 1 (SMA1) to achieve at least one episode of independent sitting by age 18 months, the open-label phase III STR1VE-EU trial found.
The primary endpoint, functional independent sitting for at least 10 seconds at any visit up to the 18 months of age study visit, was achieved in 44% of 33 patients treated with single-dose onasemnogene abeparvovec given by intravenous infusion (1.1 × 10¹⁴ vector genomes/kg) at a median age of 4.1 months, reported Eugenio Mercuri, MD, PhD, of Catholic University in Rome, Italy, and co-authors in Lancet Neurology.
None of the 23 untreated patients in the Pediatric Neuromuscular Clinical Research natural history cohort achieved that outcome (P<0.0001).
“STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic SMA type 1,” the researchers wrote. “No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favorable for this patient population, including those with severe disease at baseline.”
Mercuri and colleagues reported results from the intention-to-treat analysis for 33 patients identified between August 2018 and September 2020 from six European centers. All were younger than 6 months and had a biallelic SMN1 gene exon 7-8 deletion or point mutation and one or two copies of the SMN2 gene. Patients were followed weekly until the study end, at age 18 months. One death from hypoxic-ischemic brain damage due to a respiratory tract infection that was considered unrelated to the study drug occurred during the study.
At least one adverse event was seen in 97% of 33 treated patients, most commonly pyrexia (67%), upper respiratory infection (33%), and increased alanine aminotransferase (27%). Serious adverse events considered related to the study drug were seen in 18%.
A secondary outcome showed 97% of 32 patients were alive and free from permanent ventilatory support at age 14 months versus 26% in the in the natural history cohort (P<0.0001).
“Success rates of genetic therapies can be improved,” noted Ludo van der Pol, MD, PhD, of University Medical Center Utrecht in the Netherlands, in an accompanying editorial.
“The best results are obtained in presymptomatic infants, in whom motor function improvements can include independent walking,” he added. “The onset of spinal muscular atrophy type 1 probably occurs before birth and, despite the presymptomatic stage, after birth some motor neurons might already be at risk. These at-risk neurons, which can be considered as a neuromuscular penumbra, offer the opportunity to optimize treatment results.”
“We need to buy time for these patients,” van der Pol wrote. “Genetic tests for spinal muscular atrophy are robust and neonatal screening is feasible. Nevertheless, less than a quarter of countries that reimburse the expensive genetic treatments for spinal muscular atrophy will start neonatal screening programs in the next few years, whereas ideally, genetic therapy and screening should go hand-in-hand.”
Onasemnogene abeparvovec is a gene replacement therapy that delivers a functional SMN1 gene into motor neurons in the spinal cord where its protein product, SMN, is deficient. This contrasts with the other two genetic therapies for SMA introduced in the last several years, nusinersen and risdiplam, which increase SMN protein by modifying mRNA splicing of the imperfectly compensatory contribution of functional SMN protein produced from the SMN2 gene.
STR1VE-EU joins two prior studies of onasemnogene abeparvovec efficacy and safety for SMA. All three trials had single-arm open-label design, compared treatment with a natural history cohort, and evaluated a primary outcome of the ability to sit independently.
The phase I START trial (2017) studied 15 patients with SMA1 younger than 8 months and found all alive at 20 months of age versus 8% in the historical cohort; two patients walked independently. The phase III STR1VE-US study (previously called STR1VE; 2021) evaluated 23 patients with SMA1 and found 59% were able to sit independently for 30 seconds or longer at the 18 month of age study visit versus 0% in the historical cohort.
“STR1VE-EU had broader inclusion criteria than START and STR1VE-US, and allowed enrollment of patients with more advanced disease (i.e., those who required feeding or respiratory support),” van der Pol observed.
These baseline clinical differences in study populations may have contributed to greater variability in efficacy for STR1VE-EU compared with STR1VE-US, Mercuri and colleagues noted.
“Some of these patients had early onset and more severe disease at enrollment than did patients in STR1VE-US, but showed a response to treatment not only in terms of survival but also in functional aspects,” they wrote. “The types of safety events observed were consistent with those described previously. As such, the overall risk–benefit profile for onasemnogene abeparvovec remains favorable for patients with SMA1.”
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Gene replacement therapy enabled infants with symptomatic spinal muscular atrophy type 1 (SMA1) to achieve at least one episode of independent sitting by age 18 months, the open-label phase III STR1VE-EU trial found.
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The primary endpoint, functional independent sitting for at least 10 seconds at any visit up to the 18 months of age study visit, was achieved in 44% of 33 patients treated with single-dose onasemnogene abeparvovec.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This study was funded by Novartis Gene Therapies.
Mercurio reports personal fees from Novartis Gene Therapies, Biogen, Roche, and Scholar Rock; and grants from Biogen including support for disease registries (the International SMA Consortium Registry).
van der Pol’s employer (University Medical Center Utrecht) received fees for ad hoc consultancy from Biogen, Avexis, and Roche. van der Po received grants from non-profit Prinses Beatrix Spierfonds, Spieren voor Spieren, and Vriendenloterij; he was a member of the safety monitoring board for Novartis and is a member of the scientific advisory board for SMA Europe.
Cat ID: 130
Topic ID: 82,130,730,130,138,192,925
