Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

Abstract

IMPORTANCE This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy.OBJECTIVE The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. DESIGN, SETTING, AND PARTICIPANTSThis study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017 at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 10 13 vg/kg; or therapeutic dose, 1.1 × 10 14 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020.EXPOSURES Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. MAIN OUTCOMES AND MEASURESThe primary outcome measure was the incidence of serious adverse events (SAEs).RESULTS At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen. CONCLUSIONS AND RELEVANCEThe findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03421977.

Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

“…29 Long-term evaluation for up to 5.6 years has indicated the maintenance of motor milestones without any new safety signals in patients who received the targeted therapeutic dose in START. 30 Onasemnogene abeparvovec has not been studied for children with profound weakness, including those requiring invasive ventilator support, and the potential benefit of treatment in this subgroup of patients may be low because of irreversible loss of motor neurons as the disease progresses. Treatment of patients, including those with the most severe form of SMA who required invasive mechanical ventilation and tracheostomy before receiving onasemnogene abeparvovec, has also been reported.…”

“… 29 Long‐term evaluation for up to 5.6 years has indicated the maintenance of motor milestones without any new safety signals in patients who received the targeted therapeutic dose in START. 30 …”

Recombinant Adeno-Associated Virus Serotype 9 Gene Therapy in Spinal Muscular Atrophy

“…As motoneurons are not replicating cells there is a supposition of long-term therapy effectiveness. Until now, there are already 6 years of clinical data of sustaining the effectiveness in SMA patients ( 52 ).…”

“…In March 2021 new long-term safety and efficacy data from 13 START study patients (all 3 from cohort 1 and 10 from cohort 2) were presented during the 2021 Muscular Dystrophy Association Virtual Clinical and Scientific Conference and then published in JAMA Neurology ( 52 , 57 ). During the mean 5-year follow up, 2 of 3 patients in cohort 1 and all patients from cohort 2 remained free of permanent ventilation.…”

Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1

“…In 2019 the FDA and in 2020 the EMA approved onasemnogene abeparvovec (Zolgensma ® ) for the treatment of SMA1 [ 13 ]. Onasemnogene abeparvovec is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the SMN1 gene to the motor neurons through a single intravenous infusion [ 14 ]. The majority of SMA1 patients treated with therapeutically dosed onasemnogene abeparvovec reached the sitting position without assistance; those who were treated earlier reached this milestone much more quickly [ 15 ].…”