Onasemnogene Abeparvovec Gene-Replacement Therapy (GRT) in Pre-symptomatic Spinal Muscular Atrophy (SMA): SPR1NT Study Update

Research Question: SMA results in motor and respiratory function loss and is caused by biallelic survival motor neuron 1 gene (SMN1) deletion/mutation. Genomic copies of a similar gene (SMN2) modify disease severity. Onasemnogene abeparvovec (AVXS-101) is a one-time GRT that addresses the genetic root cause of SMA and is designed for immediate, sustained SMN protein expression in motor neurons, allowing for rapid onset and durable therapeutic effect. In a phase 1/2a study, AVXS-101 resulted in exceptional event-free survival, motor function, and developmental motor milestone achievement in symptomatic SMA type 1 patients with 2 copies of SMN2 (2xSMN2) dosed ≤6 months. This study evaluated AVXS-101 for the treatment of pre-symptomatic newborns with SMA.

Material and Method: SPR1NT is a multicenter, open-label, phase 3 study enrolling ≥27 SMA patients (2xSMN2 or 3xSMN2). Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1x10e14 vg/kg). Safety and efficacy are assessed through study end (18/24 months for patients with 2x/3xSMN2). Primary outcomes are independent sitting ≥30 seconds (2xSMN2) or standing with assistance (3xSMN2). Exploratory outcomes include motor function improvement (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND], Bayley-III).

Results: From 10 April 2018 to 27 September 2018, 7 newborns received AVXS-101 (4 female; 6 with 2xSMN2, 1 with 3xSMN2) at age 8–37 days (median: 12; mean: 21). At screening, mean (range) scaled Bayley gross and fine motor scores were 9.7 (7–14) and 9.6 (7–12) points; ≥1 pair of gross and fine motor subtest scores was available for 6/7 patients; all patients with ≥2 sets of scores had increased gross and fine motor scores compared with their baseline performance. Mean baseline CHOP INTEND score (maximum of 64) was 41.7 points, which increased by a mean of 6.8 (n = 4), 11.0 (n = 3), 18.0 (n = 3), and 22.5 (n = 2) points at 14 days, 1, 2, and 3 months, respectively; 2 patients scored ≥60 points. As of 8 March 2019, 18 newborns have been enrolled and dosed in SPR1NT; follow-up will be presented at the congress.

Discussion: Given that disease progression and motor neuron loss are rapid, prompt diagnosis through newborn screening and early intervention with effective pharmaceutical treatment combined with best supportive care is critical to enable maximal patient benefit and minimize motor neuron loss.

Conclusion: Preliminary data from SPR1NT show rapid motor function improvements in pre-symptomatic SMA patients as assessed by CHOP INTEND.

Die Autoren geben an, dass kein Interessenkonflikt besteht.