Onasemnogene, gene therapy for spinal muscular atrophy

Spinal muscular atrophy comes from mutations in the SMN1 gene, which makes survival motor neuron protein. Without enough of it, motor neurons die and muscles weaken, often fatally. The infantile form, SMA type 1, is the most severe and the most common: babies fail to reach motor milestones and die or need mechanical ventilation by age 2. The first disease-modifying drug, the antisense compound nusinersen, was approved in December 2016.

Onasemnogene abeparvovec takes a different approach and replaces the gene. An adeno-associated virus of serotype 9 carries DNA for the missing SMN protein and is given once into a vein, dosed by body weight. In a trial reported by J. R. Mendell and colleagues in 2017, 15 infants with SMA type 1 received a single infusion, 3 at a low dose and 12 at a high dose. At the data cutoff on 7 August 2017 all 15 were alive at 20 months without needing permanent ventilation, against 8 percent survival in a historical cohort. Of the 12 given the high dose, 11 sat without support, 11 fed by mouth and could speak, and 2 walked on their own. Four developed raised liver enzymes, which prednisolone damped.

The FDA approved the therapy as Zolgensma on 24 May 2019 for children under 2, the first gene therapy for SMA. Approval rested on 36 infants in two trials, with the main evidence from 21 in a trial still under way. The label carried a boxed warning that acute serious liver injury can occur, and liver function had to be checked before treatment and for at least three months after. In the United States a single treatment cost $2.125 million.

On 28 June, after approval, the manufacturer, AveXis, told the FDA that some data from animal testing in its application had been manipulated. In an August statement the FDA said the problem was confined to a small portion of product testing data used to develop the manufacturing process, did not change its view of the human trials, and that the therapy should stay on the market. The European Union granted conditional approval on 18 May 2020 for patients with SMA type 1 or with up to three copies of the SMN2 gene.