SMA treatment with Evrysdi 'could start prenatally'

Roche's Evrysdi has already shown profound benefits in children with spinal muscular atrophy (SMA) given after birth – but doctors in the US believe treatment should start even before that.

A pioneering team at St Jude Children's Research Hospital in the US say they successfully treated a child diagnosed with SMA while still in the womb with Evrysdi (risdiplam), with the result that – at age two years – no identifiable features of the progressive neurodegenerative disorder have been seen.

They carried out what was essentially a 'clinical trial of one' in the patient, whose parents were both carriers of SMA type 1 and had previously had a child with the disorder – before current treatments like Evrysdi were available – who died at 16 months.

After genetic testing using amniocentesis confirmed that their new baby was also likely to be born with SMA type 1, the expectant mother took Evrysdi for the final six weeks of the pregnancy.

Currently, treatments for SMA have improved survival and helped to preserve motor function in infants, especially if administered shortly after birth before symptoms begin, but are not a cure.

"Our primary objectives were feasibility, safety, and tolerability, so we're very pleased to see that the parent and child are doing well," said the study's corresponding author Richard Finkel, director of the Jude Center for Experimental Neurotherapeutics director.

"The results suggest it would be worthwhile to continue investigating the use of prenatal intervention for SMA," he added. Based on their early results, which have been published in a letter to the New England Journal of Medicine, the team is now hoping to carry out a more comprehensive study of in-utero treatment.

The infant was diagnosed after birth with three developmental abnormalities that are associated with SMA, including a heart defect that has now resolved and issues affecting the optic nerve and brain stem. These are thought to have occurred before Evrysdi was administered, raising questions about how early in pregnancy it might be safely possible to start treatment with the drug.

Evrysdi was approved by the FDA for use in infants with SMA aged two months and older in 2020 and had its label extended in 2022 to allow treatment from birth. It is administered as an oral liquid solution, but earlier this year Roche also got clearance for a new tablet formulation, that can be used in older children and – potentially at least – in pregnancy.

The drug has become a standard therapy for the disorder, bringing in nearly $1.8 billion in worldwide sales last year, thanks to its ease of administration compared to its main rival – Biogen's oligonucleotide Spinraza (nusinersen) – which has to be administered by injection into the cerebrospinal fluid.

Another alternative is Novartis' one-shot intravenous gene therapy Zolgensma (onasemnogene abeparvovec), which is indicated for the treatment of children less than two years of age with SMA and was approved in 2019.