Australian ‘real world’ experience with the gene therapy onasemnogene abeparvovec (Zolgensma) in infants with spinal muscular atrophy (SMA) has provided important pointers of how to balance efficacy and risks, according to paediatric neurologists.

Findings from treatment of 21 children with SMA showed that the risk of adverse reactions was potentially higher in those who received higher vector loads in line with weight and for those progressing to sequential therapy.

The findings could help guide treatment choices and help manage parental  expectations said study authors from New South Wales.

Their prospective study of 21 children aged 0.65 to 24 months on onasemnogene abeparvovec found those weighing eight kilos or more were twice as likely to have moderate to severe transaminitis than lighter patients (66% versus 33%, P < 0.05). They were also more likely to have thrombocytopaenia, with six of seven affected patients weighing at least eight kilos at the time of dosing.

While all patients had treatment-related vomiting, and transaminitis and thrombocytopaenia were common overall (occurring in 57% and 33% of patients, respectively), “our study [showed] safety and tolerability of onaesemnogene abeparvovec was greatest in children weighing < 8 kg”, said lead author Dr Arlene D’Silva and colleagues in the Department of Neurology at the Sydney Children’s Hospital in Annals of Clinical and Translational Neurology.

“This supports the rationale for newborn screening for SMA and early access to onasemnogene abeparvovec, which, to date, has been solely predicated on clinical gains seen in presymptomatic infants,” they wrote.

The IV-administered therapy helps replenish the survival motor neuron (SMN) proteins that gene mutations prevent SMA patients from making by delivering a functional human SMN cDNA transgene via a blood-brain barrier-crossing, non-replicating, recombinant adeno-associated virus.

It’s indicated for use in symptomatic or presymptomatic SMA patients up to nine months old and has helped improve survival, respiratory and bulbar function and motor milestone outcomes in studies with treatment-naïve children, often aged under six months and weighing below 8.4 kg.

In the study, 20 of 21 patients achieve stabilised or improved respiratory and bulbar function and 16 gained at least one WHO motor milestone.

Notably, some of the patients in the Australian study were older and heavier than those typically featured in clinical trials or real-world data and most had onasomnogene abeparvovec with or following nusinersen.

Treatment decisions

The real world findings could help improve outcome generalisability and potentially expand treatment options for SMA patients, the authors suggested.

“As the therapeutic paradigm shifts and more treatment options [including nusinersen, onasemnogene abeparvovec and risdiplam] emerge, the focus for clinicians and families now goes beyond just survival and motor function scores,” they wrote.

“Decision-making for therapeutic approach is thus influenced by additional benefits that are patient- and family-driven. These include stability or improvements in feeding, swallowing, fatigue, respiratory and motor function, together with reduced long-term burden of treatment.”

Onasemnogene abeparvovec could have a key role in reaching these stretch goals — with the drug showing some utility in maintaining bulbar and respiratory function in patients who initially needed support and had low scores on SMA-validated functional motor scales, the authors said.

The study’s safety and efficacy findings can be used to help manage parental expectations of clinical benefit and adverse effects which are often driven by shared experiences on social media platforms, they said.

For example,  parents should be counselled that two transaminitis peaks within the first month may be expected, they said.

The findings are also important to inform evolving treatment algorithms and may support regulatory decisions around indication expansion and reimbursement for the drug, they added.

The PBS currently reimburses the intrathecally-administered anti-sense oligonucleotide nusinersen and orally-administered small molecule risdiplam for paediatric SMA patients, and onasemnogene abeparvovec was recommended for reimbursement by the PBAC in September 2021.

Further safety and efficacy studies are needed for long-term outcomes and those associated with sequential or combination therapies.

For now though, the authors suggest early SMA screening and onasomnogene abeparvovec access may be best, particularly regarding safety outcomes.